BIOCHEMICAL MODULATION OF TUMOR-CELL ENERGY IN-VIVO .2.. A LOWER DOSEOF ADRIAMYCIN IS REQUIRED AND A GREATER ANTITUMOR-ACTIVITY IS INDUCEDWHEN CELLULAR-ENERGY IS DEPRESSED

A quadruple drug combination-consisting of a triple-drug combination o f N-(phosphonacetyl)-L-aspartate (PALA) + 6-methylmercaptopurine ribos ide (MMPR) + 6-aminonicotanamide (6-AN), designed to primarily deplete cellular energy in tumor cells, + Adriamycin (Adria)-yielded signific antly enhanced anticancer activity (i.e., tumor regressions) over that produced by either Adria alone at maximum tolerated dose (MTD) or by the triple-drug combination, against large, spontaneous, autochthonous murine breast tumors. The adenosine triphosphate (ATP)-depleting trip le-drug combination administered prior to Adria resulted in a 100% tum or regression rate (12% complete regression; 88% partial regression) o f spontaneous tumors. Histological examination of treated tumors demon strated that the treatment-induced mechanism of cancer cell death was by apoptosis. The augmented therapeutic results (100% tumor regression s) were obtained with approximately one-half the MTD of Adria as a sin gle agent and suggest the potential clinical benefit of longer, more e ffective, and safer treatment by low doses of Adria when combined with the triple-drug combination. Two likely mechanisms of action are disc ussed: (I) prevention of DNA repair; (2) complementary disruption of b iochemical pathways, by both the triple-drug combination and the bioch emical cascade of apoptosis that is induced by a DNA-damaging anticanc er agent such as Adria.