Potential of O6-methylguanine or O6-benzylguanine in the enhancement of chloroethylnitrosourea cytotoxicity on brain tumours.
The purine analogues O6-methylguanine and O6-benzylguanine are well-known as a chemical modulator of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Inactivation of the enzyme by O6-methylguanine or O6-benzylguanine is expected to enhance sensitivity of tumours to chloroethylnitrosoureas. We studied the effect of O6-methylguanine or O6-benzylguanine pretreatment on cytotoxicity of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) in brain tumour cells and transplanted brain tumours. Two-hour exposure of O6-methylguanine at higher concentrations (500 microM, 1,000 microM) increased ACNU cytotoxicity by only 2 times in ACNU-resistant C6-1 brain tumour cells. O6-Benzylguanine at concentrations between 10 and 100 microM markedly enhanced the cytotoxic effect. The ACNU sensitivity of the tumour cels pretreated with O6-benzylguanine was 5-40 times that of the cells without O6-benzylguanine. Neither O6-methylguanine nor O6-benzylguanine appreciably enhanced ACNU cytotoxicity of 9 L cells, which were originally sensitive to ACNU. Intracarotid ACNU with O6-methylguanine or O6-benzylguanine decreased proliferating activity of transplanted C6-1 brain tumours significantly during 48 hours. O6-Benzylguanine pretreatment resulted in a greater degree of suppression for a long time. The C6-1 tumours treated only with intracarotid ACNU showed a transient inhibition and a rapid regrowth during 24 hours after the treatment. These results indicate that O6-methylguanine or O6-benzylguanine increases ACNU cytotoxicity and may be feasible for effective combination therapy with chloroethylnitrosourea in the chemotherapy of malignant brain tumours.
Mineura
K
K
Neurosurgical Service, Akita University Hospital, Japan.
Izumi
I
I
Watanabe
K
K
Kowada
M
M
Kohda
K
K
Ikenaga
M
M
D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001479:Basal Ganglia / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D046508:Culture Techniques; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D015376:Nimustine / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C064976:O(6)-benzylguanine; D015376:Nimustine; D006147:Guanine; C008449:O-(6)-methylguanine