Cancer Treatments

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Treatment Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development. Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue. Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases. Surgery In theory, cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential. Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient. In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy. Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment. Radiation therapy Main article: Radiation therapy Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions. Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects. Chemotherapy Main article: Chemotherapy Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy. Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination. The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation. Alternatively, hematopoietic stem cells may be transplanted from a matched unrelated donor (MUD). Targeted therapies Main article: Targeted therapy Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib and gefitinib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin®) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies. Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to this peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity. Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors.[5] Immunotherapy Main article: Cancer immunotherapy Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells. Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation" from a genetically non-identical donor) can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe. Hormonal therapy Main article: Hormonal therapy (oncology) The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.

Chemotherapy

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Chemotherapy

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Chemotherapy, in its most general sense, refers to treatment of disease by chemicals that kill cells, specifically those of micro-organisms or cancer. In popular usage, it usually refers to antineoplastic drugs used to treat cancer or the combination of these drugs into a standardized treatment regimen.

In its non-oncological use, the term may also refer to antibiotics (antibacterial chemotherapy). In that sense, the first modern chemotherapeutic agent was Paul Ehrlich's arsphenamine, an arsenic compound discovered in 1909 and used to treat syphilis. This was later followed by sulfonamides discovered by Domagk and penicillin discovered by Alexander Fleming.

Other uses of cytostatic chemotherapy agents (including the ones mentioned below) are the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis and the suppression of transplant rejections (see immunosuppression and DMARDs).

Contents

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History

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Further information: History of cancer chemotherapy

The use of chemical substances and drugs as medication dates back to the Persian physician, Muhammad ibn Zakar?ya R?zi (Rhazes), in the 10th century, when he introduced the use of chemicals such vitriol, copper, mercuric and arsenic salts, sal ammoniac, gold scoria, chalk, clay, coral, pearl, tar, bitumen and alcohol for medical purposes.[1]

The first drug used for cancer chemotherapy, however, dates back to the early 20th century, though it was not originally intended for that purpose. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in the 1940s, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. That experience led researchers to look for other substances that might have similar effects against cancer. As a result, many other drugs have been developed to treat cancer, and drug development since then has exploded into a multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply.

[edit] Principles

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Cancer is the uncontrolled growth of cells coupled with malignant behavior: invasion and metastasis. Cancer is thought to be caused by the interaction between genetic susceptibility and environmental toxins.

Broadly, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called "programmed cell death").

Unfortunately, scientists have yet to identify specific features of malignant and immune cells that would make them uniquely targetable (barring some recent examples, such as the Philadelphia chromosome as targeted by imatinib). This means that other fast dividing cells such as those responsible for hair growth and for replacement of the intestinal epithelium (lining) are also often affected. However, some drugs have a better side-effect profile than others, enabling doctors to adjust treatment regimens to the advantage of patients in certain situations.

As chemotherapy affects cell division, tumors with high growth fractions (such as acute myelogenous leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. Malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly.
Drugs affect "younger" tumors (i.e. more differentiated) more effectively, because mechanisms regulating cell growth are usually still preserved. With succeeding generations of tumor cells, differentiation is typically lost, growth becomes less regulated, and tumors become less responsive to most chemotherapeutic agents. Near the center of some solid tumors, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumors is the fact that the chemotherapeutic agent often does not reach the core of the tumor. Solutions to this problem include radiation therapy (both brachytherapy and teletherapy) and surgery.

Over time, cancer cells become more resistant to chemotherapy treatments. Recently, scientists have identified small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Research on p-glycoprotein and other such chemotherapy efflux pumps, is currently ongoing. Medications to inhibit the function of p-glycoprotein are undergoing testing as of June, 2007 to enhance the efficacy of chemotherapy.

[edit] Treatment schemes

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There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.
Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery. Most cancers are now treated in this way. Combination chemotherapy is a similar practice which involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent.

In neoadjuvant chemotherapy (preoperative treatment) initial chemotherapy is aimed for shrinking the primary tumour, thereby rendering local therapy (surgery or radiotherapy) less destructive or more effective.
Adjuvant chemotherapy (postoperative treatment) can be used when there is little evidence of cancer present, but there is risk of recurrence. This can help reduce chances of resistance developing if the tumour does develop. It is also useful in killing any cancerous cells which have spread to other parts of the body. This is often effective as the newly growing tumours are fast-dividing, and therefore very susceptible.
Palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.

All chemotherapy regimens require that the patient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a patient can receive chemotherapy, or whether dose reduction is required.

[edit] Types

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The majority of chemotherapeutic drugs can be divided in to alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way.

Some newer agents don't directly interfere with DNA. These include monoclonal antibodies and the new tyrosine kinase inhibitors e.g. imatinib mesylate (Gleevec® or Glivec®), which directly targets a molecular abnormality in certain types of cancer (chronic myelogenous leukemia, gastrointestinal stromal tumors).
In addition, some drugs may be used which modulate tumor cell behaviour without directly attacking those cells. Hormone treatments fall into this category of adjuvant therapies.

Where available, Anatomical Therapeutic Chemical Classification System codes are provided for the major categories.

[edit] Alkylating agents (L01A)

Main article: Alkylating antineoplastic agent

Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. Cisplatin and carboplatin, as well as oxaliplatin are alkylating agents.
Other agents are mechlorethamine, cyclophosphamide, chlorambucil. They work by chemically modifying a cell's DNA.


[edit] Anti-metabolites (L01B)

Main article: antimetabolite

Anti-metabolites masquerade as purine ((azathioprine, mercaptopurine)) or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.


[edit] Plant alkaloids and terpenoids (L01C)
These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloids and taxanes.


[edit] Vinca alkaloids (L01CA)
Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include:


[edit] Podophyllotoxin (L01CB)

Podophyllotoxin is a plant-derived compound used to produce two other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the G1 phase (the start of DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action still has to be elucidated.
The substance has been primarily obtained from the American Mayapple (Podophyllum peltatum). Recently it has been discovered that a rare Himalayan Mayapple (Podophyllum hexandrum) contains it in a much greater quantity, but as the plant is endangered, its supply is limited. Studies have been conducted to isolate the genes involved in the substance's production, so that it could be obtained recombinantively.


[edit] Taxanes (L01CD)
The prototype taxane is the natural product paclitaxel, originally known as Taxol and first derived from the bark of the Pacific Yew tree. Docetaxel is a semi-synthetic analogue of paclitaxel. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase.


[edit] Topoisomerase inhibitors (L01CB and L01XX)
Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling.


[edit] Antitumour antibiotics (L01D)
See main article: antineoplastic
The most important immunosuppressant from this group is dactinomycin, which is used in kidney transplantations.


[edit] Monoclonal antibodies
Monoclonal antibodies work by targeting tumour specific antigens, thus enhancing the host's immune response to tumour cells to which the agent attaches itself. Examples are trastuzumab (Herceptin), cetuximab, and rituximab (Rituxan or Mabthera). Bevacizumab (Avastin) is a monoclonal antibody that does not directly attack tumor cells but instead blocks the formation of new tumor vessels.


[edit] Hormonal therapy
Several malignancies respond to hormonal therapy. Strictly speaking, this is not chemotherapy. Cancer arising from certain tissues, including the mammary and prostate glands, may be inhibited or stimulated by appropriate changes in hormone balance.

Some other tumours are also hormone dependent, although the specific mechanism is still unclear.

[edit] Dosage

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Dosage of chemotherapy can be difficult: if the dose is too low, it will be ineffective against the tumor, while at excessive doses the toxicity (side-effects, neutropenia) will be intolerable to the patient. This has led to the formation of detailed "dosing schemes" in most hospitals, which give guidance on the correct dose and adjustment in case of toxicity. In immunotherapy, they are in principle used in smaller dosages than in the treatment of malignant diseases.
In most cases, the dose is adjusted for the patient's body surface area, a measure that correlates with blood volume. The BSA is usually calculated with a mathematical formula or a nomogram, using a patient's weight and height, rather than by direct measurement.

[edit] Delivery

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Most chemotherapy is delivered intravenously, although there are a number of agents that can be administered orally (e.g. melphalan, busulfan, capecitabine). In some cases, isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumour sites without causing overwhelming systemic damage.

Depending on the patient, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the Hickman line, the Port-a-Cath or the PICC line. These have a lower infection risk, are much less prone to phlebitis or extravasation, and abolish the need for repeated insertion of peripheral cannulae.

Harmful and lethal toxicity from chemotherapy limits the dosage of chemotherapy that can be given. Some tumours can be destroyed by sufficiently high doses of chemotheraputic agents. Unfortunately, these high doses cannot be given because they would be fatal to the patient.

[edit] Newer and experimental approaches

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[edit] Hematopoietic stem cell transplant approaches

Stem cell harvesting and autologous or allogeneic stem cell transplant has been used to allow for higher doses of chemotheraputic agents where dosages are primarily limited by hematopoietic damage. Years of research in treating solid tumors, particularly breast cancer, with hematopoeitic stem cell transplants, has yielded little proof of efficacy. Hematological malignancies such as myeloma, lymphoma, and leukemia remain the main indications for stem cell transplants.

[edit] Isolated infusion approaches

Isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumours. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic and therefore do not treat distributed metastases or micrometastases.

[edit] Targeted delivery mechanisms

Specially targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill and/or reduced toxicity.
Specially targeted delivery vehicles have a differentially higher affinity for tumor cells by interacting with tumor specific or tumour associated antigens.
In addition to their targeting component, they also carry a payload - whether this is a traditional chemotherapeutic agent, or a radioisotope or an immune stimulating factor. Specially targeted delivery vehicles vary in their stability, selectivity and choice of target, but in essence they all aim to increase the maximum effective dose that can be delivered to the tumor cells. Reduced systemic toxicity means that they can also be used in sicker patients, and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.

[edit] Nanoparticles
Nanoparticles have emerged as a useful vehicle for poorly-soluble agents such as paclitaxel. Protein-bound paclitaxel (e.g. Abraxane) or nab-paclitaxel was approved by the US FDA in January 2005 for the treatment of refractory breast cancer, and allows reduced use of the Cremophor vehicle usually found in paclitaxel.


[edit] Side-effects

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Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (January 2008)

The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body. Important common side-effects include (dependent on the agent):


[edit] Immunosuppression and myelosuppression
Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells and platelets. The latter two, when they occur, are improved with blood transfusion. Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic G-CSF (granulocyte-colony stimulating factor, e.g. filgrastim, lenograstim, Neupogen, Neulasta).

