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Quantitation of Metabolic and Radiobiological Effects of 6-Aminonicotinamide in RIF-1 Tumor Cells in Vitro¹

Departments of Medical Physics [J. C. S., A. A. A., J. A. K.], Radiology [J. A. K.], and Medicine [J. A. K.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Beth Israel Medical Center, Department of Radiation Oncology, New York, New York 10003 [A. A. A.]

6-Aminonicotinamide (6AN) can be metabolized to 6-amino-NAD(P⁺), a competitive inhibitor of NAD(P⁺)-requiring processes, especially the pentose phosphate pathway (PPP) enzyme, 6-phosphogluconate dehydrogenase. The effect of 6AN on the flux of 1 and 6 ¹³C-labeled glucose to lactate, via glycolysis and the PPP, was investigated using ¹H-nuclear magnetic resonance. These studies showed that 6AN as a single agent caused a significant 89% (P < 0.0001) inhibition of glycolytic flux but had no detectable effect on the PPP. ³¹P-nuclear magnetic resonance studies of perifused RIF-1 cells indicated that 4 h of exposure to 6AN were sufficient to cause significant accumulation of 6-phosphogluconate, the substrate for this enzyme (P < 0.0001). A significant reduction in the phosphocreatine: inorganic phosphate ratio was observed under conditions that led to accumulation of 6-phosphogluconate (P < 0.006). Accumulation of 6-phosphogluconate and subsequent reduction in phosphocreatine correlated with significant potentiation of 6 Gy of irradiation by 6AN. These results suggest that the radiation enhancement effect of 6AN may be due to inhibition of glycolysis (mediated by 6-phosphogluconate) and the associated reduction in high-energy phosphates. Additional studies analyzing the metabolic effects of 6AN in combination with radiation are necessary to determine the role of inhibition of the PPP in 6AN enhancement of radiation.

¹ This work was supported by Grant USPHS PO 1 CA 25842 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-8835; Fax: (212) 717-3010.

Received 4/11/97. Accepted 7/18/97.

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