Inhibition of DNA repair as a means of increasing the antitumor activity of DNA reactive agents.
Inhibition of DNA repair as a means of increasing the antitumor activity of DNA reactive agents.
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DOI：
10.1016/s0169-409x(97)00028-8
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发表时间：
1997-07
影响因子：
16.1
通讯作者：
M. Dolan
中科院分区：
文献类型：
--
作者：
M. Dolan
Chemotherapeutic alkylnitrosoureas (BCNU, CCNU, streptozotocin) and alkyltriazenes (DTIC, temozolomide) produce a cytotoxic lesion at the O6-position of guanine. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase removes damage from the O6-position in a single-step mechanism without co-factors. There is extensive evidence that this protein is one of the most important factors contributing to alkylnitrosourea and alkyltriazene treatment failure. There is an inverse correlation between the level of this protein and the sensitivity of cells to the cytotoxic effects of O6-alkylating agents. Attempts have been made to modulate AGT activity using anti-sense technology, methylating agents, O6-alkylguanines, and O6-benzylguanine analogs. O6-Benzylguanine and its analogs are clearly the most potent direct inactivators of the AGT protein. The mechanism involves O6-benzylguanine acting as a low-molecular weight substrate with transfer of the benzyl group to the cysteine residue within the active site of the repair protein. Pretreatment of cells with non-toxic doses of O6-benzylguanine results in an increase in the sensitivity to O6-alkylating agents. Animal studies revealed that the therapeutic index of BCNU increased when administered in combination with O6-benzylguanine. This drug is currently in phase I clinical trials. Evidence from animal studies indicates that myelosuppression may be the dose-limiting toxicity, thus, efforts are aimed at improving the therapeutic index by the stable expression of O6-benzylguanine-resistant AGT proteins into targeted normal tissue such as bone marrow. The successful modulation of alkyltransferases brings on an exciting new era for alkylnitrosoureas and alkyltriazenes.
