Bioactivation and Resistance to Mitomycin C

This chapter analyzes the bioactivation and resistance of tumor cells to mitomycin C (MC). MC is a naturally occurring antibiotic that was isolated originally from the microorganism Streptomyces caspitosus. MC exerts its antitumor activity primarily by damaging DNA through both monofunctional and bifunctional alkylations (cross-links). Numerous studies have employed HPLC separation methods to identify specific MC-DNA lesions associated with MC treatment. Monoalkylations initially occur through the C1 position of MC to the N2 position of aguanine base in DNA and may proceed to form a DNA cross-link through the C10 position of MC to an adjacent DNA guanine at its N2 position. MC-induced cross-links are believed to be primarily responsible for cell death. A single cross-link per genome has been reported to be sufficient to cause the death of a bacterial cell. In this chapter, properties of MC as a prototypic bioreductive agent are described, and mechanism of the reductive activation of MC is elaborated. The chapter presents an overview of MC resistance protein A (MCRA). Mammalian MCRA functional homolog is discussed and rapid screening for DTD activity by using a microtiter assay is discussed. Methodology for the indirect determination of MC activation is also described in the chapter.