Enhancement of ACNU cytotoxicity by pretreatment with O6-methylguanine in ACNU-resistant brain tumors.
O6-Methylguanine is a substrate of the DNA repair enzyme O6-methylguanine-DNA methyltransferase, which is involved in the repair mechanism of DNA damage induced by chloroethylnitrosoureas such as 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). We tested the enhancement effect of O6-methylguanine pretreatment on ACNU cytotoxicity in ACNU-resistant brain tumors. Exposure to O6-methylguanine at various times ranging from 2 to 48 hours increased the cytotoxic effects of ACNU on C6-1 cells, and this effect was highest at higher concentrations 500 and 1,000 microM. Colorimetric cytotoxicity assay revealed at least a two-fold increase in ACNU cytotoxicity relative to controls without O6-methylguanine. Intraarterial ACNU after treatment with O6-methylguanine (two intravenous bolus injections of 80 and 40 mg/kg) significantly (P < 0.05 or P < 0.01) reduced the proliferation activity of transplanted C6-1 tumors for 96 hours after injection, whereas intravenous ACNU together with O6-methylguanine significantly (P < 0.05) reduced C6-1 activity for only 48 hours. Thus, pretreatment with O6-methylguanine prolonged the suppression effect of ACNU. The C6-1 tumors treated only with intravenous or intraarterial ACNU showed transient inhibition and rapid regrowth for 24 hours after treatment. These results indicate that O6-methylguanine increases ACNU cytotoxicity in an in vitro and in vivo brain tumor model.
Mineura
K
K
Neurosurgical Service, Akita University Hospital, Japan.
Izumi
I
I
Watanabe
K
K
Kowada
M
M
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003720:Densitometry; D004351:Drug Resistance; D004357:Drug Synergism; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009368:Neoplasm Transplantation; D015376:Nimustine / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013778:Tetrazolium Salts; D013844:Thiazoles; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D013778:Tetrazolium Salts; D013844:Thiazoles; D015376:Nimustine; D006147:Guanine; C008449:O-(6)-methylguanine; C022616:thiazolyl blue; D001973:Bromodeoxyuridine