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Effects of Cimetidine, Nitrite, Cimetidine plus Nitrite, and Nitrosocimetidine on Tumors in Mice following Transplacental plus Chronic Lifetime Exposure¹

Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [L. M. A.]; Department of Pharmacology, University of South Florida College of Medicine, Tampa, Florida 33612 [A. G-S.]; Sloan-Kettering Institute, Rye, New York 10580 [I. M. H.]; and Department of Pathology, Lawrence Hospital, Bronxville, New York 10708 [J. M. B.]

Cimetidine (CM), a drug widely prescribed for ulcers, readily undergoes nitrosation to form nitrosocimetidine (NCM), a genotoxic agent. In a test of the chronic effects of NCM in mice, (C57BL/6 x BALB/c) F₁ mice were exposed chronically to NCM (113 or 1130 ppm) in the drinking water from preconception through prenatal and neonatal development and adult life. Each group consisted of 40 to 80 mice of each sex, and median survival time was 27 months. Other groups were given CM alone or in combination with NaNO₂ (184 or 1840 ppm), or NaNO₂ alone. None of the chemical treatments had large effects on reproductive parameters, survival, or incidence of nonneoplastic lesions. CM treatment was associated with a small but significant increase in incidence of lymphomas in females, 41 of 59 (69%), compared with 31 of 66 controls (47%, P = 0.01). No females receiving either dose of NCM developed mammary carcinomas (0 of 91), compared with an incidence of four of 66 controls (6%, P = 0.03). Males given the high-dose combination of CM and NaNO₂ showed a higher incidence of lung tumor bearers than controls (71 of 79 versus 30 of 52, P < 0.01) and also experienced a significant, dose-dependent increase in numbers of large lung tumors (>1 cm in diameter), lung carcinoma, and metastatic lung tumors. Females given the higher dose of NCM had significantly greater incidence of mice with large lung tumors than controls (nine of 41 versus three of 66, P = 0.009). The possibility of carcinogenicity of cimetidine, nitrosocimetidine, and cimetidine plus nitrite is discussed.

¹ Supported in part by a grant from Smith, Kline & French Laboratories, Philadelphia, PA.

² To whom requests for reprints should be addressed.

Received 9/11/84. Revised 4/29/85. Accepted 5/ 1/85.