Biochemical modulation of tumor cell energy. IV. Evidence for the contribution of adenosine triphosphate (ATP) depletion to chemotherapeutically-induced tumor regression.
DNA-damaging agents, e.g. Adriamycin (ADR), are reported to cause tumor regression by induction of apoptosis. A reduction in the intracellular content of ATP is part of the biochemical cascade of events that ultimately results in programmed death of the cell, or apoptosis. A chemotherapeutic three-drug combination (PMA) consisting of N-(phosphonacetyl)-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 apoptosis. Addition of the DNA-damaging antitumor agent ADR to PMA was found to further significantly deplete ATP in CD8F1 murine breast tumors in vivo with a concomitant significant increase in the number of tumor regressions. The correlative biochemical and therapeutic results are consistent with, and support, the hypothesis that ATP depletion is a significant factor and, therefore, is a worthy therapeutic target in the production of apoptosis.
Colofiore
J R
JR
Catholic Medical Center, Woodhaven, NY 11421, USA.
Stolfi
R L
RL
Nord
L D
LD
Martin
D S
DS
D015120:6-Aminonicotinamide / Q000008:administration & dosage; D000255:Adenosine Triphosphate / Q000032:analysis*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D004317:Doxorubicin / Q000008:administration & dosage; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008778:Methylthioinosine / Q000008:administration & dosage; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D013997:Time Factors
D001224:Aspartic Acid; D015120:6-Aminonicotinamide; D008778:Methylthioinosine; C013195:sparfosic acid; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D010746:Phosphonoacetic Acid