Collaborative Book on Ukrain

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Here you are invited to take part in writing a collobarative book about Ukrain. If you want to contribute, just go to the appropriate chapter and click on "Add child page".

Introduction

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Ukrain Cancer Therapy Ukrain is an intriguing new anti-cancer therapy now available at IMI. Ukrain is a patented formula, which was developed in 1978 by Dr. Wassyl J. Nowicky, director of the Ukrain Anti-Cancer Institute of Vienna, Austria. Ukrain is a unique combination of a common herb named Greater Celandine (Chelidonium majus L.) and also known as a traditional folk remedy in the 1930s. This herb was found to be effective in some cancer cases, and is key in one of the oldest cytotoxic drugs, Thiotepa. Studies have shown Ukrain increases the oxygen consumption of both normal and malignant cells, but while oxygen consumption normalizes in non-cancerous cells within fifteen minutes, it decreases irreversibly to zero in cancer cells. This effectively kills the cancer cells. This unique combination given intravenously or intramuscularly has been shown to decrease DNA, RNA, and protein synthesis in malignant cells, causing cell death. While Ukrain has shown a strong affinity for killing cancer cells, it does not seem to have this similar toxicity to normal cells. This makes hope that this therapy can become a groundbreaking treatment for cancer. Investigations into the benefits of Ukrain for the treatment for cancer are currently underway in Austria, Canada, France, Germany, the Netherlands, Switzerland, and Thailand.

Ukrain: general information, physical, chemical and biological properties

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Since the first therapeutic use in 1978, Ukrain administered either as neoadjuvant treatment before surgery or as combination therapy or alone has been the subject of numerous experimental and clinical tests. Ukrain is reproducible and always produced as the same compound. It is confirmed chromatographically and in biological tests. Ukrain is a product that results from a reaction of alkaloids from greater celandine with Thio-TEPA in the presence of hydrochloric acid. These two main compounds, greater celandine alkaloids and Thio-TEPA, are approved and clinically widely used. Thio-TEPA is listed in many pharmacopoeia (e.g. UK, France, USA, Japan) and is approved as a cytostatic drug. Chelidonium majus (greater celandine) was first described in the so-called Ebers` papyrus in around 1550 BC and greater celandine extracts have been well known in herbal medicine for more than 3,000 years, in particular for the treatment of skin and gastrointestinal diseases. Chelidonium herba (Schöllkraut) is listed in the “Deutsches Arzneimittelbuch“ (DAB) 10, 2nd Appendix 1993. Greater celandine is used for the production of extracts which are ingredients of many drugs from the groups cholagoga and bile duct therapeutics, for example Aristochol®, Chelidophyt®, Cholagogum N Nattermann®, Cholarist®, Esberigal®, Gallopas® 100, Horvilan®, Panchelidon®, Zettagall® V etc. The active substance of the herbal remedies and extracts are alkaloids. DAB demands for the herbal remedy a minimum content of 0.6% alkaloids estimated as chelidonine (Fulde et al, 1994). Chelidonine is the main alkaloid of greater celandine. 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. The substance is patented: European Patent No. 0083600, US Patent No. 2,670,347. The active substance is a bright yellow crystalline hygroscopic powder which is readily water soluble. The injection solution is a transparent, bright yellow-brown liquid with the aroma of freshly cut grass and a bitter taste. The preparation comes as a sterile 0.1% (1 mg/ml) aqueous injection solution (pH: 3.5 to 6.5) in amber-coloured ampoules of 5 ml, with no excipients. Ukrain is readily soluble in water. Therefore it is possible to inject the drug intravenously without any excipients. It has a very strong affinity to cancer cells and accumulates in cancer cells. This has been proved by autofluorescence, radiography, and HPLC (Nowicky et al, 1988; Hohenwarter et al, 1992; Thakur et al, 1992). The National Cancer Institute (Bethesda, Maryland, USA) has proved that NSC 631570 (this abbreviation was given to Ukrain by the National Cancer Institute) has a completely different effect on malignant cells to Thio-TEPA (NSC 6396) and chelidonine hydrochloride (NSC 406034). For example: 7 • NSC 631570 is least effective [log(TGI) = -3.4] against leukaemia-HL-60(TB) in contrast to chelidonine hydrochloride, which is very effective [log(TGI) = -5.4] and to Thiotepa, which is only moderately effective [log(TGI) = -4.4]. • NSC 631570 is extremely effective [log(TGI) = -5.6] with Non-SmallLung-NCI-H460, chelidonine hydrochloride less effective [log(TGI) = -4.0] and Thiotepa shows very little effect [log(TGI) = -4.5]. • With Colon-SW-620, NSC 631570 is very effective [log(TGI) = -5.2], chelidonine hydrochloride is not effective [log(TGI) = -4.0], and Thiotepa is also not effective [log(TGI) = -4.2]. The profiles of these three different substances show very clearly that their effects on the same cell lines are very different. Results of the National Cancer Institute, Bethesda, USA, Human Cell Line Screen can be seen on the website of the Developmental Therapeutics Program NCI/NIH (National Cancer Institute, National Institute of Health) http://www.dtp.nci.nih.gov/. Until now NSC 631570 has been tested on more than 100 cancer cell lines and revealed malignotoxic action against all of them, including pancreas cancer cell lines, cis-platin resistant cell lines and human tumour xenografts. At the doses at which NSC 631570 kills cancer cells it does not affect healthy cell lines. The concentration of NSC 631570 which is toxic for healthy cells is more than 100 times higher than the concentration lethal for all cancer cell lines. Its therapeutic index is 1250 (Nowicky et al, 1996; Nowicky et al, 1996; Panzer et al. 1998; Roublevskaia et al, 2000; Cordes et al, 2002).

Mechanism of action of Ukrain.

