Induction of bleomycin resistance in a human oral squamous carcinoma cell line and characterisation of bleomycin-resistant and -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 and strong heterogeneity in BLM sensitivity, whereas SCCKN was highly sensitive to BLM and showed weak heterogeneity. When SCCTF was treated continuously with low-dose BLM (0.1 microgram/ml) but not intermittently with high-dose BLM (1 microgram/ml), the BLM sensitivity was rapidly decreased to acquire drug resistance. On the other hand, SCCKN was completely killed by the same treatments. To investigate the mechanism of induction of resistance in SCCTF, BLM-sensitive and -resistant clones, TF-S and TF-R, were isolated and analysed. Consequently, TF-R showed decreased cellular accumulation and retention of BLM, increased BLM hydrolase activity and elevated DNA repair activity concomitant with increased poly(ADP-ribose) polymerase activity as compared with TF-S. Therefore, it was suggested that antitumour drug-resistant clones were selectively grown from heterogeneous tumour cell population.
Urade
M
M
Department of Dentistry and Oral Surgery, Hyogo College of Medicine, Japan.
Ogura
T
T
Uematsu
T
T
Takahashi
Y
Y
Kishimoto
H
H
Yoshioka
W
W
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001761:Bleomycin / Q000008:administration & dosage / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013997:Time Factors; D014062:Tongue Neoplasms / Q000188:drug therapy / Q000201:enzymology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001761:Bleomycin; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases; C031262:bleomycin hydrolase