Introduction

Therapeutic resistance to the antitumor alkylating agents, as to any other type of molecular therapy, can be envisioned at three levels: (1) at the cellular level where biochemical alterations in the tumor cells confer resistance, (2) at the level of the tumor mass where physiological abnormalities and properties of the tumor confer resistance and (3) at the level of tumor/host interaction where the tumor as a tissue recruits and involves normal cells in its growth and survival. Targets for the therapeutic modulation (potentiation) of the antitumor alkylating agents can be divided into similar classes. Modulators that act at the level of individual tumor cells include: (1) enzyme inhibitors such as inhibitors of topoisomerase I and II, inhibitors of glutathione-S-transferase and S-glutamylcysteinyl synthase, inhibitors of DNA repair and mitochondrial toxins and (2) depletors of cellular protectors such as glutathione depletors. Modulators that act at the level of properties related to the tumor mass include: (1) agents that reverse hypoxic protection and agents that are selectively active under hypoxic conditions and (2) direct inhibitors of extracellular matrix degrading enzymes. Finally, modulators that act by inhibiting the ability of the tumor to mobilize host normal cells include: (1) inhibitors of endothelial cell proliferation such as antiangiogenic and angiostatic agents and (2) inhibitors of intercellular signaling pathways such as cyclooxygenase and lipoxygenase inhibitors. This review will demonstrate the potential of each of these strategies of therapeutic modulation using antitumor alkylating agents as the cytotoxic therapy.