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Mechanism of action of NSC 631570 (Ukrain). In a recent in-vitro study where various pancreatic cancer cell lines were incubated with different concentrations of NSC 631570 and Thio-TEPA and chelidonine, it was found that NSC 631570 and chelidonine lead to a significant accumulation of cells in G2/M phase in all investigated cell lines in concentrations of 0.6 ?g/ml chelidonine or above and 5 ?g/ml NSC 631570 or above. At the same concentrations a significant reduction of proliferation rates after 48 hours was also observed (all cell lines: p < 0.05). In Giemsa stains, a significant accumulation of cells in the prophase was found; fluorescent immuno-histochemistry with antibodies against alpha-tubulin revealed that NSC 631570 and chelidonine lead to a disruption of the microtubule network in the investigated cell lines. Furthermore, it was shown that in in-vitro polymerisation assays NSC 631570 and chelidonine stabilise monomeric tubulin (Ramadani et al, 2001). In another experiment with pancreas cancer cell lines, NSC 631570 (10 ?g/ml) showed a high accumulation of treated cells in the G2/M phase, whereas the apoptosis rate of peripheral mononuclear cells did not show any differences between treated and untreated cells; mitogenstimulated lymphocytes even showed an increased blastogenic response (Ramadani et al, 2000). In another experiment using cancer cell lines A431 and ME180 as well as normal human keratinocytes as control, it was demonstrated that, at concentrations of 7?M NSC 631570, cancer cells but not human keratinocytes accumulate in G2/M phase over a 24 h period. In addition, apoptosis was detected following 48 h treatment (Roublevskaia et al, 2000). Other investigations on the possible mechanism of action of NSC 631570 on malignant cells (K562 leukaemia cells) showed similar results, suggesting that NSC 631570 induces bimodal cell death programmes: First, apoptosis, mediated by quinidine sensitive Ca2+-dependent K+- channels and second, blister cell death, by preventing microtubule formation, thus inducing polyploidy (Liepins et al, 1996). From these experiments it can be concluded that NSC 631570 inhibits the cell cycle progression of pancreatic and other cancer cells in M-phase by stabilising monomeric tubulin, thus being an anti-tubulin drug agent. 8 NSC 631570 also seems to inhibit (reversibly) angiogenesis at relatively low concentrations of 10-50 ?mol, approx. 15-75 ?g/ml (Koshelnick et al, 1998). In vitro tests by the National Cancer Institute (NCI), Bethesda, USA, demonstrated an inhibitory effect of NSC 631570 against all of the 8 colon cancer cell lines tested, at molar concentrations between 10-4.5 and 10-5.5 (corresponding to concentrations between ?7.6 ?g/ml and 76.0 ?g/ml). In contrast, 5-FU barely showed any inhibition of the same cell lines at 100 to 1,000-fold higher concentrations, not achieving lethal effects even at the highest concentration (10-2.5) in contrast to NSC 631570 which is lethal at a concentration of 10-3.5, i.e. ?760 ?g/ml (Nowicky et al, 1992). Dose dependence of in vitro cytotoxic effects against tumour cell lines has also been confirmed independently by other research groups: The European Organisation for Research and Treatment of Cancer (EORTC) found that NSC 631570 was cytotoxic against 5 of 6 colorectal cell lines (human xenografts) at concentrations of 100 ?g/mL (communication from the EORTC, New Drug Development Office, 9. June 1991). Fluoroscopic examinations of malignant cells show that NSC 631570 has a strong affinity to elements of the nuclei of cancer cells but not to normal cells. In a series of experiments with 14 different cell lines of human and animal origin, including normal and cancer cell lines, effects of 4 different doses of NSC 631570 (0.1, 1.0, 10, 100 mcg/ml) on DNA, RNA and protein synthesis was investigated by measuring the incorporation of 3H-labelled thymidine, uridine and leucine (Nowicky et al, 1996). Usually, a dose-dependent inhibition of all anabolic processes, DNA, RNA and protein synthesis was found that was more pronounced in malignant cells than in normal cells, even in those normal cell lines known for fast replication rates. According to the authors, no toxic effects were seen in normal cells treated in doses that are 100% growth inhibitory to cancer cell lines. Tumour tissues from human breast cancer, treated before surgery with NSC 631570 (5 mg i.v. every 2nd day for 20 days, followed by surgery 7-10 days later) show a number of striking changes compared to the untreated tumour of control patients (Brzosko et al, 1996): Histopathological examinations demonstrate that the tumour is surrounded by connective tissue (encapsulated) with massive infiltration by mononuclear cells (mostly lymphocytes and plasma cells). Many neoplastic cells surrounded by inflammatory infiltrates are degenerated, enlarged with vacuolated cytoplasm, undergoing necrosis or already necrotic. Immunfluorescence examinations show connective tissues within the tumour heavily embedded in IgG and the predominance of IgM-positive cells. Mononuclears surrounding and infiltrating the tumour are B-lymphocytes and T-lymphocytes that are almost exclusively CD8-positive. IgM can be found in the cytoplasm and in the nucleus of tumour cells, but also on the surface of the cell membrane; it is particular abundant in necrotic foci, covering all disrupted cell fragments. Due to its autofluorescence, NSC 631570 can also be detected within neoplastic cells. When tissues of ten patients treated with NSC 631570 were examined under the electron microscope, massive changes were again found in comparison to an untreated control group (Uglyanica et al, 1996). Under the influence of NSC 631570 the endoplasmatic reticulum underwent fragmentation, and mitochondria became swollen with the cristae damaged. In addition, the cytoplasm was also swollen with an increased number of lysosomes, phagolysosomes and myelin bodies indicating destruction of cancer cells. Ultrastructures of other cells, however, were not affected. Treatment with NSC 631570 also resulted in a markedly higher number of fibroblasts and extracellular connective fibres as compared to controls. Histochemical examinations demonstrated quantitative changes in the enzyme content, in particular in those enzymes which are key factors in the citrate cycle and therefore in the flow of cell respiration; these enzymes and coenzymes are responsible for the generation and transfer of energy in the form of ATP, e.g., SDH, LDH, NADH. On the other hand, the activity of glucose-6-phosphate-dehydrogenase and acid phosphatase was increased, indicating an enhanced process of destruction of cancer cells. From these observations it may be concluded that NSC 631570 has direct effects on cancer cells in humans as it can be found within the cytoplasma; but also indirect cytotoxic activity via immunological processes, possibly changing the antigenic expression of tumour cells. NSC 631570 has low toxicity. The LD50 in rats after i.v. application is 43 and 76 mg/kg b.w. (males and females respectively), in mice 80 and 68 mg/kg b.w. (Hruby, 2000). NSC 631570 has no cumulative toxicity and is - in cases where no tumour is present – rapidly excreted (Doroshenko et al, 2000). In a 6-month i.v. toxicity study with rabbits (0 - negative control, 0 - negative control recovery, 0.07 - low dose, 0.30 - mid dose, 0.70 - high dose and 0.70 mg NSC 631570 /kg b.w. - high dose recovery, groups of 6 animals each), statistically significant differences between dosed groups and the control group were observed with regard to bone marrow (sternum) with hypocellularity (mid dosed males and females, high dosed males), karyorrhexis (mid dosed males and females), inactive megakaryocytes (high dosed males), pyknosis (mid dosed females), cytolysis (mid dosed males) and with regard to the kidneys with proximal tubuli epithelium degeneration (high dosed males and females). Differences also occurred in white blood cells, with a slight increase of leukocytes, lymphocytes and bands in the high dose group (both sexes) after 4 months. Haematocrit and reticulocytes were also slightly increased in the high dose group. Occasionally, other differences between the groups were observed but can be considered as not medically relevant (ARCS, 2001). Reproduction studies have given no indications of teratogenic, mutagenic or cancerogenic properties of the preparation, even in doses, which were 100 times larger than the therapeutic dose. NSC 631570 does not induce sensitisation and is also not genotoxic (Chlopkiewicz et al, 1992; Wyczolkowska et al, 1992; ARCS, 1999; ARCS, 2000).

