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Pharmacological Intakes of Niacin Increase Bone Marrow Poly(ADP-Ribose) and the Latency of Ethylnitrosourea-Induced Carcinogenesis in Rats¹

Ann C. Boyonoski, Jennifer C. Spronck, Robert M. Jacobs^*, Girish M. Shah, Guy G. Poirier^** and James B. Kirkland²

Department of Human Biology and Nutritional Sciences and ^* Department of Pathobiology, University of Guelph, Guelph, ON, Canada N1G 2W1; Laboratory for Skin Cancer Research, Hospital Research Center of University Laval, Ste. Foy, QC, Canada G1V 4G2; and ^** Unit of Health and Environment, Hospital Research Center of University Laval, Ste. Foy, QC, Canada G1V 4G2

²To whom correspondence should be addressed. E-mail: jkirklan{at}uoguelph.ca.

Cancer chemotherapy agents cause short-term leukopenia during treatment and the development of secondary leukemias after recovery from the original disease. We reported that niacin deficiency in rats increases the severity of nitrosourea-induced leukopenia and the subsequent development of cancers. This study was designed to test the effects of supplementing an already high quality diet with pharmacologic levels of niacin. For a period of 4 wk, nontumor-bearing weanling Long-Evans rats were pair-fed AIN-93M diets that were niacin adequate (30 mg/kg diet) or pharmacologically supplemented (4 g/kg diet) with nicotinic acid (NA) or nicotinamide (Nam). One week after the initiation of niacin feeding protocols, ethylnitrosourea (ENU) treatment began (12 doses, 30 mg/kg by gavage, every other day). ENU treatment caused leukopenia, which was not prevented by niacin supplementation. At the end of ENU treatment, all rats were switched to a niacin-adequate diet and monitored. Within 36 wk after the start of treatment, all of the ENU-treated rats either lost 5% of peak body weight or had palpable tumors > 1 cm in diameter, and were necropsied. Supplementation with NA or Nam at 4.0 g/kg diet (combined analysis) increased the latency of the ENU-induced morbidity curve, relative to niacin-adequate controls. Morbidity could be attributed in almost all cases to some form of neoplasm, with leukemias the predominant form. In short-term studies, supplementation with either NA or Nam caused dramatic increases in bone marrow NAD⁺ (1- to 1.5-fold), basal poly(ADP-ribose) (3- to 5-fold) and ENU-induced poly(ADP-ribose) levels (1.5-fold). These data show that supplementation of a niacin-adequate, high quality diet with pharmacologic levels of nicotinic acid or nicotinamide increases NAD⁺ and poly(ADP-ribose) levels in bone marrow and may be protective against DNA damage.

KEY WORDS: • niacin • leukemia • nitrosourea • poly(ADP-ribose) • chemotherapy • rats

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