A comparative study of dimethylhydrazine regioisomers and the methylazoxymethanol metabolite of 1,1- and 1,2-dimethylhydrazine in relation to transformation in human fibroblasts.

Comparative analysis of the cytotoxicity, transformation efficiency, induction of alkali labile sites (ALS) and DNA methylation in human foreskin fibroblasts was carried out with two dimethylhydrazine (DMH) regioisomers (1,1-DMH and 1,2-DMH) and the acetate (A) derivative of the metabolite methylazoxymethanol (MAM) of 1,2-DMH. Effective ED50 cytotoxic doses for MAMA, 1,1-DMH and 1,2-DMH were 0.056, 6.83 and 6.30 mM, respectively. MAMA and 1,1-DMH were more effective transformers than 1,2-DMH. However, methylation of purines accounted for less than 1% of the total radiolabel associated with DNA for all 3 agents. 1,2-DMH, 1,1-DMH and MAMA induced O6MeGua/N7MeGua ratio of 0.04, 0.32 and 0.18, respectively. Only MAMA induced measurable alkali labile lesions at transforming doses. These results suggest that other mechanisms may play a role in the initiation of transformation events by hydrazine analogues.

Bis(bioreductive) alkylating agents: synthesis and biological activity in a nude mouse human carcinoma model.

Chemical investigations leading to the construction of bis(bioreductive) alkylating agents having both conformationally restricted and mobile spacer regions are described. Two targets having the conformationally mobile ethylene spacer group, namely, 2,2'-ethylenebis[6-(hydroxymethyl)-p-benzoquinone] diacetate (3b) and 2,2'-ethylenebis[6-(bromomethyl)-p-benzoquinone] (3c), were studied in vivo and in vitro using an established epithelial/Burkitt lymphoma hybrid cell line (D98/HR1) previously shown to induce carcinomas in nude mice. Inactivity of both test compounds in vitro, the relative resistance of these cells to test drugs in vitro, and the selective antitumor properties of the bis(bromomethyl) analogue in vivo lead to the proposal that this compound undergoes bioreduction to an alkylating species in the hypoxic core of the tumor, thereby exerting its action.