Characterizations of irofulven cytotoxicity in combination with cisplatin and oxaliplatin in human colon, breast, and ovarian cancer cells

Purpose: This study assessed the cytotoxic effects of irofulven in combination with oxaliplatin and cisplatin in a panel of human cancer cell lines. Methods: Growth inhibition studies were performed using the human HT29 colon cancer cell line, irofulven-resistant derivative HT29/IF2, breast cancer cell line MCF7, and ovarian cancer line CAOV3. Irofulven–oxaliplatin combinations were compared with irofulven–cisplatin combinations in the same cell lines using similar experimental settings. Cells were exposed for 1 h to irofulven and then for 24 h to oxaliplatin or cisplatin and vice versa. Results: Single agent irofulven displayed cytotoxic effects against human colon HT29 cells, human breast cancer cell lines including MCF7, SKBR3, and ZR-75-1, and human ovarian cancer cell lines CAOV3, OVCAR3, and IGROV1, with OVCAR3 being the most sensitive cancer cell line (IC₅₀: 2.4 μM). In all tested cell lines the oxaliplatin–irofulven combination led to clear evidence of synergistic activity. In HT29 and HT29/IF2, the sequence oxaliplatin followed by irofulven appears to be the most effective whereas in MCF7 cells, irofulven given prior to or simultaneously with oxaliplatin is more effective than the other schedule. The combination displays additive activity toward CAOV3 ovarian cells when irofulven was administered prior to or simultaneously with oxaliplatin and partially synergistic when oxaliplatin was followed by irofulven. In most of the cell lines, the sequence oxaliplatin followed by irofulven appears to be the most effective as compared to other schedules. A combination of irofulven with cisplatin has the same efficacy as with oxaliplatin for the same cell lines. Cell cycle studies show that irofulven increases the proportion of cells in the S phase. Cisplatin–irofulven and oxaliplatin–irofulven combinations block cells in G1/S and potently induce apoptosis. Conclusion: Irofulven displays synergistic antiproliferative and pro-apoptotic effects when combined with oxaliplatin over a broad range of concentrations in human colon and breast cancer cells. Acquired resistance to irofulven has limited impact on the effects of cisplatin–irofulven and oxaliplatin–irofulven combinations. Based on these data, irofulven–oxaliplatin and cisplatin–irofulven combinations will be further explored in clinical trials, favoring the use schedules of oxaliplatin given prior to irofulven in patients with cancer.