ISSN:
0942-0940
Keywords:
Brain tumours
;
O6-methylguanine
;
O6-benzylguanine
;
ACNU
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary 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 cytotoxity 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 μM, 1,000 μM) increased ACNU cytotoxicity by only 2 times in ACNU-resistant C6-1 brain tumour cells. O6-Benzylguanine at concentrations between 10 and 100 μM markedly enhanced the cytotoxic effecct. 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-benzylguamne appreciably enhanced ACNU cytotoxicity of 9 L cells, which were origininally 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF01400647
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