The mitomycin bioreductive antitumor agents: cross-linking and alkylation of DNA as the molecular basis of their activity

Abstract

This review focuses on the chemical and enzymatic aspects of the reductive activation of mitomycin C, its disulfide analogs KW-2149 and BMS-181174, and, in less detail, FR66979 and FR900482, newly discovered antitumor antibiotics related to mitomycins. Furthermore, structural aspects of DNA damage induced by these drugs in vitro and in vivo are described, including the chemical and conformational characteristics of DNA interstrand and intrastrand cross-links and monofunctional alkylation products, with emphasis on DNA adducts of mitomycin C. The DNA sequence specificity of the damage and its mechanism is reviewed. The relationship between the chemical and structural properties of the DNA damage on the one hand, and the antitumor and other biological activities of the mitomycins on the other, is discussed.