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N-nitrosocimetidine as a modifier of chemically-initiated tumors in mice
L M Anderson1, A Hagiwara, A Giner-Sorolla
1Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, MD 21701.
Abstract:
N-Nitrosocimetidine (NCM) is a nitrosation product of cimetidine, a commonly-prescribed pharmaceutical agent. In spite of its known genotoxicity, NCM has failed to cause tumors in assays with rats and mice, but has given indications of enhancing or suppressive effects on tumor development. This possibility was tested by administering NCM topically to the skin or in the drinking water to mice in which tumors had been initiated by treatment with chemical carcinogens. Sencar mouse skin papillomas initiated by 7,12-dimethylbenzanthracene (DMBA) and promoted by 12-O-decanoylphorbol-13-acetate (TPA), progressed more rapidly to carcinoma on mice given treatment during stage 3 (after TPA) with NCM (1 mg/week) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 120 micrograms/week) [corrected] than on stage 3 acetone controls. Oral NCM (1 g/l drinking water) did not have this effect but rather suppressed development of keratoacanthomas, as did stage 3 MNNG or TPA. Primary lung tumors initiated in BALB/c mice by i.p. injection of urethane; and tumors of forestomach, lung, mammary, lymphoid and skin tissues caused in (C57BL/6 X DBA/2)F1 mice by oral DMBA were not markedly affected by NCM given in drinking water (1000-1800 ppm) until 14-16 months of age. These results confirm NCM's general lack of activity as an in vivo toxicant, but show that under certain circumstances it may enhance or suppress tumor development.
Insights
N-Nitrosocimetidine (NCM), a cimetidine derivative, shows varied effects on tumor development in mice. While not a direct carcinogen, NCM can enhance or suppress tumor growth depending on the administration route and tumor type.
Area of Science:
- Toxicology
- Carcinogenesis
- Pharmacology
Background:
- N-Nitrosocimetidine (NCM) is a nitrosation product of cimetidine, a widely used pharmaceutical.
- Despite known genotoxicity, NCM's in vivo carcinogenic potential and its effects on tumor development remain unclear.
Purpose of the Study:
- To investigate the potential tumor-enhancing or -suppressive effects of NCM in mouse models.
- To determine if NCM influences tumor progression initiated by chemical carcinogens.
Main Methods:
- Mice were treated with NCM topically or orally after tumor initiation with chemical carcinogens like DMBA and urethane.
- Tumor development and progression were monitored in various tissues including skin, lung, forestomach, mammary, and lymphoid tissues.
Main Results:
- Topical NCM treatment enhanced the progression of skin papillomas to carcinomas in Sencar mice.
- Oral NCM administration suppressed the development of keratoacanthomas in mice.
- NCM showed minimal impact on primary lung tumors and various tumors initiated by oral DMBA in (C57BL/6 X DBA/2)F1 mice.
Conclusions:
- N-Nitrosocimetidine exhibits context-dependent effects on tumor development, acting as a tumor promoter in some instances and a suppressor in others.
- These findings highlight the complex role of NCM in carcinogenesis, suggesting it is not a potent in vivo toxicant but can modulate tumor progression.