Pharmacological intakes of niacin increase bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats

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.