Regulatory status and marketing history of Ukrain

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Details of regulatory status and marketing history in non EU countries. NSC 631570 is manufactured from two already approved drugs – Thio-TEPA (USP XXII) and greater celandine alkaloids extract (DAB 10). European Patent No. 0083600, US Patent No. 2,670,347. NSC 631570 has anticancer action and is about 300 times less toxic than Thio-TEPA. Therefore an application for registration of NSC 631570 in Austria was first made in 1976 as a second-line therapy after all conventional treatment modalities had failed. Further in vitro, in vivo, and clinical studies have given a lot of evidence for the anticancer effect of NSC 631570. This was the reason to make a second application in 1986 for registration in Austria for treatment of adenocarcinomas, especially in the colorectal area, mammary, bladder, prostate, ovary, cervix, endometrium, plate epithelial carcinomas, small cell and non-small cell lung cancer, tumours in the head-neck area, testicle carcinomas, sarcomas, malignant melanomas and lymphomas. Similar applications were made in other countries where later NSC 631570 was approved: Belarus (White Russia, 8.1.1995, reg. #1330/95), Ukraine (15.10.1998 and 3.9.2003, reg. #3641), Georgia (5.8.1999, reg. #002861), Turkmenistan (13.4.2000, reg. #0001707), Azerbaijan Republic (5.9.2000, reg. #00267), and Tadshikistan (7.9.2000, reg. #000568) (Information for physicians in Ukrainian and English). 19 years after the application for NSC 631570 was made in Austria, the former Ministry of Health and Customer Protection with the settlement on 2.6.1995 refused my registration application at first time. I have taken the only legal remedy available for me and made a complaint against this settlement to the Supreme Administrative Court. The Supreme Administrative Court granted my appeal with the judgement on 26.2.1996, cancelled the contested settlement because of wrongfulness due to the procedure regulation violation, and ordered the procedure completion. Approximately six years after the cancelling judgement of the Supreme Administrative Court, the next negative settlement was issued on 25.4.2002, which I countered with a complaint on 7.6.2002. Recently, Ukrain has got the orphan drug status for the treatment of pancreatic cancer in Australia (Decision of Therapeutic Goods Administration, Department of Health and Ageing, Australian Government from 8.6.2004) and in the United States of America (Decision of the Office of Orphan Products Development (HF-35), Food and Drug Administration from 20.08.2003, for both documents see Bibliography).

Stage of development

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Description of the stage of development. 1. Summary of the development of the product. Since its first therapeutic use in 1978, NSC 631570 (administered either as neoadjuvant treatment before surgery or as combination therapy or alone) has been the subject of numerous experimental and clinical tests. NSC 631570 is a Chelidonium majus L. - thiophosphoric acid derivative, a complex of Chelidonium majus L.-alkaloids with triethylene-thiophosphoric acid triamide (Thio-TEPA). The injection solution contains NSC 631570 in a concentration of 1 mg/ml (at least 90% Chelidonium majus alkaloid-thiophosphoric acid derivative and a maximum of 10% of free Chelidonium majus alkaloids). NSC 631570 (active substance: Chelidonium majus L. alkaloid-thiophosphoric acid derivate) is readily soluble in water. Therefore it is possible to inject the drug intravenously. It has a very strong affinity to cancer tissue and it accumulates only in cancer cells. This has been proved by autofluorescence as well as by an American research team using a radioisotope method (Nowicky et al, 1988; Hohenwarter et al, 1992; Thakur et al, 1992). The substance is a bright yellow-brown crystalline powder. The injection solution is a transparent, bright yellow-brown liquid with the aroma of freshly cut grass and a bitter taste. The preparation comes as a sterile 0.1% (1 mg/ml) aqueous injection solution (pH: 3.5 to 6.5) in amber-coloured ampoules of 5 ml, with no excipients. Under UV light NSC 631570 shows a yellow-orange autofluorescence. Due to this autofluorescence NSC 631570 can also be easily detected in tissues. Celandine alkaloids and Thio-TEPA are the starting materials used for the production of NSC 631570. The alkaloids are hardly soluble in water. This means that it is not possible to give intravenous injections. For this reason these drugs are always only administered orally. However, by this means of administration the drugs cannot accumulate in cancer tissue. Thio-TEPA is listed in many pharmacopoeia (e.g. UK, Japan, France, USA) and is approved as a cytostatic in Austria. No free Thio-TEPA or aziridine ring compounds can be detected in NSC 631570. Ukrain is therefore definitively different from the starting materials. In vitro activity against cancer cell lines: In vitro tests by the National Cancer Institute (NCI), Bethesda, USA, demonstrated cytotoxic activity of NSC-631570 against all of the 8 colon cancer cell lines tested (pancreatic cell lines were not part of this test program) at molar concentrations between 10-4.5 and 10-5.5 (corresponding to concentrations between ?7.6 ?g/mL and 76.0 ?g/mL). In contrast, 5-FU barely showed any inhibition of the same cell lines at 100 to 1,000-fold higher concentrations, not achieving lethal effects even at the highest concentration (10-2.5), in contrast to NSC- 631570 which is lethal at a concentration of 10-3.5, i.e. ?760 ?g/mL. The experiments also show that the activity profile of NSC-631570 is clearly different from the profile of its basic components thiotepa and chelidonine hydrochloride, both less active in the majority of the 53 cell lines tested. NSC 631570 is produced from alkaloids from greater celandine and Thio-TEPA. These two compounds are approved and clinically widely used. The National Cancer Institute (Bethesda, Maryland, USA) has proved that NSC 631570 has a completely different effect on malignant cells to Thio-TEPA (NSC 6396) and chelidonine hydrochloride (NSC 406034; chelidonine is the main alkaloid of greater celandine and is an ingredient of many oral drugs). For example: 34 • NSC 631570 is least effective [log(TGI) = -3.4] against leukaemia-HL-60(TB) in contrast to chelidonine hydrochloride, which is very effective [log(TGI) = -5.4] and to Thiotepa, which is only moderately effective [log(TGI) = -4.4]. • NSC 631570 is extremely effective [log(TGI) = -5.6] with Non-SmallLung-NCI-H460, chelidonine hydrochloride less effective [log(TGI) = -4.0] and Thiotepa shows very little effect [log(TGI) = -4.5]. • With Colon-SW-620 NSC 631570 is very effective [log(TGI) = -5.2],chelidonine hydrochloride is not effective [log(TGI) = -4.0], and Thiotepa is also not effective [log(TGI) = -4.2]. The enclosed profiles of these three different substances show very clearly that their effects on the same cell lines are very different. Results of the National Cancer Institute, Bethesda, USA, Human Cell Line Screen can be seen on the website of the Developmental Therapeutics Program NCI/NIH (National Cancer Institute, National Institute of Health) http://www.dtp.nci.nih.gov/. In a series