Marked enhancement in vivo of paclitaxel's (taxol's) tumor-regressing activity by ATP-depleting modulation.
Paclitaxel alone is active against the CD8F1 murine spontaneous mammary cancer, and when administered following an ATP-depleting combination of N-(phosphonacetyl)-L-aspartate (PALA) + 6-methylmercaptopurine riboside (MMPR) + 6-aminonicotinamide (6-AN) (PMA) produced significantly enhanced partial tumor regressions over that produced by either paclitaxel alone at the maximal tolerated dose (MTD), or by the PMA drug combination alone, against advanced, first passage spontaneous murine breast tumors. The anticancer activity of paclitaxel is due to enhancement and stabilization of microtubule polymerization. Pertinently, microtubule disassembly (an ATP-dependent process) is known to sharply decrease in the presence of ATP depletion. Thus, the dramatic therapeutic enhancement observed with paclitaxel in combination with PMA is in agreement with biochemical expectations, since PMA has been shown to deplete ATP in CD8F1 tumor cells. The augmented therapeutic results were obtained with approximately one-third the MTD of paclitaxel as a single agent and suggest the potential clinical benefit of more effective treatment with lesser amounts of drug.
Martin
D S
DS
Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Stolfi
R L
RL
Colofiore
J R
JR
Nord
L D
LD
D015120:6-Aminonicotinamide / Q000008:administration & dosage; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008778:Methylthioinosine / Q000008:administration & dosage; D051379:Mice; D017239:Paclitaxel / Q000627:therapeutic use*; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D012074:Remission Induction
D000972:Antineoplastic Agents, Phytogenic; D001224:Aspartic Acid; D015120:6-Aminonicotinamide; D008778:Methylthioinosine; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D017239:Paclitaxel