Inhibition by 5-fluorouracil of cis-diamminedichloroplatinum(II)-induced DNA interstrand cross-link removal in a HST-1 human squamous carcinoma cell line.
To elucidate the mechanism of the synergistic cytotoxicity of 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum(II) (CDDP), we studied the interaction of these agents using a human squamous carcinoma cell line (HST-1). Exposure to 5-FU for 24 h and to CDDP for 1 h produced a 50% inhibitory concentration of 1.0 micrograms/ml (7.7 microM) and 2.5 micrograms/ml (8.3 microM), respectively. The cytotoxic action of CDDP was augmented, and a greater than additive effect was observed when the cells were exposed to 5-FU (1.0 micrograms/ml; 7.7 microM) for 24 h before the CDDP treatment. This synergistic activity was maximal when the interval between 5-FU and CDDP exceeded 24 h. In contrast, the cytotoxicity of CDDP was attenuated when it preceded the exposure to 5-FU. Thymidine did not alter the 5-FU-CDDP interaction. Evaluation of the kinetics of the removal of DNA interstrand cross-links, measured by alkaline elution, showed a significant reduction of this removal in the cells exposed to 5-FU followed by CDDP with a drug-free interval of 48 h, as compared with cells exposed to CDDP alone, or to 5-FU immediately followed by CDDP, although no differences were found in the formation of DNA interstrand cross-links by CDDP among these cells. No significant differences in the accumulation of intracellular platinum were detected by atomic absorption spectrophotometry. These findings suggest that 5-FU modulates the repair of platinum-DNA adducts, thereby potentiating the antitumor activity of CDDP.
Esaki
T
T
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Nakano
S
S
Tatsumoto
T
T
Kuroki-Migita
M
M
Mitsugi
K
K
Nakamura
M
M
Niho
Y
Y
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D013997:Time Factors; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D002945:Cisplatin; D005472:Fluorouracil