Hypoxic cells as specific drug targets for chemotherapy.

Hypoxic cells exist in solid tumors in regions of poor vascularity and are likely to be exposed to insufficient concentrations of chemotherapeutic agents. Furthermore, because these cells may be cycling very slowly or may be quiescent, they may not be sensitive to agents which are most active in proliferating cells. Under conditions of reoxygenation, hypoxic cells which have survived therapy may re-enter the cell cycle and repopulate a tumor which had shown responsiveness. Three classes of agents have recently been shown to be selectively toxic to hypoxic cells in vitro. For some of these agents, combinations of hypoxic cell-selective drugs and agents with selectivity for well oxygenated cells have demonstrated improved tumor cell kill in solid transplantable rodent tumor systems. The selectivity of these classes of drugs apparently stems from enhanced activation of the drug under hypoxic conditions. Although all of these drugs exhibit selectivity, the wide divergence in the therapeutic ratios for the individual agents suggests that it may be possible to develop newer agents that are highly toxic to hypoxic cells with little toxicity for normal tissues.