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


METHODS
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.
Plasencia
Carmen
C
Medical Oncology Service and Laboratory of Molecular Biology, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
Abad
Albert
A
Martinez-Balibrea
Eva
E
Taron
Miquel
M
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms; D004249:DNA Damage; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D059004:Topoisomerase I Inhibitors; C110525:amminedichloro(2-methylpyridine)platinum(II); D000077146:Irinotecan; D013940:Thymidylate Synthase; D005472:Fluorouracil; D002166:Camptothecin