In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells which produce white and red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the patient before the treatment, multiplied and then re-injected afterwards; in allogenic BMTs the source is a donor.) However, some patients still develop diseases because of this interference with bone marrow.


[edit] Nausea and vomiting
Nausea and vomiting caused by chemotherapy; stomach upset may trigger a strong urge to vomit, or forcefully eliminate what is in the stomach.
Stimulation of the vomiting center results in the coordination of responses from the diaphragm, salivary glands, cranial nerves, and gastrointestinal muscles to produce the interruption of respiration and forced expulsion of stomach contents known as retching and vomiting. The vomiting center is stimulated directly by afferent input from the vagal and splanchnic nerves, the pharynx, the cerebral cortex, cholinergic and histamine stimulation from the vestibular system, and efferent input from the chemoreceptor trigger zone (CTZ). The CTZ is in the area postrema, outside the blood-brain barrier, and is thus susceptible to stimulation by substances present in the blood or cerebral spinal fluid. The neurotransmitters dopamine and serotonin stimulate the vomiting center indirectly via stimulation of the CTZ.

The 5-HT3 inhibitors are the most effective antiemetics and constitute the single greatest advance in the management of nausea and vomiting in patients with cancer. These drugs are designed to block one or more of the signals that cause nausea and vomiting. The most sensitive signal during the first 24 hours after chemotherapy appears to be 5-HT3. Blocking the 5-HT3 signal is one approach to preventing acute emesis (vomiting), or emesis that is severe, but relatively short-lived. Approved 5-HT3 inhibitors include: Dolasetron (Anzemet®), Granisetron (Kytril®), and Ondansetron (Zofran®). The newest 5-HT3 inhibitor, palonosetron (Aloxi®), also prevents delayed nausea and vomiting, which occurs during the 2-5 days after treatment.

Another drug to control nausea in cancer patients became available in 2005. The substance P inhibitor aprepitant (marketed as Emend®) has been shown to be effective in controlling the nausea of cancer chemotherapy. The results of two large controlled trials were published in 2005, describing the efficacy of this medication in over 1,000 patients.[2]
Some studies[3] and patient groups claim that the use of cannabinoids derived from marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (Tetrahydrocannabinol or THC) such as Marinol may be practical for this application. Natural marijuana, known as medical cannabis is also used and recommended by some oncologists, though its use is regulated and not everywhere legal[1] and there is still lack of sufficient studies to prove its efficacy.


[edit] Other side effects
In particularly large tumors, such as large lymphomas, some patients develop tumor lysis syndrome from the rapid breakdown of malignant cells. Although prophylaxis is available and is often initiated in patients with large tumors, this is a dangerous side-effect which can lead to death if left untreated.
A proportion of patients report fatigue or non-specific neurocognitive problems, such as an inability to concentrate; this is sometimes called post-chemotherapy cognitive impairment, colloquially referred to as "chemo brain" by patients' groups.[4]

Specific chemotherapeutic agents are associated with organ-specific toxicities, including cardiovascular disease (e.g., doxorubicin), interstitial lung disease (e.g., bleomycin) and occasionally secondary cancer (e.g. MOPP therapy for Hodgkin's disease).


[edit] See also


[edit] References

  1. ^ The Valuable Contribution of al-Razi (Rhazes) to the History of Pharmacy, FSTC.
  2. ^ Gralla R, de Wit R, Herrstedt J, Carides A, Ianus J, Guoguang-Ma J, Evans J, Horgan K (2005). "Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials". Cancer 104 (4): 864-8. PMID 15973669.
  3. ^ Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21. PMID 11440936.
  4. ^ Tannock IF, Ahles TA, Ganz PA, Van Dam FS. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol 2004;22:2233-9. PMID 15169812.


[edit] External links

v • d • e

Chemotherapeutic agents/Antineoplastic agents (L01)

Alkylating and alkylating-like agents
Nitrogen mustards: (Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan). Nitrosoureas:(Carmustine, Fotemustine, Lomustine, Streptozocin). Platinum (alkylating-like): (Carboplatin, Cisplatin, Oxaliplatin, BBR3464, Satraplatin). Busulfan, Dacarbazine, Procarbazine, Temozolomide, ThioTEPA, Treosulfan, Uramustine

Antimetabolites
Folic acid: (Aminopterin, Methotrexate, Pemetrexed, Raltitrexed). Purine:(Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Pentostatin, Thioguanine). Pyrimidine:(Capecitabine, Cytarabine, Fluorouracil, Floxuridine, Gemcitabine)

Spindle poison/mitotic inhibitor
Taxane: (Docetaxel, Paclitaxel). Vinca: (Vinblastine, Vincristine, Vindesine, Vinorelbine).

Cytotoxic/antitumor antibiotics
Anthracycline family: (Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pixantrone, Valrubicin) - streptomyces (Actinomycin, Bleomycin, Mitomycin, Plicamycin) - Hydroxyurea

Topoisomerase inhibitors
Camptotheca: (Camptothecin, Topotecan, Irinotecan), Podophyllum:(Etoposide, Teniposide)

CI monoclonal antibodies
Receptor tyrosine kinase (Cetuximab, Panitumumab, Trastuzumab) - CD20 (Rituximab, Tositumomab) - other (Alemtuzumab, Bevacizumab, Gemtuzumab)

Photosensitizers
Aminolevulinic acid, Methyl aminolevulinate, Porfimer sodium, Verteporfin

Tyrosine kinase inhibitors

Cediranib, Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Nilotinib, Sorafenib, Sunitinib, Vandetanib

Other
retinoids (Alitretinoin, Tretinoin) - Altretamine, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase (Pegaspargase), Bexarotene, Bortezomib, Denileukin diftitox, Estramustine, Ixabepilone, Masoprocol, Mitotane, Testolactone

v • d • e

Pathology: Cancer, Tumors, Neoplasms, and oncology (C00-D48, 140-239)

Benign tumors
Hyperplasia - Cyst - Pseudocyst - Hamartoma - Benign tumor

Malignant progression
Dysplasia - Carcinoma in situ - Cancer - Metastasis

Topography
lip, oral cavity and pharynx: Oral - Head/Neck - Nasopharyngeal
digestive system: tract (Esophagus, Stomach, Small intestine, Colon/rectum, Appendix, Anus) - glands (Liver, Bile duct, Gallbladder, Pancreas)

respiratory system: Larynx - Lung
bone, articular cartilage, skin, and connective tissue: Bone - Skin - Blood

urogenital: breast and female genital organs (Breast, Vagina, Cervix, Uterus, Endometrium, Ovaries) - male genital organs (Penis, Prostate, Testicles) - urinary organs (Kidney, Bladder)

nervous system: Eye (Uvea) - Brain
endocrine system: Thyroid (Papillary, Follicular, Medullary, Anaplastic) - Adrenal tumor (Adrenocortical carcinoma, Pheochromocytoma) - Pituitary

Misc.
Tumor suppressor genes/oncogenes - Staging/grading - Carcinogenesis - Carcinogen - Research - Paraneoplastic syndrome - List of oncology-related terms

v • d • e

Major drug groups

Gastrointestinal tract (A)
Antacids • Antiemetics  • H2 antagonists • Proton pump inhibitors • Laxatives • Antidiarrhoeals

Blood and blood forming organs (B)
Anticoagulants • Antiplatelets • Thrombolytics

Cardiovascular system (C)

Antiarrhythmics • Antihypertensives • Diuretics • Vasodilators • Antianginals • Beta blockers • Angiotensin converting enzyme inhibitors • Antihyperlipidemics

Skin (D)
Emollients - Antipruritics

Reproductive system (G)

Hormonal contraception • Fertility agents • Selective estrogen receptor modulatorsSex hormones

Endocrine system (H)

Anti-diabeticsCorticosteroidsSex hormonesThyroid hormones

Infections and infestations (J, P)

Antibiotics • Antivirals • Vaccines • Antifungals • Antiprotozoals • Anthelmintics

Malignant and immune disease (L)

Anticancer agents • Immunostimulators • Immunosuppressants

Muscles, bones, and joints (M)

Anabolic steroidsAnti-inflammatories • Antirheumatics • Corticosteroids • Muscle relaxants

Brain and nervous system (N)

Anesthetics • Analgesics • Anticonvulsants • Mood stabilizers  • Anxiolytics • Antipsychotics • Antidepressants • Nervous system stimulants • Sedatives

Respiratory system (R)
Bronchodilators • Decongestants  • H1 antagonists

Therapeutic intervention: 

Dichloroacetic acid

field_vote: 

Cited from the University of Alberta in Canada "Express News"

Small molecule offers big hope against cancer
U of A researcher Dr. Evangelos Michelakis has shown that this tiny DCA molecule could make a difference in the battle against cancer.
U of A researcher Dr. Evangelos Michelakis has shown that this tiny DCA molecule could make a difference in the battle against cancer. 
- DCA is an odourless, colourless, inexpensive, relatively non-toxic, small molecule. And researchers at the University of Alberta believe it may soon be used as an effective treatment for many forms of cancer.
Dr. Evangelos Michelakis, a professor in the U of A Department of Medicine, has shown that dichloroacetate (DCA) causes regression in several cancers, including lung, breast and brain tumors.
Michelakis and his colleagues, including post-doctoral fellow Dr. Sebastian Bonnet, have published the results of their research in the journal Cancer Cell.
Scientists and doctors have used DCA for decades to treat children with inborn errors of metabolism due to mitochondrial diseases. Mitochondria, the energy producing units in cells, have been connected with cancer since the 1930s, when researchers first noticed that these organelles dysfunction when cancer is present.
Until recently, researchers believed that cancer-affected mitochondria are permanently damaged and that this damage is the result, not the cause, of the cancer. But Michelakis, a cardiologist, questioned this belief and began testing DCA, which activates a critical mitochondrial enzyme, as a way to "revive" cancer-affected mitochondria.
The results astounded him.