of experiments with 14 different cell lines of human and animal origin, including normal and cancer cell lines, the effects of 4 different doses of NSC-631570 (0.1, 1.0, 10, 100mcg/ml) on DNA, RNA and protein synthesis were investigated by measuring the incorporation of 3-H labelled thymidine, uridine and leucine (Nowicky et al, 1996). Usually, a dose-dependent inhibition of all anabolic processes, DNA, RNA and protein synthesis was found that was more pronounced in malignant cells than in normal cells, even in those normal cell lines known for fast replication rates. According to the authors, no toxic effects were seen in normal cells treated in doses that are 100% growth inhibitory to cancer cell lines. Until now NSC 631570 has been tested on more than 100 cancer cell lines and revealed malignotoxic action against all of them, including pancreas cancer cell lines, cis-platin resistant cell lines and human tumour xenografts. At the doses at which NSC 631570 kills cancer cells it does not affect healthy cell lines. The concentration of NSC 631570 which is toxic for healthy cells is more than 100 times higher than the concentration lethal for all cancer cell lines. Its therapeutic index is 1250 (Nowicky et al, 1996; Nowicky et al, 1996; Panzer et al, 1998; Roublevskaia et al, 2000; Cordes et al, 2002). Mechanism of action: NSC-631570, in concentrations between 3.5 and 5 ?M (?2.5 to 5 ?g/ml), causes a dosedependent, reversible arrest of dividing cancer cells (human epidermoid cell lines, American Type Culture Collection A431 and ME180) in the G2/M phase and to apoptosis; normal human keratinocytes serving as controls in this experiment remained largely unaffected (Roublevskaia et al, 2000). These observations could be confirmed in a recent independent experiment with pancreas cancer cell lines (Ramadani et al, publication in preparation). It could be demonstrated that NSC-631570 is a potent mitotic inhibitor, acting through stabilisation of monomeric tubulin. When four different pancreatic cell lines (American Type Culture Collection cell lines AsPC1, BxPC3, MiaPaCa2, Panc1) were incubated with NSC-631570, chelidonine or thiotepa at different concentrations, only NSC-631570 and chelidonine led to a significant dose and time-dependent accumulation of cells in the G2/M phase and to a reduction of the proliferation rates in all cell lines in concentrations of ?5?g/ml NSC-631570, and ?0.6?g/ml chelidonine. It is worth mentioning that NSC-631570 has clearly different physical properties from chelidonine: NSC-631570 is freely soluble in water, whereas chelidonine has very low solubility. 35 NSC 631570 arrests pancreatic cancer cells in prophase via inhibition of tubulin polymerisation. NSC 631570 reduces the proliferation rate and induces apoptosis in pancreatic cancer cells (Gansauge et al, 2001). The Committee for Orphan Medicinal Products (COMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) suggested that Now Pharm AG could establish a biological test procedure for the determination of the biological activity of its product Ukrain (NSC-631570), as confirmation of the stability of Ukrain in addition to the data on its primary structure obtained by chemical, biochemical and physical methods. With this aim a biological test procedure was developed. The experiments and procedures were performed to 1) characterise the effects of Ukrain on pancreatic cancer cells and 2) develop a routine test procedure to ensure comparable biological activity in each new batch of Ukrain. Test criteria were: influence on the cell cycle of pancreatic cancer cells, effect on the proliferation rate of pancreatic cancer cells, inhibition of cell division by mitotic arrest in prophase, disruption of tubulin filaments and inhibition of tubulin polymerization in vitro. All cell lines investigated showed reduced proliferation rates following incubation with NSC-631570 in a time- and dose-dependent manner indicating that NSC-631570 affects replication of these cells. In cell cycle analysis, a G2/M arrest was observed in all cell lines tested, whereas the number of cells in G1 or S phase remained nearly stable. Since the fraction of cells in sub-G1 increased continuously under the influence of NSC-631570, with a time delay to the increase of the G2/M fraction, it was supposed that a significant number of cells undergo apoptosis following G2/M phase without re-entering the G1 phase. In order to further establish this hypothesis, Giemsa stains of the nuclei were performed and indeed a highly significant arrest of cells in the mitotic prophase was observed, indicating that NSC-631570 does not act on DNA- or RNA-levels but is involved in the cell division process. Since many mitotic inhibitors act through interaction with tubulin as the major component of the mitotic spindle apparatus, fluorescence immunostaining with antibodies against tubulin was performed. Disruption of the microtubule network in cells incubated with NSC-631570 was observed. To further clarify how NSC-631570 acts on the formation of microtubules, in vitro polymerization experiments with monomeric tubulin were performed. It was shown that NSC-631570 inhibits GTPdependent and paclitaxel-mediated tubulin polymerization by stabilising monomeric tubulin. The stability and similarity of biological activity of all tested Ukrain batches was absolutely confirmed. In a study “Enhancement of macrophage tumouricidal activity by the alkaloid derivative NSC 631570. In vitro and in vivo studies” by Sotomayor et al. (University of Miami School of Medicine, Miami, Florida, USA, 1992) various doses of NSC 631570 and various routes of administration (intravenous, intraperitoneal, subcutaneous) were tested. The optimal administration route was judged to be intravenous and the optimal dose inducing the best remission was estimated to be 4 ?g per mouse. This dose corresponds to a human single dose of about 7-10 mg for 70 kg body weight (Sotomayor et al, 1992). In vivo activity: Fluorescence microscopic examinations of malignant cells (NSC-631570 has a marked autofluorescence) show that NSC-631570 has a strong affinity to elements of the nuclei of cancer cells but not to those of normal cells. In breast cancer patients treated with a total of 10 injections of 5mg NSC-631570 every second day before mastectomy, NSC-631570 could still be detected in tissues removed 1 week after the last dose. When tissues of breast cancer patients treated with NSC-631570 were examined under the electron microscope, massive changes were found in comparison to an untreated control group (Uglyanica et al., 1996): Under the influence of NSC-631570 the endoplasmatic reticulum underwent fragmentation, and mitochondria became swollen with the cristae 36 damaged. In addition, the cytoplasm was also swollen with an increased number of lysosomes, phagolysosomes and myelin bodies indicating destruction of the cancer cells. Ultrastructures of other cells however were not affected. Treatment with NSC-631570 also resulted in a markedly higher number of fibroblasts and extracellular connective fibres as enzyme content, in particular in those enzymes that are key factors in the Krebs-cycle (tricarboxylic acid cycle) and therefore in the flow of cell-respiration; these enzymes are responsible for the generation and