Bioreductive Prodrugs for Cancer Therapy

This chapter will review a particular class of antitumor prodrugs that are designed to exploit the ability of solid cancers to carry out reductive metabolism. These so-called bioreductive prodrugs are constructed in such a way that metabolic reduction leads to the production of a cytotoxic species which can then damage and kill the malignant cells. Preferential killing of cancer cells can occur in one of two ways or via of the combination of the two. The first involves the fact that the bioreductive metabolism reaction, especially when catalyzed by one-electron reductases, is oxygen sensitive—only occurring in the absence of oxygen. Because many, if not most, solid cancers contain hypoxic tumor cells because of their insufficient and aberrant vasculature, bioreductive drug activation is therefore favored in the malignant tissue. The second mechanism by which tumor selectivity vs normal tissues can be obtained occurs when one or more bioreductive enzymes are overexpressed in the cancer. This is particularly common in the case of the two-electron reductase NQO1 or DT-diaphorase. In this case, bioreductive drug activation may be independent of tumor oxygenation status.