 
Normalized Mitochondrial Function

Michelakis and his colleagues found that DCA normalized the mitochondrial function in many cancers, showing that their function was actively suppressed by the cancer but was not permanently damaged by it.
More importantly, they found that the normalization of mitochondrial function resulted in a significant decrease in tumor growth both in test tubes and in animal models. Also, they noted that DCA, unlike most currently used chemotherapies, did not have any effects on normal, non-cancerous tissues.
"I think DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells," Michelakis said. "Cancer cells actively suppress their mitochondria, which alters their metabolism, and this appears to offer cancer cells a significant advantage in growth compared to normal cells, as well as protection from many standard chemotherapies. Because mitochondria regulate cell death - or apoptosis - cancer cells can thus achieve resistance to apoptosis, and this appears to be reversed by DCA."
"One of the really exciting things about this compound is that it might be able to treat many different forms of cancer, because all forms of cancer suppress mitochondrial function; in fact, this is why most cancers can be detected by tests like PET (positron emission tomography), which detects the unique metabolic profile of cancer compared to normal cells," added Michelakis, the Canada Research Chair in Pulmonary Hypertension and director of the Pulmonary Hypertension Program with the Capital Health Authority.
Another encouraging thing about DCA is that, being so small, it is easily absorbed in the body, and, after oral intake, it can reach areas in the body that other drugs cannot, making it possible to treat brain cancers, for example.
Also, because DCA has been used in both healthy people and sick patients with mitochondrial diseases, researchers already know that it is a relatively non-toxic molecule that can be immediately tested in patients with cancer.
Furthermore, the DCA compound is not patented or owned by any pharmaceutical company, and, therefore, would likely be an inexpensive drug to administer, Michelakis added.
However, as DCA is not patented, Michelakis is concerned that it may be difficult to find funding from private investors to test DCA in clinical trials. He is grateful for the support he has already received from publicly funded agencies, such as the Canadian Institutes for Health Research (CIHR), and he is hopeful such support will continue and allow him to conduct clinical trials of DCA on cancer patients.
Michelakis' research is currently funded by the CIHR, the Canada Foundation for Innovation, the Canada Research Chairs program and the Alberta Heritage Foundation for Medical Research.
"This preliminary research is encouraging and offers hope to thousands of Canadians and all others around the world who are afflicted by cancer, as it accelerates our understanding of and action around targeted cancer treatments," said Dr. Philip Branton, Scientic Director of the CIHR Institute of Cancer.

Therapeutic Substance(s): 
Therapeutic intervention: 
Disease(s): 

Gemcitabine

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From http://en.wikipedia.org/wiki/Gemcitabine
Gemcitabine is a nucleoside analog used as chemotherapy. It is marketed as Gemzar® by Eli Lilly and Company.

Pharmacology
Chemically gemcitabine is a nucleoside analog in which the hydrogens on the 2' carbons of deoxycytidine are replaced by fluorines.

As with fluorouracil and other analogues of pyrimidines, the drug replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumor growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide").

Indications
Gemcitabine is used in various carcinomas: non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. It is being investigated for use in oesophageal cancer, and is used experimentally in lymphomas and various other tumor types. Gemcitabine represents an advance in pancreatic cancer care. It is also not as debilitating as other forms of chemotherapy.

"Adjuvant Chemotherapy With Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer: A Randomized Controlled Trial" reported in the Journal of the American Medical Association (JAMA. 2007;297:239.) suggest that gemcitabine shows benefit in patients with pancreatic cancer who were felt to have successful tumor resections.

Gansauges reserach group in Ulm, Germany has shown that a combination of Ukrain and Gemcitabine can be succesful in the treatment of Pandratic cancer

Gemcitabine became first line treatment for bladder cancer Stage 4 with metastases in combination with Cisplatin after a study with 405 patients showed similar efficacy but less toxicity compared to the former MVAC regimen ( J Clin Oncol 2000;18:3068). This new CG-regimen is Cisplatin on day 2, Gemcitabine on days 1,8,15

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Therapeutic intervention: 
Disease(s): 

Herbal Based Cancer Therapies

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There are since ages many attempts to heal Cancer through the use of herbs or herbal mixtures-
In this category we also include semi-synthetic herbal compounds like Iscador, Helixor and Ukrain.

Therapeutic intervention: 
Disease(s): 

Artemisinin derivates in the treatment of Cancer

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Artemisinin comes the
Chinese herb Artemisia annua L. Artemisine and has been used for thousand of
years in Traditional Chinese Medicine for the treatment of fever and cancer. It
is been showed to be effective against multidrug-resistant malaria and has an
excellent safety profile. Artemisinin has a very short halflife in serum and
can be hard to manufacture for the enormous needs of all the people suffering
from multi drug resistamt malaria in the world, syntethic versions of artmisin
has been manufactured. The most famous of these synthetic artemisinins are
Artemether, Dihydroartemisinin and Artesunate.
Apart from their anti-malarial activity, the artimisinins has also shown
cytotoxic effects on a number of human cancer cell lines in labarotory and
animal tests, including leukemia, ovarian cancer, colon cancer, brain
cancer, liver cancer, pancreatic and melanoma. Artesunate is very cheap and
treatments are sold for less than a few dollars for treatment of multiresistenent
malaria in Africa and South East Asia.

Side Effects
Artesunate and other related artemisinin derivatives have been widely used in China, with no
reports of any serious adverse reactions. Drug induced fever can occur. Neurotoxicity
has been observed in animal studies but not in humans. In view of the
uncertainty about toxic effects, caution should be exercised when more than one
3 day treatment is given. Cardiotoxicity has been observed following administration
of high doses.
Possible drug related adverse effects include dizziness, itching, vomiting, abdominal
pain, flatulence, headache, bodyache, diarrhoea, tinnitus and increased hair
loss, macular rash, reduction in neutrophil counts and convulsions. However, it
is likely that many of these effects are disease-related rather than drug-induced.
Occasional skin rash and pruritus has been observed with Artesunate.
There were no clinically
important local or systemic adverse effects observed in 346 patients treated
with intravenous artesunate. Electrocardiography was undertaken in a total of
82 patients. Slight sinus bradycardia occurred in a few patients and transient first
degree atrioventricular block was observed in 1 patient. Slight elevations in
hepatic transaminases were also reported, but these were more likely to be
related to the disease than to the treatment per se.


Case Story 1:
Metastatic Melanoma

One patients with a metastatic 
melanoma originating from the pigment cells in the eye was treated on a
compassionate-use basis, after standard chemotherapy
alone was ineffective in stopping tumor growth. The therapy-regimen was well
tolerated with no additional side effects other than those caused by standard
chemotherapy alone. The patient first experienced a stabilization of
the disease after the addition of artesunate to Dacarbazine, a cytostatic drug
commonly used in the treatment of malignant melanoma. Later he experienced
objective
regressions of splenic and lung metastases. This patient was still alive 47
months after first diagnosis of stage IV uveal melanoma, a situation with a
median survival of 2-5 months.

Case Story 2- A
Pituitary Adenoma treated with Artemether

The patient is 75-year-old.
He has had diabetes mellitus for 17 years for which he wastreated with oral
hypoglycemics. He had coronary bypass surgery 4 years prior to this visit. He
presented at the Primary
Health Center
complaining of gradual loss of movements in the left eye, poor vision, and unsteady
gait for more than a month, along with moderate bilateral hearing loss of
insidious onset (patient could not recall the initial onset of hearing
problemsbut estimated the course to be in years). There was no history of
headache. Prior to this visit, he consulted an ophthalmologist with complaint
of double vision. The ophthalmologist observed loss of acuity, medial
convergents quint, and diplopia in the left eye only and suspected pituitary
adenoma compressing the optic nerve (resulting in loss of acuity) and the sixth
cranial nerve (resulting in convergent squint leading todiplopia). The patient
then consulted his primary care physician. A CT scan with IV contrast on April15,
2004, revealed a rounded, dense, and relatively homogenous mass of section size
2.42.6 cm in the pituitary area of the brain.  There were no signs of apoplexy. A diagnosis
of pituitary macroadenoma was made. The patient was treated with 40 mg
(approximately0.5 mg/kg) of Artemether orally daily for 29 days starting on
April 16, 2004. This medication was given with milk 3 to 4 hours after dinner.
Two hundred units of vitamin E (D alpha tocopherol) and 500 mg of vitaminC were
given to the patient at breakfast. After 15days of treatment, his left eyeball
started moving slightly and there was a slight improvement in vision,and this
treatment was continued for 2 more weeks. Artemether therapy was then reduced
and given only every other day for a duration of 30 more days. Vitamin E and C
were given every day. Artemether therapy was reduced further and given twice a
week for approximately 10 more months. Vitamin E and Cwere given every day for
the entire period.
Results:
A CT scan performed
on August 9, 2004 (approximately4 months after the initial diagnosis and
startof treatment), showed an increase in adenoma size to3.0 × 2.4 cm. Although there was a
slight increase in size of mass, the patient’s visual and other symptoms and
signs had improved significantly. Another CT scan was performed on January 25,
2005 (approximately9 months after the initial diagnosis and start of
treatment). The tumor remained consistent in sizemeasuring 3.33 × 2.25 cm. Additionally, the
patient reported marked improvement in visual problems.The patient’s gait had
returned to normal, and his hearing had improved significantly. Also, reduced doses
of oral hypoglycemics were needed for controlof diabetes. The patient was more
alert and active than before. A CT
scan on November 15, 2005,showed no significant change in tumor size (2.6 ×
2.4cm) compared to previous CT scans. However, this scan of November 2005 did
show the density of thetumor (ranging from 51 to 59 HU) significantly decreased
since the first scan (72-77 HU) in April2004. Additionally, the November 2005
scan showed the tumor had become more heterogeneous. The patient also reported
a nearly complete symptomatic recovery.