transfer of energy in the form of ATP, e.g., NADH, SDH, LDH. On the other hand, the activity of glucose-6-phosphate-dehydrogenase and acid phosphatase was increased, indicating an enhanced destruction process of cancer cells. Susak (2004) performed a study to define histological features of pancreatic ductal adenocarcinoma after Ukrain administration. Six non-smoking, male, 57±5 years old, patients with histological verified pancreatic ductal adenocarcinoma with localisation in the mid part of the gland were operated on duodenal impassability. All the patients had previously received palliative surgical treatment with subsequent chemotherapy with gemcitabine or 5-fluoruracil. Due to extremely strong adverse events chemotherapy was discontinued. All the patients then received 2±1 courses Ukrain (30 mg weekly, 120 mg per course). The last injection of Ukrain was performed 10-12 hours before the operation. Necrosis areas squares were increased by 50-70% compared with existing previous (before Ukrain administration) stains. Tissue sclerosis was present as well as perivascular that is not common in spontaneous processes in the pancreas. In the sites where parenchymatic elements predominated on stromal necrosis, the areas were especially bright. Microcirculation disorders in the form of perivascular and perineural haemorrhages, tissue infiltration with blood, connective tissue disaggregation, marginal erythrocytes standing and pathological changes of vascular walls were present. The signs of fibrinoid infiltration and percolation of malignant tissues with fibrin is a universal phenomenon in therapeutic pathomorphosis of pancreatic cancer under Ukrain influence that leads to “immuring” of cancer cells and preventing metastasis. Neocollagenogenesis that follows fibrinoid infiltration separate single malignant cells or even little groups of malignant cells leading to their dystrophic changes, for example, impossibility of mucus secretion. The other important feature was tissue prosoplasia – increase of differentiation grade in previously less differentiated malignant cells. This event occurred predominantly in tumours rich in vascularisation and parenchyma elements. From these observations it may be concluded that NSC-631570 has direct effects on cancer cells in humans as it can be found in the cytoplasma but also that it is indirectly cytotoxic via immunological processes, possibly changing the antigenic expression of tumour cells. Increased cell-respiration may be the underlying mechanism of the sensation of heat in the area of tumours reported by many patients after treatment. Toxicity: NSC-631570 has a low acute toxicity. The LD50 in rats after i.v. application is 43 and 76mg/kg b.w. (males and females respectively), in mice 80 and 68 mg/kg b.w. (unpublished report of the Austrian Research Centre, Seibersdorf, Internal study code A-4483, Oct. 1998 and L-0400, May 2000). This is at least 300 times above the usual therapeutic dose in man. NSC-631570 has no cumulative toxicity and is - in cases where no tumour is present – rapidly excreted. In a 6-month i.v. toxicity study with rabbits (0-negative control, 0 -negative control recovery, 0.07 -low dose, 0.30 -mid dose, 0.70 -high dose and 0.70 mg NSC 631570 /kg -high dose recovery, groups of 6 animals each), statistically significant differences between dosed groups and the control group were observed with regard to bone marrow (sternum) with 37 hypocellularity (mid dosed males and females, high dosed males), karyorrhexis (mid dosed males and females), inactive megakaryocytes (high dosed males), pyknosis (mid dosed females), cytolysis (mid dosed males) and with regard to the kidneys with proximal tubuli epithelium degeneration (high dosed males and females). Differences also occurred in white blood cells, with a slight increase of leukocytes, lymphocytes and bands in the high dose group (both sexes) after 4 months. Haematocrit and reticulocytes were also slightly increased in the high dose group. Occasionally, other differences between the groups were observed but can be considered as not medically relevant (Austrian Research Centre Seibersdorf, 2001). As was previously reported by Benninger et al, 1999, greater celandine drugs can lead to toxic liver damage when given per os. Studies were recently performed to detect the possible hepatotoxic activity of Ukrain. In several recent studies Ukrain was demonstrated to be free of hepatotoxicity. In a recent study Ukrain administered at a daily dose of 2 mg/kg to male Wistar rats had a slight activating effect on the drug metabolising enzymes of the liver (Zverinsky et al, 2003). It should also be mentioned that in more than 20 clinical studies performed with Ukrain no signs of toxic effects on the liver were found. Quite the contrary, the compound can be successfully used to protect the liver from toxic damages in the acetaminophen-induced hepatitis model in rats (Levina et al, 2004). The aim of the study performed by Muller (2004) was to examine to potential for Ukrain solution for injection (Ampoule 5 mg/5 ml) to induce hepatotoxicity in the rat. The test substance was administered by intraperitoneal injection to two groups of 5 male and 5 female Sprague-Dawley rats for 5 consecutive days. Injections were made at the same time each day. The doses selected were equivalent to the maximum (0.3 mg/kg/day) and 5 times the maximum (1.5 mg/kg/day) human daily dose. Followed investigations were performed: body weights and body weight gain, observations in life, gross liver pathology, liver histopathology and plasma hepatic enzymes levels. All animals survived until the scheduled termination of the study. Body weights and body weight gain were normal. All animals were normal throughout the study. There were no increases in plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (AP) that were considered treatment-related. Gross liver pathology was normal. Histopathological examination of the liver revealed no lesions considered to be treatment-related. There were no increases in plasma levels hepatic enzymes that were considered treatment-related. There were no treatment-related sex differences. It was concluded that intraperitoneal injection of Ukrain at 0.3 mg/kg/day or 1.5 mg/kg/day for 5 consecutive days did not induce hepatotoxicity in the rat. The aim of the study by Zverinsky (2004) was to compare the effects of thiotepa, greater celandine alkaloids and Ukrain on the morphology of the liver and activity of liver enzymes in rats. Total 88 Wistar rats, weighed 180-220 g were used in the study. Rats were kept on the standard laboratory feed, at natural light and room temperature 23-250?. Animals were divided into 11 groups, 8 animals each, and were treated as follows: I and II – control; III – thiotepa, 3 mg/kg/day, intraperitoneal, for 10 days; IV – alkaloids, 20 mg/kg/day, intraperitoneal, for 10 days; V - alkaloids, 10 mg/kg/day, intraperitoneal, for 10 days; VI – alkaloids, 5 mg/kg/day, intraperitoneal, for 10 days; VII – Ukrain (concentrated) 20 mg/kg/day, intraperitoneal, for 10 days; VIII – Ukrain (ampoules) 10 mg/kg/day, intraperitoneal, for 10 days; IX – Ukrain (ampoules) 5 mg/kg/day, intraperitoneal, for 10 days; X – thiotepa, 11 mg/kg/day, intraperitoneal, for 3 days; XI – thiotepa, 6 