ANTITUMOR-ACTIVITY OF OXALIPLATIN IN COMBINATION WITH 5-FLUOROURACIL AND THE THYMIDYLATE SYNTHASE INHIBITOR AG337 IN HUMAN COLON, BREAST AND OVARIAN CANCERS

Oxaliplatin, classical [5-fluorouracil (5-FU)] and non-classical (AG33 7) thymidylate synthase inhibitors have shown promising activity in th e treatment of cancer. This study investigates the cytotoxic effects o f oxaliplatin in combination with 5-FU and AG337 in cultured human col on (HT29, CaCo2), breast (MCF-7, MDA-MB-231) and ovarian (2008) cancer cell lines, and their derived counterparts selected for their resista nce to 5-FU (HT29-5-FU), doxorubicin (MCF-7mdr) or cisplatin (2008C13) . Therapeutic experiments were conducted in mice bearing colon-HT29 xe nografts and in the GR hormone-independent mammary carcinoma model. In vitro, oxaliplatin shows potent cytotoxic activity in colon (IC50 fro m 2.1 +/- 1.1 to 5.9 +/- 1.7 mu M), ovarian (IC50 = 10 +/- 1.6 mu M) a nd breast cancer cells (IC50 from 7.4 +/- 2.7 to 17.9 +/- 7.1 mu M). O xaliplatin was a potent inhibitor of DNA synthesis and bound to cellul ar DNA. Surprisingly, the overall amount of oxaliplatin DNA binding wa s significantly inferior to that induced by isocytotoxic concentration s of cisplatin in HT29 (p=0.026). In vitro, synergistic antiproliferat ive effects were observed when oxaliplatin was added to 5-FU and AG337 . Those synergistic effects of combinations were maintained in colon H T29-5-FU cancer cells. In vivo, 5-FU increased significantly the antit umor activity of oxaliplatin in HT29 xenografts ( p=0.0036), and simil arly 5-FU and AG337 increased the activity of oxaliplatin in the GR tu mor model (p=0.0012). These data may encourage further clinical invest igation of oxaliplatin in combination with classical and non-classical thymidylate synthase inhibitors in the treatment of human cancers.