Homeopatic therapy in Cancer Treatment

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From the article by E. Ernst
"Efficacy of homeopathic therapy in cancer treatment"

A recent European survey has shown that
homeopathy is amongst the most commonly used complementary
therapies for cancer in 7 out of 14 European
countries [3].
As a palliative or supportive treatment, homeopathy is
used mainly to strengthen the body in its fight against cancer,
to improve general well-being, and to alleviate pain
resulting from disease or conventional treatments [2,3].
Homeopathy is controversial as no plausible mode of action
has been identified for substances that are so highly diluted
that they can not be measured [4]. Homeopathic remedies
are believed to be most effective when they are selected to
address a total set of symptoms and characteristics [5] and
in classical or individualized homeopathy, choice of remedies
are based on the match of a patients particular symptoms
with a remedy picture rather than conventional diagnosis
[6]. Prescribing homeopathic substances is based on its proposed
law of similars that suggests that ‘‘like cures like’’ [7].
Although Hahnemann initially diluted these substances in
order to reduce toxicity, he came to believe that the actual
process of diluting and shaking imparted additional potency
to each solution [5]. His process of testing natural substances
in healthy individuals became known as ‘‘drug proving’’ and
results continue to be collected into an encyclopaedia of
homeopathic drug effects known as the Materia Medica
[8,9]. In ‘‘classical homeopathy’’ single remedies are given to
patients, whereas in ‘‘complex homeopathy’’ several homeopathic
medicines are combined into one formula, where concentration
tends to be below 24X and usually below 12X [10]
(the numbers indicate the dilution of the homeopathic remedy;
that is, remedies are obtained by ‘‘decimal dilution’’, one
part substance to nine parts alcohol, and then labelled by the
letter X or D).
In the 1950s, Hans H. Reckeweg developed a new form of
homeopathy known as homotoxicology [11], which generally
uses formulations that contains measurable amounts of
homeopathically prepared active ingredients, designed to
work with the bodys defence mechanisms and facilitate the
bodys elimination of toxic substances (homotoxins). Homotoxicological
remedies are prepared according to the rules of
homeopathy and are used in combinations as complex remedies.
Some experts fail to differentiate between homeopathic
and homotoxicological medicines. However, there are important
differences. Homeopathy follows the ‘‘like cures like’’
principle, while homotoxicology does not [12]. Homotoxicology
often makes use of biological material that would be
atypical in homeopathy, such as material from pigs. Some reports
suggest the efficacy of homotoxicology for defined conditions,
but many caveats exist [12].
Isopathy is another subset of homeopathy that was developed
by Johann Lux in the 1830s. It differs from homeopathy
in that remedies are prepared from those substances that
cause the illness (e.g., allergens or bacteria) [13] and several
trials have suggested its clinical efficacy [14].

Therapeutic Substance(s): 
Therapeutic intervention: 
Disease(s): 

Hypericine

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Introduktion From Wikipedia, the free encyclopedia
Hypericin is a red-coloured anthraquinone-derivative, which is one of the principal active constituents of Hypericum (Saint John's wort). Hypericin is believed to act as an antibiotic and non-specific kinase inhibitor. Hypericin may inhibit the action of the enzyme dopamine beta-hydroxylase, leading to increased dopamine levels, although thus possibly decreasing norepinephrine and epinephrine.

The large chromophore system in the molecule means that it can cause photosensitivity when ingested beyond threshold amounts. Because hypericin accumulates preferentially on cancerous tissues, it is also used as an indicator of cancerous cells. In addition, hypericin is under research as an agent in photodynamic therapy, whereby a biochemical is absorbed by an organism to be later activated with spectrum-specific light from specialized lamps or laser sources, for therapeutic purposesp

Short Summaries
protective effect on Irinotecan-induced blood and gastrointestinal toxicity
Irinotecan is an important anticancer drug in management of advanced colon cancer. A marked protective effect on Irinotecan-induced blood and gastrointestinal toxicity is obtained by combination of St. John’s wort (SJW) in recent clinical and rat studies. These results indicated that the aqueous and ethanolic extracts of SJW leads to a selective accumulation of CPT 11 in Cancer Cells, which can in part explain the protective action of St. John’s wort

Therapeutic Substance(s): 
Therapeutic intervention: 
Disease(s): 

A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort

field_vote: 
Average: 8 (1 vote)
Therapeutic Substance(s): 
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Publication type: 
References: 
Disease(s): 

1: Curr Drug Metab. 2007 Feb;8(2):157-71.Links
A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort.
Hu ZP, Yang XX, Chen X, Cao J, Chan E, Duan W, Huang M, Yu XQ, Wen JY, Zhou SF.

Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, 117543, Singapore.

Irinotecan (CPT-11) is an important anticancer drug in management of advanced colon cancer. A marked protective effect on CPT-11-induced blood and gastrointestinal toxicity is obtained by combination of St. John's wort (SJW) in recent clinical and rat studies. However, the mechanism is unclear. This study aimed to explore the effects of SJW on the pharmacokinetics of CPT-11 and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-term (3 days) and long-term (14 days) pretreatment with SJW were conducted in rats to examine the effects of co-administered SJW on the plasma pharmacokinetics of CPT-11, SN-38 and SN-38 glucuronide. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were utilized to study the effects of aqueous and ethanolic extracts (AE and EE) and major active components (hyperforin, hypericin and quercetin) of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation. Co-administered SJW for consecutive 14 days significantly decreased the initial plasma concentration (C0) of CPT-11, the area under the concentration-time curve (AUC(0-10hr)) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 microg/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 microg/ml, SJW EE at 5 microg/ml, and quercetin at 10 microM significantly increased the glucuronidation of SN-38 in H4-II-E cells. A 2-hr pre-incubation of quercetin (100 microM) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1 microM) significantly decreased the intracellular accumulation of CPT-11. In addition, pre-incubation of hypericin, SJW EE and quercetin significantly increased the intracellular accumulation of SN-38. Aqueous and ethanolic SJW extracts and its major active components did not alter the plasma protein binding of CPT-11 and SN-38. These results indicated that the aqueous and ethanolic extracts of SJW and its major active components could markedly alter glucuronidation of SN-38 and intracellular accumulation of CPT-11 and SN-38, which probably provides partial explanation for the altered plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing effects on the toxicities of CPT-11. Further studies are needed to explore the role of both pharmacokinetic and pharmacodynamic components in the protective effect of SJW against the toxicities of CPT-11.

Enhanced radiation sensitivity and radiation recall dermatitis (RRD) after hypericin therapy – case report and review of literat

field_vote: 
Average: 8 (1 vote)
Therapeutic Substance(s): 
Therapeutic intervention: 
Publication type: 
Disease(s): 

Radiat Oncol. 2006; 1: 32.
Published online 2006 September 1. doi: 10.1186/1748-717X-1-32.
Enhanced radiation sensitivity and radiation recall dermatitis (RRD) after hypericin therapy – case report and review of literature
Kurt Putnik,1 Peter Stadler,1 Christof Schäfer,1 and Oliver Koelbl

Full text link = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16948841

BACKGROUND: Modern radiotherapy (RT) reduces the side effects at organ at risk. However, skin toxicity is still a major problem in many entities, especially head and neck cancer. Some substances like chemotherapy provide a risk of increased side effects or can induce a "recall phenomenon" imitating acute RT-reactions months after RT. Moreover, some phototoxic drugs seem to enhance side effects of radiotherapy while others do not. We report a case of "radiation recall dermatitis" (RRD) one year after RT as a result of taking hypericin (St. John's wort).

CASE REPORT: A 65 year old man with completely resected squamous cell carcinoma of the epiglottis received an adjuvant locoregional RT up to a dose of 64.8 Gy. The patient took hypericin during and months after RT without informing the physician. During radiotherapy the patient developed unusual intensive skin reactions. Five months after RT the skin was completely bland at the first follow up. However, half a year later the patient presented erythema, but only within the area of previously irradiated skin. After local application of a steroid cream the symptoms diminished but returned after the end of steroid therapy. The anamnesis disclosed that the patient took hypericin because of depressive mood. We recommended to discontinue hypericin and the symptoms disappeared afterward.

CONCLUSION: Several drugs are able to enhance skin toxicity of RT. Furthermore, the effect of RRD is well known especially for chemotherapy agents such as taxans. However, the underlying mechanisms are not known in detail so far. Moreover, it is unknown whether photosensitising drugs can also be considered to increase radiation sensitivity and whether a recall phenomenon is possible. The first report of a hypericin induced RRD and review of the literature are presented. In clinical practise many interactions between drugs and radiotherapy were not noticed and if registered not published. We recommend to ask especially for complementary or alternative drugs because patients tend to conceal such medication as harmless.

Mistletoe Therapy in Cancer

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Preparations from the European mistletoe (Viscum album L.) are among the most prescribed drugs in cancer patients in several European countries. The most common brand names are Iscador, Helixor and Viscum Album. Proponents claim that mistletoe extracts stimulate the immune system, improve survival, enhance quality of life and reduce adverse effects of chemo- and radiotherapy in cancer patients. Critics claim that there is still not evidence to support such claims.

Controlled Clinical Trials

In a randomized controlled study from 2008 on altogether 508 patients Iscador was shown to prolong overall survival of corpus uteri cancer patients. Psychosomatic self-regulation as a measure of autonomous coping with the disease, rised significantly more under Iscador therapy than under conventional therapy alone at a follow up of 12 months.

Treatment with HELIXOR
proved to be beneficial for breast cancer patients since it significantly improved quality of life and significantly reduced persistant signs/symptoms of the disease/treatment during the validated aftercare period of approximately five years in 167 patients treated with Helixor.

In an open study from 2008 33 patients with primary breast cancer receiving adjuvant chemotherapy and simultaneous treatment with Iscador was compared with 33 controls without mistletoe therapy. Reductions in quality of life seemed to be smaller during add-on-therapy with mistletoe. Laboratory parameters showed no difference compared to the control group.Mistletoe patients showed better quality of life and a reduction of in the need of symptom relieving glucocorticoid(cortisone) cotreatment.

A study on altogether 10 patients with early stage cervix cancer and healthy volunteers showed that dose-escalation of Iscador reduces the monocyte-related clinical side effects, like temperature increase and skin reactions. The most interesting clinical long-term effect is the bystander stimulation of various memory T cells that might mediate in vivo antitumor and antiinfectious T-cell response under mistletoe-extract immunization.

In three controlled cohort studies
with altogether 374 patients, Iscador may have the effect of prolonging overall survival of cervical cancer patients. In the short term, psychosomatic self-regulation increases more markedly under complementary Iscador therapy than under conventional therapy alone.

Grossarth et al found in 2006 that Iscador showed a clinically relevant effect on breast tumor progression as measured by overall survival as well as by the time to recurrences, lymphatic or distant metastases on 244 patients with breast cancer. In the short term, psychosomatic self-regulation increased more markedly under complementary Iscador therapy than under conventional therapy alone.

Meta-analysis and Review Articles
A Cochrane review from 2008 found that there was not enough evidence to reach clear conclusions about the effects on any of these outcomes and it is therefore not clear to what extent the application of mistletoe extracts translates into improved symptom control, enhanced tumour response or prolonged survival. Adverse effects of mistletoe extracts were reported, but appeared to be dose-dependent and primarily confined to reactions at injection site and mild, transient flu-like symptoms. In the absence of good quality, independent trials, decisions about whether mistletoe extracts are likely to be beneficial for a particular problem should rely on expert judgement and practical considerations.