mg/kg/day, intraperitoneal, for 3 days. Thiotepa solution as well as celandine alkaloids solution were prepared immediately before administration. The injections was performed daily at noon. The animals were sacrificed 24 hours after the last administration. Blood was sampled. A part of the liver was removed for morphology and biochemistry examination, the remainder was 38 washed out with 1.15% potassium chloride solution. Microsomal and cytosolic fractions were then separated by means of differentiated centrifugation. Activity of acid phosphatase and alkaline phosphatase, triglycerides and total cholesterol, choline esterase activity, thymol test and endogenic intoxication were measured. Administration of thiotepa at a dose of 11 mg/kg body weight for 3 days caused the death of all treated animals on the day 4. Administration of thiotepa at the dose of 6 mg/kg caused the death of all animals on the day 6 or 10. The treatment with thiotepa at all doses caused significant decrease of the body weight. In the group X (thiotepa, 11 mg/kg i.p. for 3 days) total cholesterol, triglycerides and acid phosphatase activity increased by 88, 133 and 196%, respectively (all values p<0.0001). Low molecular tyrosine- and tryptophan-containing peptides increased by 168 and 65%, respectively. Significant decrease in the concentration of reduced glutathione (GSH) by 34% was also revealed. In the groups III and X, superoxide dismutase activity increased significantly compared to the control group. A minor decrease of this enzyme activity was revealed in the group XI. Other parameters did not statistically differ compared to the control group. In the groups treated with celandine alkaloids (5, 10 or 20 mg/kg/day), the most pronounced changes of biochemistry parameters were revealed in the group IV (20 mg/kg/day). The body weight increase was by 36% lesser compared with the control group. Serum choline esterase activity decreased by 38%, indicating the damage to the liver cells. Low molecular tryptophan peptides increased by 43% and GSH decrease was revealed. Serum triglycerides were significantly increased. Superoxide dismutase activity was increased by 36% in the cytosolic liver fraction. All alkaloids treated groups revealed decrease of GSH in the liver and positive thymol test. Thymol test is considered as one of the most sensitive among liver function tests. Such results of the thymol test indicate the damage to the liver cells in the groups treated with alkaloids. Other parameters did not statistically differ from these in the control group. After administration of Ukrain at the doses of 5, 10 or 20 mg for 10 days, superoxide dismutase activity was increased in blood as well as in the liver; GSH was decreased in the liver. the These effects were non-dose-dependent. Other parameters did not statistically differ from the control group. It was concluded, that administration of Ukrain oppositely to thiotepa and alkaloids in similar doses has no hepatotoxic activity. It confirms the previously findings that the drug possesses other pharmacological properties comparing with the start components for its synthesis (see Results of the Ukrain, thiotepa and alkaloids testing at the NCI, Maryland, Bethesda, USA). Reproduction studies have given no indications of teratogenic, mutagenic or cancerogenic properties of the preparation, even in doses, which were 100 times larger than the therapeutic dose. NSC 631570 does not induce sensitisation and is also not genotoxic (Chlopkiewicz et al, 1992; Wyczolkowska et al, 1992; Austrian Research Center Seibersdorf, 1999; Austrian Research Center Seibersdorf, 2000). Pharmacokinetics: In a pilot study, NSC-631570 was administered to 6 healthy men at a dose of 20 mg / 20 ml, undiluted, as a slow intravenous injection; plasma concentration was determined 5, 15, 30, 45, 60, 90, 120, 150, and 180 min after administration, urine was collected over 24 hours. In this study the half life of NSC-631570, t1/2 ??was 27.55?2.45 minutes and the apparent volume of distribution (V) was 27.93?1.38 l. Around 47% of NSC-631570 was found in the urine, more than half of the amount being eliminated during the first 6 hours (Uglyanica, Karavay, Nefyodov, et al., Unpublished report 1999). No significant changes with regard to results of physical examination, laboratory parameters and ECG were reported. 39 Binding to human plasma proteins seems to be insignificant at around 2% (Doroshenko et al., 2000). In another study (Danysz et al, 1992) NSC 631570 was administered to 19 healthy volunteers intramuscularly or intravenously at doses from 5-50 mg every one, two or three days for up to 40 days. In all cases NSC 631570 was generally well tolerated. Some volunteers reported localised pain with a burning sensation during intramuscular injection. The pain disappeared spontaneously after about two minutes. Drowsiness during the day was also reported by some volunteers. There were no notable changes in clinical conditions. All haematological, chemical and urine parameters studied revealed only minimal fluctuations within normal range. Spasmotic and cholagogic actions of the preparation were reported by two volunteers who had mild dyspepsia. During the study period these symptoms disappeared. It is worth emphasising that during the period of NSC 631570 administration, numerous catarrhal and influenza infections were prevalent in the study area. However, no such infections were observed in any of the volunteers taking NSC 631570. A tendency to an increase in the CD4/CD8 cell ratio was noted. After drug administration all volunteers were in good or even better general states of health than before therapy. At the beginning of NSC 631570 administration some volunteers felt slight fatigue, a slight increase in body temperature and increased thirst and enhanced urination. The results of this study showed no evidence that NSC 631570 had any harmful side effects. From animal experiments it may be concluded that NSC-631570 concentrations are highest in tumour tissues (2.84-fold higher than in plasma) followed by normal liver and kidney tissues; the lowest concentration was found in muscles and the brain. NSC-631570 does not significantly cross the blood-brain barrier (Doroshenko et al, 2000). NSC-631570 can be detected in tumour tissues within minutes after i.v. injection and concentrates in the nucleoli of tumour cells; healthy cells remain unaffected. The presence of NSC-631570 in tumour tissues can be demonstrated up to 19 days after injection by means of its autofluorescence under UV light. However, NSC-631570 is rapidly excreted from healthy tissues. No dose-limiting signs of accumulation were observed during repeated injections of NSC- 631570.

Bibliography on Ukrain

