Biochemical modulation of tumor cell energy in vivo: II. 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-amino-nicotinamide (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: (1) 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 agents such as Adria.
Martin
D S
DS
Cancer Research Department, Catholic Medical Center of Brooklyn, New York.
Stolfi
R L
RL
Colofiore
J R
JR
Nord
L D
LD
Sternberg
S
S
D015120:6-Aminonicotinamide / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D004734:Energy Metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008778:Methylthioinosine / Q000008:administration & dosage; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives
D001224:Aspartic Acid; D015120:6-Aminonicotinamide; D008778:Methylthioinosine; C013195:sparfosic acid; D004317:Doxorubicin; D010746:Phosphonoacetic Acid