title: Niacin deficiency decreases bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats.
abstract: Cancer chemotherapy agents cause damage in the bone marrow, resulting in leukopenia during treatment and secondary cancers after recovery from the original disease. We created an experimental model of alkylation-based chemotherapy using ethylnitrosourea (ENU) to investigate the effect of niacin status on cancer induction. For 4 wk, nontumor-bearing weanling Long-Evans rats were fed niacin-deficient (ND) diets or were pair-fed (PF) identical quantities of a niacin-adequate diet. One week after the initiation of niacin feeding protocols, ENU treatment began (12 doses, 30 mg/kg by gavage, every other day). At the end of dietary modulation and ENU treatment, all rats were fed a high quality control diet and monitored for weight loss (>5%) and palpable tumors (>1cm), at which point they were necropsied for the presence of disease. The morbidity curves were significantly different; ND rats reached 20% morbidity 10 wk earlier than PF rats. In the first 20 wk after ENU treatment, ND rats developed 17 malignancies, including 11 leukemias, whereas PF rats developed 3 malignancies with 2 leukemias. In the end, there was a 47% greater average number of malignancies in ND vs. PF rats, despite a more rapid onset of morbidity. In short-term studies, niacin deficiency caused an 80% decrease in bone marrow NAD(+). Basal poly(ADP-ribose) levels were dramatically reduced by niacin deficiency. A single dose of ENU increased poly(ADP-ribose) levels fivefold in PF rats, whereas levels in ND rats remained 90% lower. Niacin deficiency did not alter the initial accumulation of DNA damage, indicating that drug metabolism is not an underlying factor in the diet-induced changes. These data show that niacin deficiency alters poly(ADP-ribose) metabolism in the bone marrow and increases the risk of nitrosourea-induced leukemias.
authors.affiliation: Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Boyonoski
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Spronck
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Gallacher
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jacobs
authors.forename: Girish M
authors.initials: GM
authors.lastname: Shah
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.forename: James B
authors.initials: JB
authors.lastname: Kirkland
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000633:toxicity*; D008297:Male; D009017:Morbidity; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D009525:Niacin / Q000008:administration & dosage / Q000172:deficiency* / Q000378:metabolism; D009752:Nutritional Status; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors
chemical_list: D000477:Alkylating Agents; D011064:Poly Adenosine Diphosphate Ribose; D009525:Niacin; D005038:Ethylnitrosourea