Schedule-dependent reversion of acquired cisplatin resistance by 5-fluorouracil in a newly established cisplatin-resistant HST-1 human squamous carcinoma cell line.
In vitro continuous stepwise exposure of HST-1 human squamous carcinoma cell line to cisplatin (CDDP) for 12 months resulted in a 3.5-fold stably resistant subline designated HST-1/CP0.2. Compared with parental cells, this cell line showed a 1.8-fold increase in cellular glutathione (GSH) and a 50% reduction in initial numbers of DNA interstrand cross-links (ICLs), despite similar levels of intracellular platinum accumulation. Evaluation of the kinetics of DNA ICL removal at nearly equivalent levels of DNA ICL formation indicated that HST-1/CP0.2 cells appeared to remove DNA ICLs more rapidly than do HST-1 parental cells. Thus, both elevated cellular GSH and increased DNA repair capacity would be the major factors contributing to CDDP resistance. Pretreatment of HST-1/CP0.2 cells with 5-FU, with drug-free intervals of 24 to 48 hr before exposure to CDDP, completely reversed CDDP resistance, or even increased the sensitivity to a level greater than that of parental cells, whereas the opposite sequence had no effect on resistance. In parallel with augmentation of the cytotoxicity, the levels of cellular GSH were significantly reduced over 48 hr by 5-FU pretreatment. However, depletion of cellular GSH using buthionine sulfoximine resulted in partial reversal of CDDP resistance, indicating that reduction of cellular GSH alone is not sufficient for complete reversal of CDDP resistance. Our data, together with evidence that 5-FU modulates the repair of platinum-DNA cross-links, suggest that schedule-dependent, complete reversal of CDDP resistance by 5-FU might be attributed to its inhibitory effects on both GSH levels and the repair of platinum-DNA adducts. Thus, optimization for the drug administration schedule is important when aiming at therapeutic synergy and circumvention of acquired CDDP resistance.
Esaki
T
T
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Nakano
S
S
Masumoto
N
N
Fujishima
H
H
Niho
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004249:DNA Damage; D004351:Drug Resistance; D005472:Fluorouracil / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005978:Glutathione; D002945:Cisplatin; D005472:Fluorouracil