Preclinical antitumor and antiangiogenic activity of a metronomic schedule of cisplatin against human transitional cell carcinom

Sub-category: Bladder Cancer

Category: Genitourinary Cancer

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27, 2009 (suppl; abstr e16018)

Abstract No: e16018

Author(s): W. Jian, J. M. Levitt, S. P. Lerner, G. Sonpavde; Baylor College of Medicine, Houston, TX; Baylor College of Medicine, Texas Oncology, Houston, TX

Abstract:

Background: Conventional cisplatin every 3 weeks is frequently precluded in patients with TCC due to renal dysfunction. A metronomic schedule of other chemotherapeutic agents demonstrates anti-angiogenic and anti-tumor activity coupled with better tolerability. A rationale can be made to preclinically evaluate the activity of a metronomic (weekly or 3 days a week) schedule of cisplatin in a preclinical system of TCC.

Methods: The activity of cisplatin was assessed in vitro against HUVECs (human umbilical vein endothelial cells). MTT, flow cytometry with Annexin-FITC and scratch assays were employed to assess proliferation, apoptosis and migration, respectively. The activity of cisplatin was evaluated in vivo in murine xenograft models of TCC. The subcutaneous xenografts included 5 x 10⁶ RT4 or 5637 human TCC cells injected into 6- to 8-week-old female athymic BALB/c nu/nu mice. Cisplatin was administered 4 mg/kg IP (intraperitoneal) weekly for up to 6 weeks and compared with untreated mice. Then, 3 groups of tumor-bearing mice received either no therapy, cisplatin 6 mg/kg weekly or cisplatin 2 mg/kg for 3 days a week for up to 6 weeks. Tumor size is measured twice a week. Nephrotoxicity is assessed by serum creatinine and kidney histopathological examination. IHC (immunohistochemistry) of xenografts is performed to measure proliferation (ki-67), apoptosis (cleaved caspase-3) and angiogenesis (CD31).

Results: Cisplatin demonstrated significant anti-proliferative, anti-migration and pro-apoptotic activity against HUVECs in vitro. Cisplatin 4 mg/kg weekly inhibited tumor growth, induced higher apoptosis and down-regulated angiogenesis and proliferation in vivo compared to controls. Results from the experiment comparing cisplatin 6 mg/kg weekly with 2 mg/kg 3 days a week (i.e. more metronomic, with potentially more anti-angiogenic and anti-tumor activity and less nephrotoxic) will be presented.

Conclusions: A metronomic schedule of cisplatin inhibits tumor growth and demonstrates anti-angiogenic activity in a preclinical model of human TCC. The clinical evaluation of a metronomic schedule of cisplatin may be warranted.