Dezaguanine mesylate: a new antipurine antimetabolite

3-Deazaguanine (dezaguanine, USAN; CI-908) is a new antipurine antimetabolite which is entering Phase I studies in the USA. This compound differs from guanine only in the substitution of a carbon for the 3-nitrogen of guanine. Dezaguanine has an unusual spectrum of activity against experimental rodent tumors; its activity against transplantable rodent leukemias is only modest, but it has significant activity against transplantable rodent solid tumors, particularly mammary adenocarcinomas. Mammary adenocarcinoma models against which this compound is active include slow and fast-growing tumors, hormone sensitive and hormone insensitive tumors, and the subrenal capsule implanted human breast cancer xenograft, MX-1. Dezaguanine must be converted to its nucleotides to be active. Dezaguanine nucleotides inhibit synthesis of guanine nucleotides, and can be incorporated into nucleic acids in place of guanine nucleotides; incorporation into DNA may be particularly important in the cytotoxicity of this compound. Addition of certain purines or purine nucleosides can prevent dezaguanine cytotoxicity in vitro. Preclinical studies suggest that dezaguanine does not undergo deamination to 3-deazaxanthine, and is not metabolized by xanthine oxidase. Therefore, this compound may not be subject to metabolic inactivation in vivo, and active metabolites may have a prolonged half-life. This concept is supported by the prolonged half-life of radiolabelled dezaguanine in rats. Finally, dezaguanine can cross the blood-brain barrier. In summary, the novel biochemical and experimental antitumor properties of dezaguanine indicate that this compound could have better activity against some human solid tumors than currently used purine antimetabolites.(ABSTRACT TRUNCATED AT 250 WORDS)