The main objective of the NCDDG is to modulate the DNA repair protein, O6- alkyguanine-DNA alkyltransferase (AGT), in efforts to increase the therapeutic index of alkylnitrosoureas. This program will examine the metabolism of AGT-inactivating analogs with a particular focus on three groups: O6-benzylguanine compounds containing ester linkages, 8- substituted O6-benzylguanine analogs and substituted pyrimidines. The rationale for the choice of ester prodrugs is that these agents are significantly more active upon hydrolysis by esterases which may lead to tumor specificity. The 8-substituted O6-benzylguanine derivatives are highly effective compounds and would be expected to be metabolized much differently than O6-benzylguanine. The rationale for the choice of substituted pyrimidines is that these agents are considerably more potent than O6-benzylguanine in cells and are rapidly cleared making them ideal candidates for regional therapy. More specifically, the objectives of this program are; 1) To determine the rate of hydrolysis of selected esterified O6-benzylguanine analogs in human tumor cell lines and human tissues. 2) To determine the effect of metabolism on AGT-inactivating potency of selected AGT modulators in vitro. 3) To identify rat urinary metabolites of selected analogs. 4) To determine the metabolites of selected analogs in vitro using rat and human liver microsomes and cytosol. 5) To determine the human enzymes responsible for the metabolism of selected compounds. An understanding of the metabolic transformation of an analog would represent an important step towards the rational development of alkyltransferase modulators for neoplastic diseases.
|Gerson, S L; Schupp, J; Liu, L et al. (1999) Leukocyte O6-alkylguanine-DNA alkyltransferase from human donors is uniformly sensitive to O6-benzylguanine. Clin Cancer Res 5:521-4|