Niacin deficiency decreases bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats.
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.
Boyonoski
Ann C
AC
Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
Spronck
Jennifer C
JC
Gallacher
Lisa M
LM
Jacobs
Robert M
RM
Shah
Girish M
GM
Poirier
Guy G
GG
Kirkland
James B
JB
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
D000477:Alkylating Agents; D011064:Poly Adenosine Diphosphate Ribose; D009525:Niacin; D005038:Ethylnitrosourea