Prof Edzard Ernst stated in 2006
that mistletoe has been tested extensively as a treatment for cancer, but the most reliable randomised controlled trials fail to show benefit, and some reports show considerable potential for harm. The costs of regular mistletoe injections are high. I therefore recommend mistletoe as a Christmas decoration and for kissing under but not as an anticancer drug. At the risk of upsetting many proponents of alternative medicine, I also contend that intuition is no substitute for evidence.

Other Interesting Articles
Bar sela et al found in 2006 that installation of Iscador M into the peritoneal cavity may reduce the need for repeated punctures.

Therapeutic Substance(s): 
Therapeutic intervention: 
Disease(s): 

Ukrain

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File attachments: 

Ukrain, also called NSC 631570 is an experimental anticancer drug invented by the Ukrainian researcher Wassil Nowicky and tested clinically for the first time in 1978. It is a product that results from a reaction of alkaloids from greater celandine with the classic cancer medicine Thio-TEPA in the presence of hydrochloric acid.

Content
Ukrain contents mixture of alkaloids. Chelidonine is generally considered the most important one. Chelidonine, like some other celandine alkaloids, is hardly soluble in water. This makes intravenous injections impossible. The preparation of Ukrain together with Thio-TEPA and hydrochlric acid makes the alkaloids water soluble and injectable. addition. It is probable the anti-cancer effect of Ukrain is a result of a combined action of all its constituents. Previously it has been postulated that the active component of Ukrain was a trimeric structure containing three chelidonine molecules connected by a Thiro-thepa skeleton. This has not been confirmed in later investigations.

Licensing Status
Ukrain has obtained drug licenses in Mexico, United Arab Emirates and several states of the former Soviet Union. Recently, Ukrain has got the orphan drug status for the treatment of pancreatic cancer in Australia and in the United States of America.

Clinical Investigations
Ukrain has been investigated in multiple phase I and phase II clinical trials on a large variety of cancer types with very promising results. Ukrain can also have a possible future role in the treatment of Hepatitis C and other viral infections.
Click on this link to go to a summary of all the clinical investigations and case reports on Ukrain.
The Clinical publications on Ukrain have been summarized 2005 in an article by Prof Edzard Ernst, UK.

Other investigations on Ukrain

In vitro investigations on Ukrain of Ukrain has shown effect on a wide variety of cancer cell cultures, a possibleantidepressant and anti-dementia effect and radioprotective properties on normal cells, but not on cancer cells.
It has been shown toinduce apoptosis and to have a selective toxicity for cancer cells. This selective toxicity has been challenged by another research group, which found no selective toxicity for Ukrain in certain cancer cell cultures.

Animal investigations
Animal experiments has shown no acute toxicity in rats,or rabbits and to have effect on a large variety of animal cancers, and bone density in rats.
It seems to have possible interactions with alcohol and morphine and to have a painkilling effect that is antagonized by the morphine blocker Naltrexone. It has been shown to have a selective uptake in tumor tissue in rats and to increase the level of thyroid hormones in Rabbits.
It has been shown to have a protective effect against against bacterial infections and an antiviral effect.

Controversies around Ukrain

Ukrain and its manufacturer Nowicky Pharma has been subject to many controversies. These controvesities will be summarized and debate on this page.
The inventor, Dr Wassil Nowicky describes many events of postulated personal persecution and even a murder attempt in the book, "Who is afraid of Ukrain?", authored together with the austrian journalist, Eleonore Thun-Hohenstein. He has made a summary of his view in a letter, published here.

External Links:

Nowicky Pharma, Austria
Nowicky Pharma, Ukraine
Information for Physicians from the manufacturer.

Therapeutic intervention: 
Therapeutic Substance(s): 
Disease(s): 

Animal studies on Ukrain

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Studies on anti-cancer effect
Effect on HA-1 hepatoma in mice
Treatment by antitumor drug Ukraine increased life span of mice with HA-1 hepatoma (transplanted intravenously), decreased the increment of tumor weight. In the abdominal fluid such treatment caused a decrease of number of tumor cells and an increase of number of macrophages. Ukrain increased cystatin C level, revealing protective mechanism of action. Another study also showed similar results.

Multiple effects on mice
A marked progressive anticancer and antimetastatic effect was observed on Lewis carcinoma in mice. The antimetastatic effect of the drug manifested as a decrease in both number and volume of lung metastases. Ukrain also made an increase in the endocrine function of the thymus (a central organ of the immune system), an increase in serum interferon, adhesion of
peritoneal macrophages and formation of antibodies against thymus-dependent antigen by spleen plasma cells. It increased the number of lymphoid cells and monocytes in peripheral blood. In addition to the increase in lymphocytes, the number of large granular lymphocytes also increased,
i.e., cells possessing natural cytotoxic activity.

Effect on rat hepatosarcoma
Both Ukrain and the cancer drug Cyclophosphamide were able to induce signs of Apoptosis in a cell culture consisting of liver cancer cells from rats.

Effect on sarcoma-45 in rats
The effect of Ukrain on the growth kinetics of the experimental tumor sarcoma-45 in rats was studied. Ukrain was proved to be an effective antitumor agent on biological and mathematical models in accordance with standardized instructions for screening.
Selective uptake in tumor tissue in rats?
Ukrain penetrates into tissues after injection in labaratory rats by active transport or by favored diffusion. A relatively higher affinity for Ukrain was observed in tumor tissue and liver, while affinity was lowest in the brain and muscles. The presence of tumors decreased Ukrain concentrations in plasma and normal tissues in comparison with those in control animals.

Effect on breast cancer in mice
Intravenous, but not subcutaneous or intraperitoneal, administration of Ukrain
was found to be effective in delaying tumour growth in an actual therapeutic
protocol initiated five days after tumour implantation on mice. No untoward side-effects
were observed. Ukrain induced the activation of tumouricidal function of white blood cells from the abdominal cavity(peritoneum) from tumour bearing but not from normal mice.

Radioprotective effects
Radioprotective effects on the glucocorticoid and thyroid systems in rats
Ukrain minimized the consequences of radiation therapy on parts of the endocrine system in rats.
Two hundred and sixty rats were infected by tularemia and the equine encephalomyelitis (EEM) virus 24 hours after irradiation. Irradiation prior to infection was found to decrease the survival rate. Preventive administration of Ukrain increased the survival rate.
Ukrain decreases bone-marrow suppression in rats exposed to gamma radiation by improving hemopoiesis and immunogenesis.
The radioprotective effects of Ukrain are far superior to all its components taken separately , both measured by survival of mice irradiated by different doses, and by the protection coefficient a. These observations suggest that the influence of Ukrain on radiation effects does not result from the antiradiation properties of its components but rather from the concerted action of the specific combination found in Ukrain.

Drug Interactions
Ukrain have a significant pain-killing effect on mice and interacts with morphine so that the effect of morphine diminishes. This raises concerns about their combined usage.
In another studyUkrain seemd to have pain killing properties only in very high dosis in mice, while
enhancing the effect of morphine in some test settings, and antagonizing the effect in other tests.
The interaction between Ukrain and Naltrexone, a nonselective opioid receptor antagonist, was studied in the 'writhing syndrome' test in mice. The results show that the antinociceptive effect of both single dose and prolonged administration of Ukrain is completely antagonized by Naltrexone.
Ukrain significantly (p<0.001) enhanced the anticonvulsive action of valproate in a mouse electroshock-induced seizure model. This was observed with UKRAIN doses of 9.5 and 19.0 mg/kg, but not at 4.75 mg/kg. No significant influence on the activity of other anti-epileptics (diazepam, carbamazepine, diphenylhydantoin, phenobarbital) was observed

Ukrain against infections?
Protective effect against bacterial infections
Ukrain increases the survival of mice exposed to letal doses of E.Coli ans Stafylococcus Aureus bacterias.
Antiviral effect on mice and embryos
Ukrain seems to have antiviral effect against the Influenza Virus, when tested on embryos and mice.

Other effects
Effect on bone density in rats
Ukrain was shown to affect bone tissue metabolism in rats. Its action could be slightly osteopenic at the highest doses administered to intact animals for a prolonged period of time. By far, the most important finding seems to be the anabolic effect of Ukrain on bone in ovariectomized rats, which is most probably related to induced increase in the production of sex hormones, predominantly estrogens. This means it is likely that Ukrain can counteract the loss of bone due tp estrogen deficiency in postmenopausal women.

Interactions with Alcohol?
Ukrain seems to inhibit the enzyme thay breaks down alcohol in rats. This means that there is reason to be careful when combining alcohol and Ukrain.
Ukrain and Thyroid Hormones in Rabbits
The influence of Ukrain on serum levels of thyroid hormones was studied in rabbits of both sexes. An increase in the thyroxine level was found at a dose of 1.5 and 3.0 mg/kg i.v. in male rabbits, whereas increased triiodothyronine was noted when Ukrain was given at all studied doses. In females the thyroxine level was not altered by Ukrain administration, whereas the triiodothyronine concentration was increased following Ukrain at 0.3, 1.5 and 3.0 mg/kg i.v. It is probable the altered thyroid hormone levels as a result of Ukrain application may contribute to the drug's potent immunomodulatory action.

Lack of toxicity in Rabbits
6 week Ukrain application to rabbits did not change their body organs and total body weight. The drug did not affect biochemical parameters of peripheral blood, except for a minor reduction in the total plasma level and increases in serum uric acid and urea indicating enhanced catabolism of proteins and minor changes in white blood cells.

Long term effects on rodents
A three month treatment with Ukrain significantly depressed the spontaneous locomotor
activity and did not affect the motor coordination of mice and rats of both
sexes. Ukrain did not affect the body weight gain as well as the mass of internal
organs; the exception was an increase in the mass of the spleen in rats.
Biochemical studies indicated that the three month treatment depressed
the whole brain dopamine concentrations and did not affect the noradrenaline
(NA) and Serotonin(5-HT) concentrations.
In another investigation, Ukrain showed no clinical signs of toxicity in hamsters and rats
and no teratogenic effect could be noted in either species. Slight embryotoxic effects were noted in
hamsters exposed to Ukrain at doses which were otherwise not embryotoxic to rats.
Ukrain was found to be non-mutagenic and non-genotoxic in a standardized genotoxicity experiment.
Ukrain did not show any tendences to induce any signs of allergic shock in a standardized animal experiment on mice.

