MARKED ENHANCEMENT IN-VIVO OF PACLITAXELS (TAXOLS) TUMOR-REGRESSING ACTIVITY BY ATP-DEPLETING MODULATION

Paclitaxel alone is active against the CD8F1 murine spontaneous mammar y cancer, and when administered following an ATP-depleting combination of N-(phosphonacetyl)-L-aspartate (PALA) + 6-methylmercaptopurine rib oside (MMPR)+ 6-aminonicotinamide (6-AN) (PMA) produced significantly enhanced partial tumor regressions over that produced by either paclit axel alone at the maximal tolerated dose (MTD), or by the PMA drug com bination alone, against advanced, first passage spontaneous murine bre ast tumors. The anticancer activity of paclitaxel is due to enhancemen t and stabilization of microtubule polymerization. Pertinently, microt ubule disassembly (an ATP-dependent process) is known to sharply decre ase in the presence of ATP depletion. Thus, the dramatic therapeutic e nhancement observed with paclitaxel in combination with PMA is in agre ement with biochemical expectations, since PMA has been shown to deple te ATP in CD8F1 tumor cells, The augmented therapeutic results were ob tained with approximately one-third the MTD of paclitaxel as a single agent and suggest the potential clinical benefit of more effective tre atment with lesser amounts of drug.