The Metabolism of Antineoplastic Triazenes

Abstract

Is there a future for antineoplastic triazenes in the clinic? The answer is probably no as they have been under investigation now for nearly two decades without showing satisfactory promise in the treatment of human malignancies. However, 1-aryl-3,3-dialkyltriazenes are certainly very interesting experimental agents. In particular, studies of their metabolism have furnished a marked contribution to our understanding of the link between xenobiochemistry and biological activity. These studies were mostly conducted in the 60s and 70s and they established clearly that aryldialkyltriazenes require metabolism to exert their antineoplastic and carcinogenic activity (for review see ref. 1). More recently the discovery of the remarkable antineoplastic activity in mice of mitozolomide and related imidazotetrazinones, molecules in which the triazene moiety is part of a ring structure, has led to the studies of their mode of action and their metabolism^2,3. The role which metabolism plays as a determinant of biological activity is less clear for the imidazotetrazinones than in the case of the aryldimethyltriazenes. In this overview the metabolism of antineoplastic aryldimethyltriazenes and imidazotetrazinones is compared. Such a comparison might eventually contribute to the ultimate assessment of the therapeutic benefit of treatment with these agents, if indeed there is one.