ACTIVE EFFLUX SYSTEM FOR CISPLATIN IN CISPLATIN-RESISTANT HUMAN KB CELLS

Mutants, KCP-4 and PC-5, resistant to an anticancer agent, cisplatin, were selected in multiple steps from human epidermoid KB carcinoma cel ls and human prostate PC-3 carcinoma cells, respectively. KCP-4 and PC -5 were 63 and 10 fold more resistant to cisplatin than the parental c ells, respectively. KCP-4 cells exhibited increased resistance to cisp latin analogues and were also slightly cross-resistant to melphalan, c yclophosphamide, mitomycin C and methotrexate. KCP-4 cells were not cr oss-resistant to doxorubicin, daunorubicin, vincristine or CdSO4. The accumulations of cisplatin in KCP-4 cells and PC-5 in medium containin g 50 mu M cisplatin were approximately 20% of those in the parental ce lls. Revertant analysis suggested that a defect in cisplatin accumulat ion may be related to cisplatin resistance in PC-5 cells. The uncoupli ng agent of oxidative phosphorylation, 2,4-dinitrophenol, increased th e accumulation of cisplatin in KCP-4 and cisplatin-resistant human pro state carcinoma PC-5 cells to nearly the same level as in their parent al KB-3-1 and human prostate carcinoma PC-3 cells without 2,4-dinitrop henol, but did not increase accumulation in KB-3-1 and PC-3 cells. Add ition of glucose in the medium inhibited the enhancement of cisplatin accumulation in KCP-4 cells by 2,4-dinitrophenol. Enhanced active effl ux of cisplatin from KCP-4 cells was observed. A cell-cell hybridizati on test showed that the cisplatin resistance and the accumulation defe ct behaved as codominant traits. These data suggest that an active eff lux system for cisplatin exists in cisplatin-resistant KCP-4 cells.