Characterization of carboplatin-resistant sublines derived from human larynx carcinoma cells

Abstract

In human larynx carcinoma cells, resitance to carboplatin (CBDCA) was induced by continuous five-day exposure of parental lines to the increasing CBDCA concentration in culture medium, reaching the clinical level of 9.23 μg/ml. Three clones were selected and characterized; CBP-3, CBP-6 and CBP-7, CBP-3 clone was 2.0-fold, CBP-6 2.1-fold, and CBP-2 2.9-fold more resistant to carboplatin. The response of these sublines to different cytostatics was compared to the response of the parental cell lines to the same drug. CBP-7 and CBP-6 clones exhibited cross-resitance 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 cloposite (Et), CBP-6 became sensitive and CBP-7 resistant to vinblastine (VBL). Other clones did not change change their sensitivity to cis-DDP, 5-FU, Et or VBL. None of the three clones did alter the sensitivity to mitomycin C, doxorubicin (Dox) or vincristine (VCR). There was no change in the growth rate. Glutathione (GHS) levels were elevated in all three clones, but the increase was significant only for CBP-7 clone. Similarly, the activity of glutathione transferase (GST) was elevated in all clones, but this increase was not significant for CBP-7 clone. The analysis of the c-myc, c-Ha-ras and c-fos genes reveal no change in the c-myc expression, induction of the c-Ha-ras oncogene in CBP-6 and CBP-7 cells, and increased expression of the c-fos in CBP-6 and CBP-7 clones. The cross-resistance profiles, GSH and GST biochemistry and oncogene expression indicate that the acquired resistance to carboplatin is a complex, multifactorial process in these cells.