Pretreatment with 5-fluorouracil enhances cytotoxicity and retention of DNA-bound platinum in a cisplatin resistant human ovarian cancer cell line.
A combination of 5-fluorouracil (5-FU) and cisplatin (cis-Diamminedichloroplatinum(II); CDDP) was administered to CDDP-sensitive (A2780) and -resistant (2780CP) human ovarian cancer cell lines in vitro in order to investigate the effects of 5-FU pretreatment on CDDP cytotoxicity, removal of DNA-bound platinum (Pt-DNA) and cellular glutathione (GSH) level. The cells were incubated with various doses of 5-FU for 24 hours, and then exposed to various doses of CDDP after a drug-free interval of 24 hours. Pretreatment with 5-FU (0.5 - 2.0 microg/ml) augmented the cytotoxicity of CDDP in 2780CP cells, but did not affect A2780 cells. 2780CP cells lost 23.0 to 41.9% of their total Pt-DNA determined by flameless atomic absorption spectrophotometry at 6 to 24 hours after exposure to 10.0 microg/ml CDDP alone; nevertheless, 1.0 microg/ml 5-FU pretreatment caused a significant delay in removal of Pt-DNA (3.8, 1.5 and 7.2% at 6, 12 and 24 hours after exposure to CDDP, respectively). At 24 hours after 15.0 microg/ml CDDP exposure, 2780CP cells pretreated with 5-FU lost only 15.7% of their total Pt-DNA, although the platinum removal rate with CDDP alone was 28.4%. The GSH levels in 2780CP cells were similar in the presence or absence of 5-FU pretreatment. These data indicated that 5-FU pretreatment enhances the cytotoxicity of CDDP and reverses CDDP resistance in 2780CP cells and that its mechanism is related to the inhibitory effect of 5-FU on DNA repair, and not to cellular GSH levels.
Tanaka
T
T
Department of Surgery, Kyushu Dental College, Kitakyushu, Japan.
Masuda
H
H
Naito
M
M
Tamai
H
H
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018736:DNA Adducts; D004273:DNA, Neoplasm; C057270:cisplatin-DNA adduct; D005978:Glutathione; D002945:Cisplatin; D005472:Fluorouracil