Phase I clinical and pharmacokinetic study of oxaliplatin, irinotecan and capecitabine
Oxaliplatin, classical [5-fluorouracil (5-FU)] and non-classical (AG337) thymidylate synthase inhibitors have shown promising activity in the treatment of cancer. This study investigates the cytotoxic effects of oxaliplatin in combination with 5-FU and AG337 in cultured human colon (HT29, CaCo2), breast (MCF-7, MDA-MB-231) and ovarian (2008) cancer cell lines, and their derived counterparts selected for their resistance to 5-FU (HT29-5-FU), doxorubicin (MCF-7mdr) or cisplatin (2008C13). Therapeutic experiments were conducted in mice bearing colon-HT29 xenografts and in the GR hormone-independent mammary carcinoma model. In vitro, oxaliplatin shows potent cytotoxic activity in colon (IC50 from 2.1 +/- 1.1 to 5.9 +/- 1.7 microM), ovarian (IC50 = 10 +/- 1.6 microM) and breast cancer cells (IC50 from 7.4 +/- 2.7 to 17.9 +/- 7.1 microM). Oxaliplatin was a potent inhibitor of DNA synthesis and bound to cellular DNA. Surprisingly, the overall amount of oxaliplatin DNA binding was significantly inferior to that induced by isocytotoxic concentrations of cisplatin in HT29 (p=0.026). In vitro, synergistic antiproliferative effects were observed when oxaliplatin was added to 5-FU and AG337. Those synergistic effects of combinations were maintained in colon HT29-5-FU cancer cells. In vivo, 5-FU increased significantly the antitumor activity of oxaliplatin in HT29 xenografts (p=0.0036), and similarly 5-FU and AG337 increased the activity of oxaliplatin in the GR tumor model (p=0.0012). These data may encourage further clinical investigation of oxaliplatin in combination with classical and non-classical thymidylate synthase inhibitors in the treatment of human cancers.