INDUCTION OF BLEOMYCIN RESISTANCE IN A HUMAN ORAL SQUAMOUS CARCINOMA CELL-LINE AND CHARACTERIZATION OF BLEOMYCIN-RESISTANT AND BLEOMYCIN-SENSITIVE CLONES

We examined the change of sensitivity to antitumour agents by repeated treatment with bleomycin (BLM) using two oral squamous carcinoma cell lines, SCCTF and SCCKN. SCCTF exhibited minimal sensitivity to BLM an d strong heterogeneity in BLM sensitivity, whereas SCCKN was highly se nsitive to BLM and showed weak heterogeneity. When SCCTF was treated c ontinuously with low-dose BLM (0.1 mu g/ml) but not intermittently wit h high-dose BLM (1 mu g/ml), the BLM sensitivity was rapidly decreased to acquire drug resistance. On the other hand, SCCKN was completely k illed by the same treatments. To investigate the mechanism of inductio n of resistance in SCCTF, BLM-sensitive and -resistant clones, TF-S an d TF-R, were isolated and analysed. Consequently, TF-R showed decrease d cellular accumulation and retention of BLM, increased BLM hydrolase activity and elevated DNA repair activity concomitant with increased p oly(ADP-ribose) polymerase activity as compared with TF-S. Therefore, it was suggested that antitumour drug-resistant clones were selectivel y grown from heterogeneous tumour cell population.