Effect of 6-aminonicotinamide on the pentose phosphate pathway: 31P NMR and tumor growth delay studies.
6-aminonicotinamide (6AN) has been shown to enhance radiosensitivity in vitro, although previous in vivo studies failed to show an effect. 31P NMR spectra were obtained by using a one-dimensional chemical shift imaging technique on a first generation transplant of the CD8FI spontaneous mammary carcinoma tumor model. Spectra were obtained both before and 10 h after treatment with 6AN (20 mg/kg). Changes in pH, nucleoside triphosphate/inorganic phosphate, and phosphocreatine/ inorganic phosphate measured at 10 h post-6AN were not significant. A new peak was detected 10 h post-6AN, which was assigned to 6-phosphogluconate (6PG), indicating inhibition of the pentose phosphate pathway (PPP). Based on the spectral data demonstrating inhibition of the PPP at 10 h post-6AN, tumor-bearing mice were irradiated (15 Gy x 3 fractions) on Days 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), radiation alone (15 Gy x 3), or saline were also studied. Tumor growth delay 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 radiation induced a tumor growth delay of 57.0 +/- 3.8 days. This was significantly greater than the TGD values for treatment with 6AN alone or radiation (P < 0.01). No complete regressions were noted after treatment with 6AN or radiation alone. Concomitant therapy with 6AN plus radiation yielded 6/28 complete regressions (21%), which was significantly greater than radiation (P < 0.05) or 6AN alone (P < 0.01) on this mammary carcinoma.
Koutcher
J A
JA
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Alfieri
A A
AA
Matei
C
C
Meyer
K L
KL
Street
J C
JC
Martin
D S
DS
D015120:6-Aminonicotinamide / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D003131:Combined Modality Therapy; D005260:Female; D005942:Gluconates / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D009368:Neoplasm Transplantation; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D010761:Phosphorus Radioisotopes; D013723:Teratogens / Q000494:pharmacology*
D005942:Gluconates; D010761:Phosphorus Radioisotopes; D013723:Teratogens; D015120:6-Aminonicotinamide; C008884:6-phosphogluconic acid