EFFECT OF 6-AMINONICOTINAMIDE ON THE PENTOSE-PHOSPHATE PATHWAY - P-31NMR AND TUMOR-GROWTH DELAY STUDIES

6-aminonicotinamide (6AN) has been shown to enhance radiosensitivity i n vitro, although previous in vivo studies failed to show an effect, P -31 NMR spectra were obtained by using a one-dimensional chemical shif t imaging technique on a first generation transplant of the CD8FI spon taneous mammary carcinoma tumor model. Spectra were obtained both befo re and 10 h after treatment with 6AN (20 mg/kg). Changes in pH, nucleo side triphosphate/inorganic phosphate, and phosphocreatine/inorganic p hosphate measured at 10 h post-6AN were not significant. A new peak wa s detected 10 h post-6AN, which was assigned to 6-phosphogluconate (6P G), indicating inhibition of the pentose phosphate pathway (PPP). Base d on the spectral data demonstrating inhibition of the PPP at 10 h pos t-6AN, tumor-bearing mice were irradiated (15 Gy x 3 fractions) on Day s 1, 10 or 11, and 21 10 h after administration of 6-aminonicotinamide (20 mg/kg). Tumor-bearing mice receiving 6AN alone (20 mg/kg x 3), ra diation alone (15 Cy x 3), or saline were also studied, Tumor growth d elay studies indicated that 6AN alone induced a small but significant tumor growth delay (4.3 +/- 0.8 days). Radiation alone induced a tumor growth delay of 34.5 +/- 2.7 days. Treatment with 6AN followed by rad iation induced a tumor growth delay of 57.0 +/- 3.8 days. This was sig nificantly greater than the TGD values for treatment with 6AN alone or radiation (P < 0.01). No complete regressions were noted after treatm ent with 6AN or radiation alone. Concomitant therapy with 6AN plus rad iation yielded 6/28 complete regressions (21%), which was significantl y greater than radiation (P < 0.05) or 6AN alone (P < 0.01) on this ma mmary carcinoma.