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 microM). 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: