Induction of kidney tumours by a single dose of dimethylnitrosamine: dose response and influence of diet and benzo(a)pyrene pretreatment

Abstract

Summary.-Seven days on a protein-free diet increases the susceptibility of rats to the action of DMN as a renal carcinogen. The dose response for the induction of kidney tumours by a single dose of dimethylnitrosamine (DMN) in these rats is reported. The first tumour was not found until 28 weeks after the dose. At 100 weeks the incidence ranged from 22.50/o at the lowest dose (20 mg/kg) to 97°h at the highest dose (60 mg/kg). The incidence in probits at any time between 50 and 100 weeks was linearly related to the log dose. Epithelial and mesenchymal tumours were produced in an approximate ratio of 2:1. The protein -free diet alters the rate of metabolism of DMN in the rat, and increases the alkylation of nucleic acids by this carcinogen in the kidney. Further treatment of the rat with benzo(a)pyrene can reverse, to some extent, the change in metabolism, but does not reverse the change in alkylation. It is shown that the change in kidney-tumour incidence produced by the change in diet, and by the treatment with benzo(a)pyrene, corresponds to the changes these treatments produce in the alkylation of kidney DNA by the carcinogen.

DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N-nitrosodimethylamine to N-nitrosomethyldodecylamine

“…In carcinogenicity studies employing administration by gavage (C2 and C4) and in drinking water (Cl-C5), kidney tumours were not reported. The reason for this discrepancy is not known but there seems to be a general tendency for rat kidney to undergo malignant transformation following pulsed doses rather than chronic exposure in drinking water (25).…”

Urinary Tract

“…These tumors appear to replace segments of the renal parenchyma with a variable population of mature fat cells, lipoblasts, spindle cells and prominent blood vessels. 432,441 Areas of fibrosarcoma mixed with primitive mesenchyme, myxomatous tissue, leiomyosarcoma or rhabdomyosarcoma are also described. Most appear to be slow growing benign neoplasms but some are malignant for they show marked cellular and nuclear pleomorphism, wide extension into the kidney and metastases.…”

Experimental Models for the Sequential Analysis of Chemically-Induced Renal Carcinogenesis

“…(45) demonstrated the enhancing capacity of a no protein-high carbohydrate diet for renal tumor induction, leading to the basis of a high frequency system for RMT (40). Pretrcatment with the special diet decreases microsomal enzyme activity in the liver and increases the amount of DMN reaching the kidney and other extrahepatic organs (45,46). Under this regime the LD5O for DMN is almost doubled (41), enabling a higher dose to be administered to the animal which results in a substantially increased tumor yield.…”