[Reduced cisplatin-uptake by cisplatin-resistant human ovarian cancer cells]

We have developed a human ovarian carcinoma cell line (KFr) which is relatively stable and resistant to cis-diamminedichloroplatinum (cisplatin) after repeated exposure to escalating doses of the drug. This resistant cell line (KFr) was 9.7-fold resistant to carboplatin (JM-8), 8.8-fold resistant to (glycolato-O, O') diammineplatinum (II) (254S), and 7.1-fold resistant to Cis-1, 1-cyclobutanedicarboxylato (2R)-2-methyl-1, 4-butanediammineplatinum (II) (NK121), respectively. The KFr cell line proved to be 3.1-fold resistant to L-phenylalanine mustard (L-PAM). On the other hand, no cross-resistance to vincristine (VCR), 5-fluorouracil (5-FU) and daunomycin (DM) was observed. In addition, we examined the level of platinum in whole cells after 1-16 h exposure to 20 micrograms cisplatin. The parent cell line (KF) took up cisplatin in a time-dependent manner until 4 h. The uptake reached the plateau level after 4 h. On the other hand, the uptake by the KFr cell line reached the plateau level at 1 h-exposure time; after 4 h the uptake was about 1/3 of that by the KF cell line. The release of cisplatin from both cell lines showed a similar pattern, reaching the plateau within the first 30 min. Based upon these results, we assumed that the impairment of transport of influx systems of cisplatin into cells was the mechanism of resistance.