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.
Hasegawa
R
R
First Department of Pathology, Nagoya City University Medical School, Japan.
Tanaka
H
H
Tamano
S
S
Shirai
T
T
Nagao
M
M
Sugimura
T
T
Ito
N
N
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