Therapeutic Substance(s): 
Disease(s): 

Clinical Investigations on Ukrain

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Short Summaries:

Ukrain against Pancreatic Cancer

Gemcitabine and Ukrain against Pancreas Cancer 2007
30 patients with pancreatic cancer received chemotherapy with Gemcitabine, combined with Ukrain after their cancer operations. Mild side effects were observed in 53%, no severe side effects occurred. In 80% of the patients recurrence of the disease was observed. The survival rates were 86.7% after one year, 76.6% after two years, 46.7% after three years and 23.3% after five years, which is much better than any previosuly known treatment results. The median survival time was 33.8 months.

Gemcitabine Versus Ukrain versus Ukrain/Gemcitabine 2002
90 patients with non-operapable pancreatic cancer were randomized into three different treatment arms. Patients in arm A received Gemcitabine, those in arm B received Ukrain, and those in arm C received gemcitabine and Ukrain.
In all three arms therapy was well tolerated and toxicity was moderate. Median survival was in arm A 5.2 months, in arm B 7.9 months, and in arm C 10.4 months. Actuarial survival rates after 6 months were 26%, 65% and 74% in arms A B and C, respectively.

Ukrain against Pancreatic Cancer 2002
21 patients were treated with 10 mg ukrain every second day x10. The control group received supportive treatment only. Ukrain treatment was well tolerated. Mean values on pain measure and
[url]=http://en.wikipedia.org/wiki/Performance_status]Karnofsky index[/url] were significantly better in the ukrain group than in controls (P<0.05). One-year survival was 76% in the ukrain group, compared to 9.5% in the control group.
Median survival after treatment with ukrain was 574 days, compared to 197 days in the control group.

Ukrain against Pancreatic Cancer 2000
42 patients with advanced symptomatic pancreas cancer were randomly assigned to receive either vitamin C and Ukrain , or vitamin C and normal saline . The one-year survival was 81% in the Ukrain group compared with 14% in the control group. The 2-year survival was 43% in the Ukrain group compared with 5% in the control group. Median survival was 17.17 months for Ukrain-treated patients and 6.97 months for the control group.

Breast Cancer
Ukrain against Breast Cancer 2000
75 patients with histologically confirmed breast cancer were divided into three groups of 25. The control group received symptomatic corrective therapy prior to their breast operation. The two other groups were given neoadjuvant therapy with Ukrain injections. The first group received a total course dose of 50 mg and the second group received a total Ukrain dose of 100 mg. Five to seven days after the last injection patients from all groups were subjected to operation. Practically all patients who were administered Ukrain noticed remarkable positive changes in the second half of treatment: improvement in appetite, normalization of sleep, disappearance of general weakness and the appearance of confidence in recovery. After the course of treatment with Ukrain, the contours of the tumorous node became more clearly defined, which facilitated operation. Changes in the tumor tissue were one-sided in their qualitative differences in comparison to the control group and were not dose-dependent. The results of this study showed the efficiency of both doses (50 and 100 mg) of Ukrain with the higher dosage performing slightly better.

Bladder Cancer
Mechanism in Bladder Cancer 2000
Ukrain prevents active free amino acid transport into urinary bladder tumor tissue, inhibiting the activities of protein biosynthesis, gluconeogenesis and energy production. The combined decrease in Glutamine and Leucine levels in urinary bladder tumor tissue is a specific sign of the antitumor effect of Ukrain and a mechanism of its cancerostatic action by controlling the processes of amino acid pool formation in the tumor.

Ukrain in Bladder Cancer 1998
28 patients with relatively small bladder cancer tumors were divided in three groups. The first group was treated with a total dose of 100 mg Ukrain, the second group received 200 mg Ukrain, and the third group was treated with 300 mg Ukrain. In all patients Ukrain was administered i.v. at a dose of 10 mg per day. Ukrain, at a total dose from 100-300 mg as neoadjuvant therapy in patients with T1N0M0 bladder cancer, resulted in either complete or partial regression of tumors in 60.7 +/- 9.2% of cases. The best treatment regime included three courses of Ukrain at 2-week intervals.

Prostate Cancer
Prostate Cancer 2000
15 patients with newly diagnosed prostate cancer received Ukrain at a total dose of 100 mg After two to three injections of Ukrain, all the patients noted considerable subjective improvements in their state. Ukrain increased the amount of total T-lymphocytes, including "active" T-lymphocytes, decreased the content of T-suppressors and increased that of T helpers, correspondingly raising the T helper/T-suppressor ratio.

Colorectal Cancer
Rectal Cancer 1998
48 patients suffering from rectum cancer were included in a randomized study were 24 patients received an intensive course of X-ray therapy together with chemotherapy with 5-fluorouracil before operation. The 24 patients in group II were treated with Ukrain as monotherapy, 10 mg each second day before operation and a total of 40 mg after surgical intervention. Repeated Ukrain courses were also given 6 months after surgical operation. Recurrence were found to have developed 14 months later in six patients in group I 25.0%, 8.3% in group II.

Colorectal Cancer 1996
96 patients with colorectal carcinomas were included in a randomised study. 48 patients were treated with UKRAIN (15 of them with metastasising and 33 with non-metastasising colorectal tumours) and 48 patients were treated with the chemotherapeutic drug 5-FU and radiotherapy. The survival rate after 21 months was 78% in the group treated with UKRAIN and 33% in the group treated with 5-FU and radiotherapy.

Lung Cancer
Lung Cancer 1992
Lymphocyte subsets were evaluated in nine men (aged 42-68 years, mean 57 years) with histologically proven lung cancer, previously untreated. Ukrain was applied as an intravenous injection every three days. One course consisted of 10 applications of 10 mg each. The results showed a restoration of cellular immunity that was accompanied by an improvement in the clinical course of the disease. This effect was particularly pronounced in patients who responded to
further chemotherapy. Objective tumour regression (CR+PR) was seen in 44.4% of
treated patients. Four out of nine patients (44.4%) died of progressive disease
during the course of this study.

Cervix Cancer
Cervix Cancer 1992
Nine women with a stage IB voluminous uterine cervical cancer received Ukrain before and after operation. Three out of nine eligible cases had partial responses after operation, while six cases remained stable. There were signs of activation of the immune defence. Two patients were treated with adjuvant radiotherapy due to lymphatic involvement and all nine patients were still alive at least six months after follow-up.

Meta-analysis
Ernst ans Schmid 2005
Ernst et al. searched for all relevant randomised clinical trials Ukrain .
Seven trials met the inclusion criterias. Without exception, their findings suggest that Ukrain has curative effects on a range of cancers. However, the methodological quality of most studies was considered poor. In addition, the interpretation of several trials was impeded by other problems. The data from randomised clinical trials suggest Ukrain to have potential as an anticancer drug. However, they meant that numerous caveats prevented a positive conclusion, and that independent rigorous studies are urgently needed

Case Reports
Kidney Cancer with Liver metastasis from 2000
A 52-year-old man with renal cell carcinoma was treated with surgery and chemotherapy (vinblastine). Ukrain was administered after tumor progression to the vena cava inferior and appearance of liver metastasis. The drug induced a complete remission, which has lasted 32 months since the first therapy course.

Synovial Sarcoma from 2000
A 23-year-old woman, diagnosed with a synovial sarcoma of the peritoneum, underwent an operation for tumor extraction, and got Ukrain afterwards. Nearly 4 years after Ukrain therapy, the patient is in complete remission.

Breast Cancer from 2000
A 50-year-old female patient with breast cancer (stage IV) was treated with Ukrain because of the impossibility of radiotherapy and chemotherapy. Ukrain facilitated the surgeon in performing an operation to remove the primary tumor as well as the metastatic lymph nodes. After the second and third courses of Ukrain, the patient demonstrated clinical remission.

Case Series from 2000
A total of 203 advanced-stage cancer patients suffering from different types of cancer who had exhausted all conventional forms of therapy were treated with the Ukrain. Forty-one patients (20.2%) achieved total remission, 122 (60.1%) partial remission and only 40 (19.7%) did not respond to treatment.

Treatment of Kaposis Sarcoma and AIDS from 1996
Two case reports are presented of therapy with Ukrain for the treatment of AIDS patients with Kaposi's sarcoma. During treatment the Kaposi's sarcoma lesions diminished in size, showed decolouration and no lesion appeared in the 30-day interval after the beginning of treatment. Both patients tolerated Ukrain well and showed an improved immunohaematological status: an increase in total leukocytes, T-lymphocytes and T-suppressor numbers. In one case T-helper lymphocytes were also increased.

Treatment of Astrocytoma from 1996
Ukrain, a semisynthetic thiophosphoric acid compound of alkaloid chelidonine from Chelidonium majus L. (1) causes regression of various tumours. Among other effects, its action seems to depend on the stimulation of the immune system which very often is deficient in cancer patients. Its use in a patient with subtotal extirpation of a frontal anaplastic grade III astrocytoma seems to have reduced growth speed significantly

Urethral Carcinoma from 1996
In a patient with low grade differentiated urethral carcinoma (histologically: urothelial carcinoma G2 and G3, pT1 with low grade differentiation) operation was carried out, with recurrence after two months. Instead of reoperation the patient was given Ukrain as monotherapy. No carcinoma was detected four months later by histological examination or during examinations three years later.

Oesophageal carcinoma from 1996
A poorly differentiated squamous cell oesophageal carcinoma was diagnosed in a patient after an 11 month history of difficulty in swallowing. The condition was inoperable according to clinical and X-ray contrast examinations. Radiation therapy with three courses of chemotherapy was carried out, but no amelioration was obtained. Ukrain therapy (course of 46 ampoules) was undertaken; this changed the situation entirely: all the subjective problems disappeared and no residual cancer was seen on the X-rays. Complete remission is seen nearly four years after Ukrain therapy.

Ovary cancer from 1996
A patient with adenocarcinoma in the right ovary with lymphangitis carcinomatosa, staged as G II-G III pT3, pNX, pMX, was treated after palliative surgery by chemotherapy and, simultaneously, with Ukrain. Two and a half years after treatment the patient is without any signs of tumour recurrence.

Cervix cancer from 1996
A grade IV cervical cancer was treated with endocervical cone biopsy (electrocoagulation) in a 28 year-old lady. Three years later examination revealed cervical carcinoma in situ and a conization was recommended, which the patient refused. She was treated with Ukrain instead. The grading regressed steadily and after one year of Ukrain therapy all stagings were normal. Three years after the start of Ukrain therapy she gave birth to a healthy child. Eight years later she has no recurrence and is healthy.

Breast Cancer from 1996
A patient with breast cancer who was not previously given any therapy before receiving Ukrain had a full clinical remission with 12 years without any oncopathological symptoms.

