A concomitant ATP-depleting strategy markedly enhances anticancer agent activity

Most anticancer agents effect DNA damage which initiate the cell death pathways of necrosis and apoptosis, but cancer cells of lesser sensitivity are only sublethally injured, and recover. The two death pathways and their interelationships in the presence of endogenous inhibitors of apoptosis and genetic 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 opportunity for further reduction of these key metabolites to lower levels that will not support life. Data in tumor-bearing animals is reviewed demonstrating that a combination of ATP-depleting agents plus a de novo pyrimidine inhibitor (PALA) administered concomitantly with each of nine different anticancer agents markedly enhances tumor regression rates,and even produces some cures. It is necessary to deplete tumor ATP levels seveerely (>85%) by a combination of agents that block both synthesis (6-methylmercaptopurine riboside, a purine de novo synthesis inhibitor) and generation of ATP(6-aminonicotinamide, an inhibitor of glycolysis.) Cell viability cannot be sustained if the intracellular ATP level is reduced to 15% of normal or below. In vivo data employing this novel therapeutic strategy with cisplatin is presented. The potential significance of these findings to the improvement of cancer treatment is discussed.