A concomitant ATP-depleting strategy markedly enhances anticancer agent activity

Most anticancer agents effect DNA damage which initiate the cell death path ways of necrosis and apoptosis, but cancer cells of lesser sensitivity are only sublethally injured, and recover. The two death pathways and their int erelationships in the presence of endogenous inhibitors of apoptosis and ge netic deletions that facilitates only sublethal damage, are reviewed. Both ATP and pyrimidine levels in the sublethally injured cancer cells are reduced but not to low levels insuffient to sustain cell viability. However , this sublethal damage by the anticancer agent creates a therapeutic oppor tunity for further reduction of these key metabolites to lower levels that will not support life. Data in tumor-bearing animals is reviewed demonstrat ing that a combination of ATP-depleting agents plus a de novo pyrimidine in hibitor (PALA) administered concomitantly with each of nine different antic ancer agents markedly enhances tumor regression rates, and even produces so me cures. It is necessary to deplete tumor ATP levels seveerely (> 85%) by a combination of agents that block both synthesis(6-methylmercaptopurine ri boside, a purine de novo synthesis inhibitor) and generation of ATP(6-amino nicotin-amide, an inhibitor of glycolysis.) Cell viability cannot be sustai ned if the intracellular ATP level is reduced to 15% of normal or below. In vivo data employing this novel therapeutic strategy with cisplatin is pres ented. The potential significance of these findings to the improvement of c ancer treatment is discussed.