Breast Cancer with lung metastasis from 1996
A recurrent breast cancer with lung metastases was treated with the new anticancer drug Ukrain. Lymph nodes and lung metastases disappeared. The patient showed a full clinical remission.

Rhabdomyosarcoma from 1996
A six year old child was diagnosed to have a rhabdomyosarcoma of the muscles of the right buttock. Because of impossibility of radiotherapy and chemotherapy, treatment with Ukrain 10 mg i.v. once every two days, 10 injections (100 mg) was instituted. The following clinical effects were recorded: reduced pain in joints, improved appetite and condition, increased physical activity, reduced fever.

Malignant Melanoma from 1996
A patient with a metastasizing malignant melanoma (stage III) was treated with Ukrain monotherapy. Before and during the first Ukrain course of treatment the patient excreted melanin in the urine. After the third course melanin was no more detectable and the patient has been without any symptoms of disease for the last 12 years.
A female patient was treated for a metastatic malignant melanoma. She was treated chemotherapeutically, with interferon, and surgically. After recurrence two years later the chemotherapy regime was changed and Ukrain therapy was administered between the chemotherapy series. The patients multiple metastases in the lungs and a complete remission which lasted at least more than one year was achieved.

Case Series from 1992 with sedative and anti-allergic effects
Preliminary clinical observations and studies on immunological
response-indicators were made in eight patients with malignant tumours, who had been administered parenteral injections of Ukrain. The results suggest that the preparation is a non-toxic immunostimulator inducing production of thymodependent
T lymphocytes. The preparation improves general health of patients, has anti-allergic action, and sedative and anti-inflammatory effects. It can inhibit growth of malignant tumours.

Case Series from 1992, II
Thirty six stage III cancer patients were treated with Ukrain injected intravenously every second day in a dose of 10 mg per
injection. Each patient received 300 mg of the drug (30 injections). The results obtained indicate that Ukrain, in a concentration not cytostatic in normal cells, is cytostatic for malignant ones, and may suppress
the growth of cancer. The compound also has immunoregulatory properties,
regulating the T lymphocyte subsets

Case Reports from 1992
More than 400 documented patients with various cancer types have been treated with Ukrain.The authors report on a 9 year old girl with "untreatable" Ewing Sarcoma, a 58 year old woman with colon cancer with lymph node metastasis and a 69 year women with breast cancer with skeleton metastasis. All were treated with Ukrain with complete remission lasting at least several years as a result.
Case Reports from 1991
Twenty-seven patients with various malignancies were treated with
Ukrain.The study showed an activation of the immune defence in the treated patients as well as a favourable course of their disease and in general well-being.

Other Publications
Debate in the Lancet about how to set up a phase II study 2000-2001
Two english researchers proposed to set up a phase II study on 8 different cancer types with 15 patients in each group testing the effect of ukrain. They claim that the manufacturer of Ukrain, Nowicky pharma refused to participate in this project unless the made a dose finding study on pancreatic cancer instead. One of the issues would be who would fund an independent investigation comittee. The english researchers suspect accuse Nowicky pharma of being afraid performing an objective evaluartion. In the end both sides publicly agreed that tehy want to perform the investifation, but we are still waiting for it the investigation to happen....

Treatment of Hepatitis C
Ukrain can be used in the treatment of Chronic hepatitis C, alone or in combination with Interferon, preparations; in the cases with Hepatit C Virus genotype 1b, Ukrain seems more promising than IFN. Individual therapy with Ukrain and IFN increased the efficacy of treatment 2.5-fold in comparison with standard monotherapy with the same preparations, significantly decreased the number of side effects and dramatically improved cost-effectiveness.

Ukrain in healthy volunteers 1992
Phase I of a clinical study of Ukrain was performed in 19 healthy outpatient volunteers. During the intramuscular injections the volunteers felt only localized pain; some reported drowsiness, increased thirst and polyurea. There was a slight, insignificant increase in body temperature and negligible decrease of blood pressure in some cases. In conclusion, it can be said that Ukrain is well tolerated in healthy volunteers in the doses of 5, 10, 20, and 50 mg/injection, even during prolonged (up to three years) administration.

Phase II trial from 1992
70 patients, ranging in age from 14 to 80 years, were given Ukrain to determine the appropriate dose range for
and the clarification of dose/response relationships, in order to provide
an optimal background for wider therapeutic trials. The patients were treated with different dosages and with different dosage intervals. All patients were at terminal stages of their disease.

Therapeutic Substance(s): 
Therapeutic intervention: 

Pre-Clinical Investigations on Ukrain

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Here you can Publish Data on Pre-Clinical Investigations on Ukrain by clicking on "Add child page" below.

Effect on Glioblastoma
Glioblastoma is a very dangerous brain tumor with small chances of survival. Ukrain modulates the activation of certain genes and proteins involved in tumor invasion. After treatment with high dose Ukrain, the concentration of the so-called glial fibrillary acidic protein increased within the cancer cells. There was no effect on the Connexin 43 protein. Ukrain-induced programmed cancer cell death(Apoptosis) were in 4.63 % in low concentration, 10.9 % at medium concentration and 28.9% in high concentration. The Apoptosis was likely to be mediated by release of the substance cytochrome c in the cell cytoplasm(Cell fluids).

Stimulation of immune defence
Ukrain stimulates the immune defence and has cell killing and growth inhibition effects on various cancer cells. Ukrain induced programmed cancer cell death in womb cancer cells cultures by activating the so-called intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B.

Active Substance?
Habermehl with co-workers found Ukrain to be a potent inducer of apoptosis. However, mass spectrometric analysis of Ukrain failed to detect the suggested Ukrain molecule that has been postulated yto mediate the effect of Ukrain. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain.
The potent proapoptotic effects of Ukrain seems not to be due to the suggested "Ukrain-molecule" but to the cytotoxic efficacy of Chelidonium majus L. alkaloids including chelidonine.Panzer[/b]] with co-researchers also made a study, were
chemical analyses of Ukrain by thin layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry failed to demonstrate the proposed trimeric structure of Ukrain.

Ewing tumors
Using the MTT assay, the cytotoxicity of Ukrain was compared with the cytotoxicity of Chelidonium majus L. alkaloids, and the cancer drugs thiothepa, doxorubicin, cyclophosphamide and etoposide against four human [url=Ewing tumor cell cultures. The sensitivity profile of Ukrain was comparable to that of the C. majus L. alkaloids, and different from that of thioTEPA, cyclophosphamide, etoposide and doxorubicin. This indicates that ukrain might be of use in the treatment of Ewing tumors.

Antidepressant ant anti-dementia effect?
Chelidomium Majus alkaloids, Ukrain and the pharmaceutical compound Sanguirythrine seems to diminish the breakdown of the Neurotransmitters Serotonin and Acetylcholin. This could be a theorethical explanation to the many reported about better mood and concentration ability when taking Ukrain, as this is typical actions for antidepressants and anti dementia medicines.

MAO-inhibiting effect
It has been shown that the major alkaloids from plants Chelidonium majus L. and Macleaya (Bocconia) are irreversible inhibitors of oxidative deamination reaction of serotonin and tyramine as substrates, catalyzed by rat liver mitochondrial monoamine oxidase (MAO). Among the examined agents, alkaloid chelidonine and drug "Ukrain" were the strongest inhibitors of the reaction. As it is well known, the MAO inhibitors appear to be, as a rule, pronounced antidepressants. The combination of malignotoxicity and antidepressive activity in drug "Ukrain" seems to be favourable for its clinical applications.

Resistance to ionizing radiation
This studydata give the first mechanistic insights into specific cellular resistance mechanisms behind the cytotoxic and radiosensitivity-modifying effects of the drug Ukrain by showing that fibronectin and laminin increase resistance to ionizing radiation and the cytotoxic drug Ukrain in human tumour and normal cells in vitro.

Radioprotective properties on normal cells, but not on cancer cells.
Exponentially growing human tumour cell lines from breast, pancreas, colorectal, glioblastoma, and human skin and lung fibroblastic cells when exposed to Ukrain and radiation,
Ukrain cytotoxicity was time- and dose-dependent. The combination of Ukrain plus radiation gave enhanced toxicity in colorectal cancer and glioblastoma cells, but not in breast cancer and pancreatic cancer cells. Most strikingly, Ukrain managed to protect normal skin and lung cells from the harmful effects of radiation.

Effect on alcohol dehydregonase
Ukrain seems to inhibit the enzyme thay breaks down alcohol. This means that there is reason to be careful when combining alcohol and Ukrain.

induktion of apoptosis
The induction of apoptosis by Ukrain was studied in Chinese hamster ovary cells. Ukrain was found to be capable of the in vitro induction of apoptosis in the cell lines studied. The effect was less expressed in cells with multiple drug resistance. Ukrain enhanced the effects of etoposide, i.e., the combined effect of both agents was evident at significantly reduced concentrations. This suggests that pharmacological compositions of the drugs may reduce the effective doses used in chemotherapy and thus significantly diminish its toxic side effects.

Exposure of a prostate cancer cells culture to Ukrain resulted in cell growth inhibition which is concomitant with apoptosis. After 24 h treatment with 3.5 microM of Ukrain as many as 73% cells were found in a state of beginning apoptosis. The rate of apoptotic cells rose steadily with increased drug concentration in a dose-dependent manner and reached 20% at a dosage of 17.5 microM.

A method for determination of Ukrain in blood plasma
the main fluorescent component of Ukrain was determined by liquid chromatography . Ukrain was resolved from fluorescent peaks of the sum of alkaloids of Chelidonium majus L. although several peaks of alkaloids were retained in Ukrain as traces. The height of the main peak was nearly constant, while the alkaloid peaks varied depending on the series of the preparation; chelidonine and ThioTEPA gave no peaks. Ukrain possesses neither significant stable binding to plasma proteins nor adsorption in blood cells.

Acute toxicity in rats
The acute toxicity of Ukrain was determined after a single intravenous, intramuscular or oral administration in rats. It was found that the intravenous LD50 was greater than 43 mg active ingredient/kg body weight in the males and 76 mg active ingredient/kg body weight in the females. . In both sexes the intramuscular LD50 was greater than 165 mg active ingredient/kg body weight.

