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Enhancing effect of O 6 ‐alkylguanine derivatives on chloroethylnitrosourea cytotoxicity toward tumor cells
Author(s) -
Mineura Katsuyoshi,
Izumi Ichiro,
Watanabe Katsuo,
Kowada Masayoshi,
Kohda Kohfuku,
Koyama KenIch,
Terashima Isamu,
Ikenaga Mituo
Publication year - 1994
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910580515
Subject(s) - guanine , cytotoxicity , hela , methyltransferase , o 6 methylguanine dna methyltransferase , cell culture , chemistry , microbiology and biotechnology , dna , biochemistry , in vitro , cancer research , biology , methylation , nucleotide , genetics , gene
O 6 ‐Alkylguanine derivatives are well known as chemical modulators of the DNA repair enzyme O 6 ‐methylguanine‐DNA methyltransferase (MGMT). Depletion of the enzyme by these derivatives leads to increase sensitivity of tumor ceils to chloroethylnitrosoureas. We tested the effect of O 6 ‐methylguanine, O 6 ‐benzylguanine, O 6 ‐(p‐methylbenzyl)guanine, O 6 ‐( p ‐chlorobenzyl)guanine, O 6 ‐(p‐methoxybenzyl)guanine, O 6 ‐methylhypoxanthine and O 6 ‐benrylhypoxanthine on the sensitivity of tumor cell lines to I‐(4‐amino‐2‐methyl‐5‐pyrimidinyl)methyl‐3‐(2‐chloroethyl)‐3‐nitrosourea hydrochloride (ACNU) using a colorimetric cytotoxicity assay. The sensitivity of MGMT‐proficient tumor cells including HeLa S3, C6‐1, C6‐2/ACNU, U‐138 MG and U‐373 MG cells was greatly enhanced by 2 hr pretreatment of 10‐100 μM O 6 ‐benzylguanine, O 6 ‐( p ‐methylbenzyl)guanine and O 6 ‐( p ‐chlorobenzyl)guanine, but not by O 6 ‐methylguanine or O 6 ‐methylhypoxanthine. O 6 ‐(p‐methoxybenzyl)guanine moderately sensitized the 2 cell lines, HeLa S3 and C6‐1, tested in our study to ACNU cytotoxicity. O 6 ‐Benzylhypoxanthine at the high concentration (100 μM) sensitized, to some extent, 3 MGMT‐proficient cell lines. Lesser degrees of enhancement by the O 6 ‐benzylguanine derivatives were noted in MGMT‐deficient tumor cells. Biological effects of O 6 ‐alkylguanine derivatives on enhancing ACNU cytotoxicity of tumor cells suggest that the exocyclic 2‐amino and O 6 ‐benzyl groups in O 6 ‐benzylguanine skeleton are both essential for the inhibition of MGMT activity.