Potentiation of BCNU antitumor efficacy by 9-substituted O 6-benzylguanines. Effect of metabolism

Abstract

Metabolism of BGS and dBG to BG explains the unexpected high efficacy of these compounds in potentiating the antitumor activity of BCNU in the athymic mouse model. The faster and more effective suppression of tumor MGMT by dBG and its greater efficacy, as compared with BGS, also correlates with a more rapid accumulation of BG in blood after dBG than after BGS administration, which results in faster and complete suppression of MGMT in Daov xenografts. Thus, metabolism of dBG and BGS to BG appears to be the determining factor for continuous and prolonged suppression of MGMT activity, and that near complete suppression of such activity during and following BCNU administration is required for the higher efficacy of treatments. Similarly, the failure of CMBG to suppress tumor MGMT to the same extent as BGS, in spite of their similar ED50 values, could be attributed to the metabolism of this compound mainly by pathways other than conversion to BG.

O 6-Benzylguanine suppression of O6-alkylguanine-DNA alkyltransferase in anaplastic gliomas

“…We chose an interval of 6 h from drug infusion to obtaining the specimen since this was in the range of the optimal time course of AGT inhibition in most experimental studies (Kokkinakis et al, 1996). The prior report of BG inhibition of AGT in intracranial tumors used an 18-h interval from drug infusion to tumor resection (Friedman et al, 1998).…”

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

“…The effectiveness of these guanosine derivatives results from their efficient cellular uptake and catabolism into O 6 -BG[79].…”

DNA repair mechanisms protect our genome from carcinogenesis

“…The compound O 6 -benzylguanine (BG), for instance, is a DNA repair inhibitor that inactivates the enzyme MGMT (O 6 -methylguanine-DNA methyltransferase), involved in the removal of alkyl adducts from the O 6 -position of guanine (174). BG and its analogue O 6 -benzyl-2'-deoxyguanosine (dBG) (175) are both capable of potentiating the cytotoxic effects of chloroethylating agents, such as BCNU and CCNU in medulloblastoma tumor xenografts (176,177) and colon carcinoma cells (174). Another study has revealed that BG alone is capable of reducing the volume of pancreatic tumors in mice, besides sensitizing pancreatic cancer cells to gemcitabine (178).…”