Antiproliferative effects of ZD0473 (AMD473) in combination with 5-Fluorouracil or SN38 in human colorectal cancer cell lines.

摘要

Purpose : ZD0473 (AMD473) [cis-amminedichloro(2-methylpyridine) platinum(II)] is a novel platinum agent of proven activity in vitro against a variety of human tumor-derived cell lines even with intrinsic or acquired resistance to CDDP. The aim of this study is to provide the basis for a rational design of ZD0473-based combination in colon cancer. Experimental design : We evaluated the cytotoxic effect of ZD0473 administered alone or in combination with 5-Fluorouracil (5FU) or SN38 in a panel of sensitive and 5FU-resistant colorectal cell lines (HT29/HT29-5FUR and LoVo/LoVo-5FUR). We analyzed four sequential schedules of administration: ZD0473 --> 5FU, 5FU --> ZD0473, ZD0473 --> SN38 and SN38 --> ZD0473. MTT-assay and isobologram analyses were performed to determine the synergism/antagonism. Results : The pattern of response towards ZD0473, administered as single agent, was similar in all cases and independent of the 5FU-resistance phenotype (IC50 from 48.1 to 76.6 microM) and/or p53 status. No differences in sensitivity to ZD0473 alone or in combination were observed between DNA-mismatch repair-proficient (HT29/HT29-5FUR) and -deficient (LoVo/LoVo-5FUR) cells. ZD0473 administered prior to 5FU leads to synergistic/additive effect in all cell lines, while the 5FU --> ZD047 schedule was only synergistic in HT29 cells. Exposure to ZD0473 prior to SN38 leads to a synergistic/additive schedule in LoVo/LoVo-5FUR cells, while SN38 --> ZD0473 schedule was only synergistic in parental cell lines. Conclusions : The combinations of ZD0473 and 5FU or SN38 have shown to be active in sensitive and 5FU-resistant colorectal cell lines when a correct schedule of administration is applied. These results may be further exploited to promote new schedules of administration for advanced colorectal cancer treatment.