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B I B L I O G R A P H Y (1) Nowicky JW. New Immuno-stimulating anti-cancer preparation "Ukrain". 13th International Congress of Chemotherapy, Vienna, 28th August to 2nd September, 57, 1983, PS 12 5 33/A-6, part 288/ (2) Nowicky JW. Cancer Treatment Using Anticancer Preparation Alkaloid Derivative Ukrain. IV Mediterranean Congress of Chemotherapy, 19-25 October 1984, Rhodos, Greece, Chemioterapia, Supplement to n. 2, Volume 4, 1169, April 1985. (3) Nowicky J, Greif M, Hamler F, Hiesmayr W, Staub W. Biological Activity of Ukrain in Vitro and in Vivo. V Mediterranean Congress of Chemotherapy. 26 October-1 November 1986 Cairo, Egypt, Chemioterapia, Supplement to n. 2, Volume 6, 683, June 1987. (4) Nowicky JW, Greif M, Hamler F, Hiesmayr W, Staub W. Macroscopic UV-Marking through Affinity. Journal of Tumor Marker Oncology, Volume 3, Number 4, 463, 1988. (5) Nowicky J, Hiesmayr W, Nowicky W. Sensitisation for Specific Lysis in Target-Effektor-System with Derivatives of Chelidonium majus Alkaloids - Ukrain. Extracted from the Proceedings of the 16th International Congress of Chemotherapy; 852. 1, June 1989, Israel. (6) Nowicky JW. Biological and physiological effects of Ukrain. Journal of Cancer Research and Clinical Oncology, Supplement Vol. 116, A3. 112. 46, 1990. (7) Slesak B, Nowicky JW, Harlozinska A. In vitro effect of thiophosphoric acid derivatives from Chelidonium majus L. on normal lymphocyte subpopulations. Journal of Cancer Research and Clinical Oncology, Supplement Vol. 116, A3. 112. 50,1990. (8) Liepins A. Enhancement of cell mediated lysis of tumor cells by Chelidonium majus L. Alkaloids (Ukrain). Journal of Cancer Research and Clinical Oncology, Supplement Vol. 116, A3. 118. 10, 1990. (9) Nowicky JW, Liepins A, Zbroja-Sontag W, Staniszewski A, Danilos J. Evaluation of clinical studies of Ukrain in cancer patients. Art:Bar.206, Zona:Barcel-fos, 29-Nov-90,09:37:310. (10) Nowicky JW, Staniszewski A, Zbroja-Sontag W, Slesak B, Nowicky W, Hiesmayr W. Evaluation of Thiophosphoric acid alkaloid derivatives from Chelidonium Majus L. (''Ukrain'') as an immunostimulant in patients with Various Carcinomas. Drugs Exptl. Clin. Res., XVII(2) 139, 1991. (11) Nowicky JW, Liepins A, Slesak B, Staniszewski A, Harlozinska-Szmyrka A, Zbroja-Sontag W, Danilos J. Evaluation of clinical studies of Ukrain in cancer patients. Journal of Chemotherapy, Supplement n. 4, 522, 1991. (12) Liepins A, Nowicky JW. Ukrain is Selectively Cytostatic and/or Cytotoxic to Human Tumor and HIV-Infected Cells but not to Human Normal Cells. Recent Advances in Chemotherapy, Anticancer Section, Proceedings of the 17th International Congress of Chemotherapy, Berlin, 2660, 1991. (13) Vatanasapt V, Wongpratoom W, Mairiang P, Mairiang E, Chaiyakam C, Buddhisawasd V, Pairojkul C, Nowicky JW. Preliminary report on clinical experience in the use of Ukrain. Thai Cancer Journal, Volume 17 No. 1-2, 20, 1991. (14) Nowicky JW, Liepins A, Staniszewski A, Slezak B, Nowicky W, Hiesmayr W. The malignotoxic and immune modulating property of the alkaloid derivative Ukrain. Journal of Cancer Research and Clinical Oncology, Suppl. Vol. 118, V1. 09. 05, 1992. (15) Kleinrok Z, Jagiello-Wojtowicz E, Matuszek B, Chodkowska A. Basic Central Pharmacological Properties of Thiophosphoric acid alkaloid derivatives from Chelidonium Majus L. Pol. J. Pharmacol. Pharm., Vol. 44, 227, 1992. 1 (16) Remiszewska M, Wutkiewicz M, Jastrzebski Z, Czyzewska-Szafran H, Danysz A. Pharmacological Effects of Ukrain in Rats and Rabbits. Acta Poloniae Pharmaceutica-Drug Research, Vol. 49 no. 4, 43, 1992. (17) Liepins A, Nowicky JW. Activation of Spleen Cell Lytic Activity by the Alkaloid Thiophophoric Acid Derivative: Ukrain. International Journal of Immunopharmacology, 14, 8, 1437-1442, 1992. (18) Slesak B, Nowicky JW, Harlozinska A. In Vitro Effects of Chelidonium Majus L. Alkaloid Thiophosphoric Acid Conjugates (Ukrain) on the Phenotype of Normal Human Lymphocytes. Drugs Exptl. Clin. Res., XVIII, 17, 1992. (19) Chlopkiewicz B, Marczewska J, Ejchart A, Anuszewska E, Koziorowska J. Evaluation of Mutagenic; Genotoxic and Transforming Properties of Ukrain. Drugs Exptl. Clin. Res., XVIII, 31, 1992. (20) Kleinrok Z, Jagiello-Wojtowicz E, Nowicky JW, Chodkowska A, Feldo M. Interaction between Ukrain and Aminophenazone in Analgesic Test in Rodents. Drugs Exptl. Clin. Res., XVIII, 97, 1992. (21) Musianowycz J, Judmajer F, Manfreda D, Spängler P, Albrecht H, Hoffmann J, Meijer D. Clinical Studies of Ukrain in Terminal Cancer Patients (Phase II). Drugs Exptl. Clin. Res., XVIII, 45, 1992. (22) Danilos J, Zbroja-Sontag W, Baran E, Kurylcio L, Kondratowicz L, Jusiak L. Preliminary studies on the effect of Ukrain (Tris {2-{[5BS-(5BA,6B, 12BA)]-5B,6,7,12B,13,14-hexahydro-13-methyl[1,3] benzodioxolo [5,6-C]-1-3-dioxolo[4,5,-i] phenanthri-dinium-6-ol]-ethaneaminyl} phosphinesulfide.6HCl) on the immunological response in patients with malignant tumours. Drugs Exptl. Clin. Res., XVIII, 55, 1992. (23) Wyczolkowska J, Czuwaj M, Maslinski C. The immunomodulating preparation Ukrain does not induce anaphylactic sensitization in mice and guinea pigs. Drugs Exptl. Clin. Res., XVIII, 35, 1992. (24) Nowicky JW, Manolakis G, Meijer D, Vatanasapt V, Brzosko WJ. Ukrain both as an anticancer and immunoregulatory agent. Drugs Exptl. Clin. Res., XVIII, 51, 1992. (25) Staniszewski A, Slesak B, Kolodziej J, Harlozinska-Szmyrka A, Nowicky JW. Lymphocyte subsets in patients with lung cancer treated with thiophosphoric acid alkaloid derivatives from Chelidonium majus L. (Ukrain). Drugs Exptl. Clin. Res., XVIII, 63, 1992. (26) Sotomayor E, Rao K, Lopez DM, Liepins A. Enhancement of macrophage tumouricidal activity by the alkaloid derivative Ukrain. In vitro and in vivo studies. Drugs Exptl. Clin. Res., XVIII, 5, 1992. (27) Pengsaa P, Wongpratoom W, Vatanasapt V, Udomthavornsuk B, Mairieng E, Tangvorapongchai V, Pesi M, Krusan S, Boonvisoot V, Nowicky JW. The effects of thiophosphoric acid (Ukrain) on cervical cancer, stage IB bulky. Drugs Exptl. Clin. Res., XVIII, 69, 1992. (28) Lohninger A, Hamler F. Chelidonium majus L. (Ukrain) in the treatment of cancer patients. Drugs Exptl. Clin. Res., XVIII, 73, 1992. (29) Kleinrok Z, Jagiello-Wojtowicz E, Nowicky JW, Chodkowska A, Feldo M, Matuszek B. Some pharmacological properties of prolonged administration of Ukrain in rodents. Drugs Exptl. Clin. Res., XVIII, 93, 1992. (30) Juszkiewicz T, Minta M, Wlodarczyk B, Biernacki B. Teratological evaluation of Ukrain in hamsters and rats. Drugs Exptl. Clin. Res., XVIII, 23, 1992. (31) Jagiello-Wojtowicz E, Kleinrok Z, Surmaczynska B, Baran E, Feldo M, Nowicky JW. Effect of single and three months treatment with Ukrain on amino-transferases (ALT and AST) and on the serum protein level in rodents. Drugs Exptl. Clin. Res., XVIII, 85, 1992. 