EVALUATION OF CHEMOTHERAPY AND RADIATION ENHANCEMENT AND P-31 NMR SPECTRAL CHANGES INDUCED BY BIOCHEMICAL MODULATION

The combination of N-(phosphonacetyl)-L-aspartate (PALA), 6-methylmerc aptopurine riboside (MMPR), and 6-aminonicotinamide (6AN) has been sho wn to be an effective antineoplastic regimen and also to enhance the e ffects of their other antineoplastic agents (1-4). To further enhance the effect of this combination, we investigated the effects of adding adriamycin, at its maximally tolerated dose, to this regimen. The resp onse rate (complete regression + partial regression) for the four-drug regimen was higher than for the three-drug regimen, and the tumor gro wth delay was also significantly higher than for treatment with PALA, MMPR, 6AN, or after treatment with maximally tolerated doses of adriam ycin alone (11 mg/kg). The addition of adriamycin to PALA, MMPR, 6AN d id not result in enhancement of the effect of radiation, as measured b y tumor growth delay studies and tumor control (complete and partial r egression rate). The mechanism of action of the combination of PALA, M MPR, and 6AN is not known definitively, but a possible mechanism previ ously suggested is biochemical modulation of energy metabolism and inh ibition of production of tumor ATP. Treatment with PALA< MMPR, 6AN, an d adriamycin (at 2.5 hr post MMPR, 6AN) resulted in a nadir NTP/Pi val ue, as determined by P-31 NMR spectroscopy, at approximately 10 hr pos t MMPR + 6AN (7.5 hr post adriamycin), which was not significantly dif ferent from the NTP/Pi value determined after treatment with the three -drug combination.