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Tumors in rat kidney generated by initiation with trans-4-acetylaminostilbene and several promoting treatments
A Hoffmann1, W Romen, H G Neumann
1Institute of Pharmacology and Toxicology, University of Würzburg, Federal Republic of Germany.
Abstract:
trans-4-Acetylaminostilbene (AAS) is a complete carcinogen in rats and produces quite selectively tumors in Zymbal's glands. On the basis of DNA adduct formation, it has been proposed that this model arylamine initiates neoplastic transformation of cells in many tissues, particularly liver and kidney, which, in the classical sense are considered to be non-target tissues for this chemical. In the present study an initiating treatment with AAS was followed by unilateral nephrectomy and the application of two nephrotoxic substances, gentamycin or beta-cyclodextrin which, among other activities, stimulate cell proliferation specifically in kidney. The initiating dose of AAS, given alone, gave rise to Zymbal's gland and mammary tumors in female Wistar rats within 88 weeks but not to liver or kidney tumors. When the initiation treatment was followed by unilateral nephrectomy, alone or in combination with gentamycin, or by beta-cyclodextrin, four tumors in two out of ten animals, eight tumors in three/ten, and seven tumors in three/ten, respectively, were observed in the kidney. The administered dose of gentamycin was not sufficient to induce tumors on its own. The results support the view that the genotoxic effects of AAS produce promotable lesions in rat kidney. None of the animals that had been treated with AAS, with or without other treatments, developed tumors or the predominant types of preneoplastic lesions in the liver within 88 weeks; this supports the notion that liver, like kidney, is not a target for complete carcinogenesis for this chemical.
Insights
trans-4-Acetylaminostilbene (AAS) initiates tumors in specific rat tissues. Kidney tumors developed when AAS initiation was combined with treatments that stimulate cell proliferation, suggesting genotoxic effects create promotable lesions.
Area of Science:
- Toxicology
- Carcinogenesis
- Oncology
Background:
- trans-4-Acetylaminostilbene (AAS) is a known carcinogen in rats, primarily causing Zymbal's gland tumors.
- While AAS induces DNA adducts in various tissues, liver and kidney are traditionally considered non-target organs for its carcinogenic effects.
- This study investigates the potential of AAS to initiate neoplastic transformation in non-traditionally targeted tissues like the kidney.
Purpose of the Study:
- To determine if trans-4-Acetylaminostilbene (AAS) can initiate kidney tumors when combined with agents that promote cell proliferation.
- To explore the role of genotoxic effects of AAS in creating pre-neoplastic lesions in the rat kidney.
- To confirm that the liver is not a target organ for complete carcinogenesis by AAS.
Main Methods:
- Rats received an initiating dose of AAS.
- Following AAS initiation, rats underwent unilateral nephrectomy or were treated with nephrotoxic substances (gentamicin or beta-cyclodextrin) to stimulate kidney cell proliferation.
- Tumor development in the kidney, liver, Zymbal's glands, and mammary glands was monitored over 88 weeks.
Main Results:
- AAS alone induced Zymbal's gland and mammary tumors but not kidney or liver tumors.
- Combining AAS initiation with unilateral nephrectomy, gentamicin, or beta-cyclodextrin resulted in kidney tumors.
- Gentamicin alone did not induce tumors, indicating its role was in promoting proliferation of AAS-initiated cells.
Conclusions:
- The genotoxic effects of AAS can initiate lesions in the rat kidney that are promotable by agents inducing cell proliferation.
- Kidney and liver are not classical target organs for complete carcinogenesis by AAS.
- This research supports the hypothesis that AAS initiates neoplastic transformation in non-target tissues under specific conditions.