2 (32) Jagiello-Wojtowicz E, Kleinrok Z, Nowicky JW, Matuszek B, Baran E, Surmaczynska B. Effect of single and prolonged administration of Ukrain on prolactin concentration in rats. Drugs Exptl. Clin. Res., XVIII, 89, 1992. (33) Jagiello-Wojtowicz E., Kleinrok Z., Matuszek B., Surmaczynska B., Baran E., Nowicky W., Nowicky J.W. Effect of three months treatment with Ukrain on peripheral blood morphology in rodents. Drugs Exptl. Clin. Res., XVIII, 79, 1992. (34) Jagiello-Wojtowicz E., Kleinrok Z., Feldo M., Chodkowska A., Nowicky J.W. Effect of Ukrain on the efficacy of anti-epileptic drugs against maximal electroshock-induced seizures in mice. Drugs Exptl. Clin. Res., XVIII, 107, 1992. (35) Jagiello-Wojtowicz E., Kleinrok Z., Chodkowska A., Feldo M., Nowicky J.W. Modification of antinociceptive action of morphine by Ukrain in rodents. Drugs Exptl. Clin. Res., XVIII, 101, 1992. (36) Hohenwarter O., Strutzenberger K., Katinger H., Liepins A., Nowicky J.W. Selective inhibition of in vitro cell growth by the anti-tumour drug Ukrain. Drugs Exptl. Clin. Res., XVIII, 1, 1992. (37) Danysz A., Kokoschinegg M., Hamler F. Clinical studies of Ukrain in healthy volunteers (phase I). Drugs Exptl. Clin. Res., XVIII, 39, 1992. (38) Brüller W. Studies concerning the effect of Ukrain in vivo and in vitro. Drugs Exptl. Clin. Res., XVIII, 13, 1992. (39) Nowicky J.W. Biological Properties of Ukrain in Experimental and Clinical Investigations. International Medical Reviews, Avalanche Ltd. St. Petersburg, Russia, 1, 1, 5, 1993. (40) Nowicky J.W., Nowicky W., Liepins A. Cytostatic and cytotoxic effects of Ukrain on malignant cells. VIII Mediterranean Congress of Chemotherapy, 24-29 May 1992, Athens, Greece, Journal of Chemotherapy, Supplement n. 1, Volume 5, 797, 1993. (41) Nowicky J.W. Ukrain Antineoplastic Immunomostimulant. E09/029, NSC-631570, NSC-B238865, UKSR-222, W122, Drugs of the Future, Prous Science Publishers, Copyright Prous Science, 18 (11), 1015, November 1993. (42) Kamyshentsev M.V., Voltchek I.V., Btailovskaya I.V., Leschev A.L., Lavinsky Y.C. and Nowicky J. W. Testing Ukrain as an Anti-Influenza Remedy. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 645, 1993. (43) Liepins A., Sotomayor E. M., Lopez D. M. and J.W. Nowicky. Biological Response-Modifying Properties of the Alkaloid Derivative Ukrain (NSC 631570). Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 783, 1993. (44) Nowicky J. W., Manolakis G., Meijer D., Vatanasapt V., Brzosko W.J. and Lohninger A. Immunological and Tumoricidal Properties of Ukrain. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 793, 1993. (45) Lohninger A., Musianowyc J., Judmaier F., Manfreda D., Spängler P., Albrecht H., Hoffmann J. and Mejer D. Results of Phase II Clinical Studies with Ukrain. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 794, 1993. 3 (46) Voltchek I.V., Nowicky J.W., Zolotukhin N.N., Kamyshentsev M.V., Miroshnichenko A.G., Leschev A.L. and Belskikh A.N. Some Immunohematological Effects of Ukrain. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 798, 1993. (47) Nowicky Jaroslaw W., Markowska Janina and Brzosko Witold J. Ukrain and Natural Killer Cells. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 863, 1993. (48) Zemskov V.S., Yaremchuk O.Ya., Susak Ya.M., Deneka E.R., Kravchenco O.V. and Kamenets L.Ya. Experience of the Application of Ukrain in Oncological Practice in Ukraine. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 870, 1993. (49) Nowicky J.W., Cisak E., Liepins A., Susak Ja.M., Semskow W. Stimulation of phagocytic activity in vitro, in vivo and in the clinic by Ukrain. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 68, April 1994. (50) Kurik M.V., Susak Y.M., Kravchenko O.V. Some biophysical properties of Ukrain. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 79, April 1994. (51) Lisnyak O.I., Lozjuk R. M. Biological activity of some thiophosphamide derivatives of alkaloids with respect to influenza virus. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 96, April 1994. (52) Lozjuk R.M., Lisnyak O.I., Lozjuk L.V. Theoretical grounds and experimental confirmation of antiviral effect of the preparation Ukrain. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 95, April 1994. (53) Brzosko W.J., Graczyk A., Konarski J., Nowicky J.W. Synergic influence of Ukrain and protoporphyrine amino conjugates on human malignant cell lines. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 110, April 1994. (54) Brzosko W.J., Uglianica K., Fomin K., Nowicky J.W. Influence of Ukrain on breast cancers. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 109, April 1994. (55) Zemskov V.S., Susak Ya.M., Zemskov S.V. Ukrain monotheraphy for treatment of colorectal cancer. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 78, April 1994. (56) Liepins A., Nowicky J.W. Selective induction of programmed cell death (apoptosis) in malignant cells by the alkaloid derivative Ukrain (NSC-613570). 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 93, April 1994. 4 (57) Jagiello-Wojtowicz E., Kleinrok Z., Nowicky J., Hodkowska A., Feldo M., Matuszek B., Jablonska M., Gorzelak M. Effect of six month treatment with Ukrain on early osteoporosis induced by ovariectomy in rats. 11th Future Trends in Chemotherapy, Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (Switzerland), Abstracts: abs. 49, April 1994. (58) Nowicky J.W., Wladyslawa Nowicky, Hiesmayr W., Potopalsky A.. Alterations of DNA; RNA and protein synthesis in malignant cells under the influence of Ukrain. XVI International Cancer Congress 1994, 30 October - 5 November 1994, New Delhi, India, abs. PSB 15 -17, 319. (59) Voltchek I. Ukrain - Drug of the Future in the Cancer Treatment? Terra Medica, Nr. 1, 1995, 24 - 25 (in Russian). (60) Ciebiada I., Korczak E., Denys A., Nowicky J. W. Effect of Ukrain preparation on immune response in mice affected by influenza virus. Journal of Chemotherapy, Vol. 7 (Suppl.), n. 4, 1995 101-104. (61) Voltchek I., Kamyshentsev M., Lavinsky Y., Nowicky J., Medvedev Y., Litvinchuk L. Comparative Study of the Cytostatic Effects of Oliphen and Ukrain. Journal of Chemotherapy, Vol. 8 - n. 2, 1996, 144-146. (62) Liepins A., Nowicky J.W., Bustamante J.O., Lam E. Induction of Bimodal Programmed Cell Death in Malignant Cells by the Derivative Ukrain (NSC-631570). Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 1 - 7. (63) Nowicky JW, Hiesmayr W, Nowicky W, Liepins A. Influence of Ukrain on DNA, RNA and Protein Synthesis in Malignant Cells. Drugs Exptl. Clin. Res., XXII (Suppl.), 1996, 9-19. (64) Nowicky J.W., Hiesmayr W., Influence of Ukrain on Human Xenografts in vitro. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 21 - 25. (65) Jin Y.M., Nowicky J.W., Liepins A. Mitogenic Properties of Ukrain (NSC-631570) on Human Peripheral Blood Monocytes: Clinical Implications. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 27 - 30. (66) Liepins A., Nowicky J.W. Modulation of Immune Effector Cell Cytolytic Activity and Tumour Growth Inhibition in vivo by Ukrain (NSC-631570). Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 31 - 42. (67) Susak Y.M., Zemskov V.S., Yaremchuk O.Y., Kravchenko O.B., Yatsyk I.M., Korsh O.B. Comparison of Chemotherapy and X-ray Therapy with Ukrain Monotherapy for Colorectal Cancer. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 43 - 50. (68) Uglanica K.N., Fomin K.A., Nefyodov L.I., Nowicky J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients with Surgically Treated Breast Cancer (Introductory Remarks). Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 51 - 54. (69) Uglanica K.N., Brzosko W.J, Fomin K.A., Nowicky J.W. Influence of Ukrain on Breast Cancer. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 55 - 62. (70) Uglanica K.N., Fomin K.A., Nefyodov L.I., Nowicky J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients with Surgically Treated Breast Cancer. Part I. Clinical and Laboratory Parameters. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 63 - 66. (71) Uglanica K.N., Fomin K.A., Nefyodov L.I., Vilkiewich T.W., Nowicky J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients with Surgically Treated Breast Cancer. Part II. Hormonal Profile. Drugs Exptl. Clin. Res., Vol. XXII (Suppl.), 1996, 67 - 70. 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