Selective toxicity for cancer cells
Ukrain selectively inhibits growth of ME180 and A431 cancer cells at a concentration range from 3.5 microM to 7.0 microM and induces apoptosis. In contrast, normal human skin cells showed no damaging effect of Ukrain.
Exposure of cultured carcinoma cells to Ukrain resulted in cell growth inhibition and apoptosis at doses as low as 7 microM. In contrast, the same drug concentrations were not affective towards normal human keratinocytes. In order to investigate whether cell cycle control mechanisms are effected in response to Ukrain, we analyzed cell cycle distribution and levels of cyclins and cyclin-dependent kinases in drug treated carcinoma cells. We found alterations in levels of mitotic cyclins A and B1, and cyclin-dependent kinases CDK1 and CDK2, after treatment. We also observed an upregulation of CDK inhibitor p27 in both cancer cell lines which may lead to the G2/M cells accumulation, which in turn leads to apoptosis.

Selective cytotoxic effect on cancer cells
The inhibitory effect of Ukrain on malignant cells and on normal cells, in vitro,
has been compared. To obtain a 50% inhibition of cell growth, a tenfold
concentration had to be used with normal endothelial cells compared to a human
osteosarcoma cell line. A laser scanning microscope showed a high uptake of
Ukrain in malignant cells, while the content in normal cells under the same
experimental conditions was substantially lower.

No selective toxicity for Chelidonine
Chelidonine is one of the major alkaoids found in Greater Celandine.
The effects of chelidonine in two normal (monkey kidney and Hs27), two transformed (Vero and Graham 293) and two malignant (WHCO5 and HeLa) cell lines, were examined. Chelidonine proved to be a weak inhibitor of cell growth, but no evidence for selective cytotoxicity was found in this study.

No selective toxicity for Ukrain?
Ukrain is alleged to be an effective chemotherapeutic drug which causes minimal side-effects as a result of selective toxicity towards malignant cells only. Panzer previously failed to confirm this claim and found Ukrain to be equally toxic to normal, transformed and malignant cell lines by causing a metaphase arrest. In this study Panzer have found the antimitotic actions of Ukrain to be reversible in low doses in vitro. He hypothesizes that the lack of side-effects found in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling normal cells to overcome the metaphase arrest and survive.

In vitro effect on multiple tumors
A comparative in vitro study between the effects of Ukrain and antitumor drugs cyclophosphamid and cisplatin on total thiol content in Guerin carcinoma, Guerin/cis-DDP carcinoma, and in animal livers was carried out. The cancer cell cytotoxicity of Ukrain was found similar to that of known antitumor drugs.

Effect of Glucose, succinate and temperature on Ukrain activity
The influence of glucose, succinate, and the pH of the medium on the cytotoxic activity of the preparation Ukrain was studied. It was established that glucose (5 mmol) reduces the cytotoxic activity of Ukrain, while succinate (5 mmol) increases it. The activity of the preparation was practically absent at pH 6.1-6.7 of the incubation medium and was at a maximum at pH 7.3-8.0. A temperature of 41.5 degrees C has no influence on the effectiveness of Ukrain.

Therapeutic Substance(s): 
Disease(s): 

Ukrain: Debated Subjects

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There are many viewpoints of Ukrain, and this is the place were you really can find out what you believe is the truth by turning all the coins and looking at all the arguments.
The Main subjets of debate have been

1. What is the active substance of Ukrain?

2. Do Nowicky Pharma refuse to participate in independent evaluations?

3. Has Ukrain been unfairly blocked to obtain license in Austria and the EU?

4. Do Ukrain have selective toxicity for cancer cells?

Therapeutic Substance(s): 
Therapeutic intervention: 
Disease(s): 

Ukrain Debate 1: What is the active Substance of Ukrain?

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This is a debate about the active substance of Ukrain.
Nowicky Pharma firts proposed that the active substance is a trimeric structure, that in later tests by Panzer and Habermehl have been postulated not to be present.
Panzer says that "Chemical analyses of Ukrain by thin layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry was inconsistent with the proposed trimeric structure and demonstrated that at least some commercial preparations of Ukrain consist of a mixture of C. majus alkaloids (including chelidonine)", Habermehl is saying that "mass spectrometric analysis of Ukrain failed to detect the suggested Ukrain molecule that has been postulated yto mediate the effect of Ukrain. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain". Nowicky Pharma, the manufacturer of Ukrain declares in their EMEA Orphan Drug License application: "Chelidonine, like some other celandine alkaloids, is hardly soluble in water. This makes intravenous injections impossible. For this reason drugs derived from celandine alkaloids are always administered only orally. In addition, these drugs cannot accumulate in cancer tissue. Ukrain is a Chelidonium majus L.-thiophosphoric acid derivative, a complex reaction mixture of Chelidonium majus L. alkaloids with triethylene-thiophosphoric acid triamide (Thio- TEPA). The injection solution contains Ukrain in a concentration of 1 mg/ml. No Thio-TEPA or free aziridine ring compounds can be detected. The finished product contains still alkaloids, however, in contrast to the starting material, in a water-soluble, injectable, active form".

Please add your viewpoints on the active substance of Ukrain by clicking on "add child page" below.

Therapeutic Substance(s): 
Therapeutic intervention: 
Disease(s): 

Metformin in the treatment of Cancer

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Metformin in the treatment of Cancer

Cancer cells use more energy(glucose) than normal cells, partly because they divide rapidly, which requires energy, and partly because they use other metabolic pathways to produce energy than normal cells. There fore they also require more insulin, a hormone needed for the incorporation of sugar into cells.

Too much insulin secretion, or hyperinsulinemia adversely affects prognosis in cancer patients and is an independent risk factor for several types of cancer, thus explaining the obesity-cancer association. Insulin can promote cancer through a direct effect on  the body organs acting on the insulin/insulin-like growth factor family of receptors, or indirectly by affecting the levels of other modulators, such as insulin-like growth factors, sex hormones, and adipokines (cytokines  secreted by adipose tissue). Recent evidence indicates that the abnormally high proliferative activity of premalignant and malignant cells requires high levels of nutrients to meet the increased demands for energy consumption and protein biosynthesis. Aberrations of genes involved in the intracellular metabolic pathways, such as the AMPK/LKB1 pathway, thus represent an emerging hallmark of carcinogenesis that is increasingly being recognized as a plausible preventive and therapeutic target for cancer treatment. The AMPK pathway is a central cellular key energy sensor allowing cell division, which is a highly energy-consuming process, only if cells have sufficient metabolic resources. The AMPK  pathway is also activated by weight loss and physical activity.

Metformin is the drug of choice for the management of type 2 diabetes mellitus. It improves insulin resistance and glycemic control and can safely be combined with other classes of antidiabetic agents. Its primary action is to inhibit hepatic glucose production through an LKB1/AMPK–mediated mechanism; however, it also improves insulin sensitivity in peripheral tissues. Metformin lowers cardiovascular mortality by 25% compared with other oral diabetic treatments or placebo and was able to reduce the incidence of diabetes in persons at high risk, with beneficial effects persisting for at least 10 years. It has good safety profile and is well tolerated in subjects with normal glycemic levels, with transient nausea and diarrhea being the most evident side effects. Importantly, its cost is extremely low (in the order of a few cents per tablet), thus being easily accessible in clinical practice.

Interest in metformin in cancer prevention and treatment reflects the recent convergence of several areas of research. Exciting preclinical studies have shown that metformin can inhibit the growth of cancer cells both cell culture tests  and animal tests. The recent evidence that metformin results in (a) initiation of an LKB1-mediated AMPK-dependent energy stress response that can adversely affect survival of cancer cell lines and (b) inhibition of cancer related genes and proteins like phosphoinositide 3-kinase/Akt/mTOR has provided a molecular basis for a direct, insulin-independent antitumor effect and strengthened the rationale to evaluate metformin in cancer clinical trials

In a meta-analysis of epidemiologic studies(1) to assess the effect of metformin on cancer incidence and mortality in diabetic patients, eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and less significant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin was associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients.

The observation that metformin was associated with greater risk reduction in specific major cancer killers such as colon, pancreatic, and breast cancer is consistent with the notion that diabetes or elevated insulin and glucose levels play an important role in the development of these tumors and has important clinical research implications. For instance, metformin has been shown to reverse the effects of the high-energy diet on the growth of colon cancer cells and, in a recent pilot clinical trial on 26 nondiabetic patients with a possible precancerous lesion called aberrant crypt foci, metformin at a dose 250 mg/d for 1 month suppressed the mean number of aberrant crypt foci per patient, compared with control/untreated subjects. Moreover, metformin can prevent the promotional effect of high-fat diet on pancreatic carcinogenesis in the hamster and inhibits pancreatic cancer growth in mice.. As for breast cancer, metformin at low doses was shown to inhibit cellular transformation and selectively killed cancer stem cells in four genetically different types of breast cancer(6). Several preclinical trials are currently under way to assess the antiproliferative effect of metformin on malignant, premalignant, and hyperplastic breast cells.

The association of metformin with reduced cancer mortality provides the rationale for the study of metformin in the cancer treatment setting. A recent retrospective study in breast cancer patients showed that diabetic cancer patients treated with metformin and neoadjuvant chemotherapy had a higher pathologic complete response rate than the control groups. A phase III adjuvant trial of metformin is currently being launched by National Cancer Institute Canada and National Cancer Institute United States to assess the efficacy of metformin in reducing breast cancer recurrence in 3,582 women with stage I and II breast cancer (2).

At the European Institute of Oncology, the Division of Cancer Prevention and Genetics is planning to conduct a clinical trial to evaluate the activity of metformin on tumor cell proliferation in breast cancer patients undergoing surgery. It will be a presurgical randomized, double blind, placebo-controlled phase II biomarker trial: 100 histologically confirmed breast cancer patients will be randomly assigned to metformin (850 mg twice/daily) or placebo for 28+7 days till surgery to assess drug activity on tumor proliferation, as measured by Ki-67. The confirmation of the efficacy of metformin on cancer cell proliferation may lead the way to larger chemoprevention clinical trials(4).

Therefore we have recently started to give many of our cancer patients at Humlegården metformin.

 

 References:

  1. Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis.

  2. Metformin in Breast Cancer: Time for Action

  3. Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin.

  4. Is it time to test metformin in breast cancer clinical trials?

  5. Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy.

  6. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission

  7. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study.

  8. Metformin induces unique biological and molecular responses in triple negative breast cancer cells.

 

 

  1. Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis.

  2. Metformin in Breast Cancer: Time for Action

  3. Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin.

  4. Is it time to test metformin in breast cancer clinical trials?

  5. Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy.

  6. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission

  7. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study.

  8. Metformin induces unique biological and molecular responses in triple negative breast cancer cells.

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