IN-VIVO DETECTION BY P-31 NMR OF PENTOSE-PHOSPHATE PATHWAY BLOCK SECONDARY TO BIOCHEMICAL MODULATION

The chemotherapeutic regimen of N-(phosphonacetyl)-L-aspartate (PALA) followed 17 h later by 6-methylmercaptopurine riboside (MMPR) and 6-am inonicotanamide (6AN) has been shown to be a potent sensitizer of anti -neoplastic therapy We undertook this study to compare the therapeutic and metabolic effects of this triple drug combination vs one of its c omponents, 6AN, in a murine mammary carcinoma, After treatment with PA LA, MMPR and 6AN, a new peak was detected which was assigned to 6-phos phogluconate (6PG), which is a marker of inhibition of the pentose pho sphate pathway at the B-phosphogluconate dehydrogenase step, Treatment with PALA, MMPR and 6AN also induced a decrease in the ratios of nucl eoside triphosphate/inorganic phosphate (NTP/P-i) and phosphocreatine/ inorganic phosphate (PCr/P-i) similar to previous results with a diffe rent tumor model, These effects were most pronounced at 6 and 10 h. In addition, an increase in PME/phosphocholine (PME'=downfield peak in t he phosphomonoester region) was detected, which was expected because o f the cytotoxic effect of this regimen, Treatment with 6AN alone also resulted in the detection of 6PG with a maximum intensity at 6 h post- 6AN. Treatment with 6AN alone induced a smaller change in 6PG and fail ed to cause a decrease in PCr/P-i or NTP/P-i at 6 and 10 h. The enhanc ed response to the combination of PALA, MMPR and 6AN vs 6AN alone, bot h with regard to cytotoxicity and radiosensitization, may be due to en ergy depletion.