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

A quadruple drug combination-consisting of a triple-drug combination of N-(phosphonacetyl)-L-aspartate (PALA) + 6-methylmercaptopurine riboside (MMPR) + 6-aminonicotanamide (6-AN), designed to primarily deplete cellular energy in tumor cells, + Adriamycin (Adria)-yielded significantly 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 triple-drug combination administered prior to Adria resulted in a 100% tumor regression rate (12% complete regression; 88% partial regression) of spontaneous tumors. Histological examination of treated tumors demonstrated that the treatment-induced mechanism of cancer cell death was by apoptosis. The augmented therapeutic results (100% tumor regressions) were obtained with approximately one-half the MTD of Adria as a single agent and suggest the potential clinical benefit of longer, more effective, and safer treatment by low doses of Adria when combined with the triple-drug combination. Two likely mechanisms of action are discussed: (I) prevention of DNA repair; (2) complementary disruption of biochemical pathways, by both the triple-drug combination and the biochemical cascade of apoptosis that is induced by a DNA-damaging anticancer agent such as Adria.