Toxicological review of busulfan (Myleran)

Busulfan is a bifunctional alkylating agent that appears to be cytotoxic to slowly proliferating or non-proliferating stem cell compartments, although its specific molecular and cellular mechanisms are unknown. It is the drug of preference in treatment of chronic myelogenous or granulocytic leukemia because its cytotoxic activity results in primary damage or destruction of hematopoietic cells. Additional effects resulting from the cytotoxicity of busulfan in hematological and other tissues, as documented by both human and animal model studies, include lethality, sterility, teratogenicity, and alteration of immune function. Busulfan has been shown to be mutagenic to microorganisms, mammalian cells in culture, Drosophila, and rodents. This agent is also considered potentially carcinogenic to humans. Various tissue hyperplasia and preneoplastic cells have been observed in animal model studies with busulfan, and case reports on human patients implicate busulfan as the causative agent in induction of secondary malignancies. Reports from human and animal studies of busulfan's cytotoxicity, teratogenicity, carcinogenicity, and mutagenicity have been reviewed. This information may be useful in a quantitative assessment of the effects of this agent and the identification of significant deficiencies in the data base. Demonstration that busulfan induces mutations in both somatic and germ cells suggests the need to assess its risk to humans.