BIOCHEMICAL MODULATION OF TUMOR-CELL ENERGY .4. EVIDENCE FOR THE CONTRIBUTION OF ADENOSINE-TRIPHOSPHATE (ATP) DEPLETION TO CHEMOTHERAPEUTICALLY-INDUCED TUMOR-REGRESSION

DNA-damaging agents, e.g. Adriamycin(R) (ADR), are reported to cause t umor regression by induction of apoptosis. A reduction in the intracel lular content of ATP is part of the biochemical cascade of events that ultimately results in programmed death of the cell, or apoptosis. A c hemotherapeutic three-drug combination (PMA) consisting of N-(phosphon acetyl)-L-aspartate (PALA) + 6-methylmercaptopurine riboside (MMPR) 6-aminonicotinamide (6AN) significantly lowers levels of ATP in CD8F1 murine breast tumors in vivo and produces tumor regression by apoptosi s. Addition of the DNA-damaging antitumor agent ADR to PMA was found t o further significantly deplete ATP in CD8F1 murine breast tumors in v ivo with a concomitant significant increase in the number of tumor reg ressions. The correlative biochemical and therapeutic results are cons istent with, and support, the hypothesis that ATP depletion is a signi ficant factor and, therefore, is a worthy therapeutic target in the pr oduction of apoptosis.