Synergistic enhancement of small and large intestinal carcinogenesis by combined treatment of rats with five heterocyclic amines in a medium-term multi-organ bioassay.
The carcinogenic potential of five heterocyclic amines in combination was analyzed using a medium-term multi-organ bioassay. Male F344 rats were initially treated with five known carcinogens (diethylnitrosamine, N-methyl-N-nitrosourea, N-butyl-N-(4-hydroxybutyl)-nitrosamine, 1,2-dimethylhydrazine and 2,2'-dihydroxy-di-n-propylnitrosamine) over a 4 week period to induce preneoplastic changes in a variety of organs (wide spectrum initiation) and then given the five heterocyclic amines, all having the intestines as a target of their carcinogenicity, individually or in combination in the diet for a further 24 weeks. In the small and large intestines, simultaneous administration of five heterocyclic amines at doses 1/5 or 1/25 of those used in reported carcinogenicity studies resulted in higher incidences and multiplicities of adenocarcinomas than expected from the five individual effects, although the differences were not statistically significant. A synergistic effect based on the additive model was most evident (P < 0.141) with multiplicity data for carcinoma in the small intestine at the 1/25 dose. A similar trend was observed for Zymbal gland (P < 0.077), but not other carcinoma induction. Thus the results suggested that synergism depends on the carcinogenic organotropism of individual agents as well as the doses applied in combination.
First Department of Pathology, Nagoya City University Medical School, Japan.
R
R
Hasegawa
H
H
Tanaka
S
S
Tamano
T
T
Shirai
M
M
Nagao
T
T
Sugimura
N
N
Ito
D019813:1,2-Dimethylhydrazine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002085:Butylhydroxybutylnitrosamine / Q000008:administration & dosage; D002273:Carcinogens / Q000008:administration & dosage*; D004052:Diethylnitrosamine / Q000008:administration & dosage; D004127:Dimethylhydrazines / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007093:Imidazoles / Q000633:toxicity; D007414:Intestinal Neoplasms / Q000139:chemically induced*; D008297:Male; D008770:Methylnitrosourea / Q000008:administration & dosage; D009602:Nitrosamines / Q000008:administration & dosage; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004127:Dimethylhydrazines; D007093:Imidazoles; D009602:Nitrosamines; D002085:Butylhydroxybutylnitrosamine; D004052:Diethylnitrosamine; C012457:diisopropanolnitrosamine; D008770:Methylnitrosourea; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019813:1,2-Dimethylhydrazine; C023847:Glu-P-2