Respecting Cancer Drug Transportability: A Basis for Successful Lead Selection

Abstract

Tirapazamine is a prodrug that yields a DNA-directed alkylating agent after activation in hypoxic tumor cells. The basis for its development was its selective activation in that fraction of the tumor cell population that is most refractory to radiation and conventional chemotherapeutics ( 1 ) . Yet the actual level of clinical activity attributable to tirapazamine has been modest ( 2 ) . Therefore, a reexamination of the basis for the drug's action is timely if this general strategy is to be further improved. Recent studies on the mechanisms allowing cancer cells to proliferate and function in a hypoxic environment have led to the conclusion that persistent activation of hypoxia-inducible factor, with the attendant downstream activation of angiogenesis and glycolytic activity, is a crucial difference in behavior of cancer cells compared to normal cells ( 3 ) . Accordingly, strategies for the design of treatments predicated on this difference are of enormous interest.