Potential of O6-methylguanine or O6-benzylguanine in the enhancement of chloroethylnitrosourea cytotoxicity on brain tumours

• Published in: Acta neurochirurgica 1994-01, Vol.128 (1-4), p.13-20
• Main Authors: MINEURA, K, IZUMI, I, WATANABE, K, KOWADA, M, KOHDA, K, IKENAGA, M
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Basal Ganglia - drug effects; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Cell Count; Cell Division - drug effects; Culture Techniques; DNA Repair - drug effects; DNA, Neoplasm - drug effects; Drug Synergism; Glioma - drug therapy; Glioma - pathology; Guanine - analogs & derivatives; Guanine - pharmacology; Male; Medical sciences; Neurology; Nimustine - pharmacology; Nimustine - therapeutic use; Rats; Rats, Wistar; Tumors of the nervous system. Phacomatoses
• ISSN: 0001-6268; 0942-0940
• DOI: 10.1007/BF01400647

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.