CHARACTERIZATION OF CARBOPLATIN-RESISTANT SUBLINES DERIVED FROM HUMANLARYNX-CARCINOMA CELLS

In human larynx carcinoma cells, resistance to carboplatin (CBDCA) was induced by continuous five-day exposure of parental lines to the incr easing CBDCA concentrations in culture medium, reaching the clinical l evel of 9.23 mu g/ml. Three clones were selected and characterized: CB P-3, CBP-6 and CBP-7. CBP-3 clone was 2.0-fold, CBP-6 2.1-fold, and CB P-7 2.9-fold more resistant to carboplatin. The response of these subl ines to different cytostatics was compared to the response of the pare ntal cell lines to the same drug. CBP-7 and CBP-6 clones exhibited cro ss-resistance to cisplatin (cis-DDP), CBP-7 clone became markedly more sensitive and CBP-3 slightly more sensitive to 5-fluorouracil (5-FU), CBP-6 became sensitive to etoposide (Et), CBP-6 became sensitive and CBP-7 resistant to vinblastine (VBL). Other clones did not change chan ge their sensitivity to cls-DDP, 5-FU, Et or VBL. None of the three cl ones did alter the sensitivity to mitomycin C, doxorubicin (Dox) or vi ncristine (VCR). There was no change in the growth rate. Glutathione ( GHS) levels were elevated in all three clones, but the increase was si gnificant only for CBP-7 clone. Similarly, the activity of glutathione transferase (GST) was elevated in all clones, but this increase was n ot significant for CBP-7 clone. The analysis of the of c-myc, c-Ha-ras and c-fos genes reveal no change in the c-myc expression, induction o f the c-Ha-ras oncogene in CBP-6 and CBP-7 cells, and increased expres sion of the c-fos in CBP-6 and CPB-7 clones. The cross-resistance prof iles, GSH and GST biochemistry and oncogene expression indicate that t he acquired resistance to carboplatin is a complex, multifactorial pro cess in these cells.