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Influence of Dosage Schedule on the Biological Characteristics of N-Nitrosomethylurea-induced Rat Mammary Tumors¹

David P. Rose², Brian Pruitt, Patricia Stauber, Erdoan Ertürk and George T. Bryan

Division of Clinical Oncology, Wisconsin Clinical Cancer Center, University of Wisconsin, Madison, Wisconsin 53792

The incidence, latent period, and hormone dependence of tumors produced in female Sprague-Dawley rats by two modes of induction with N-nitrosomethylurea were studied. In one group of 150 animals, the carcinogen was administered i.v. in three doses of 5 mg/100 g body weight given 4 weeks apart (Method 1); a second group of 150 animals received the same dose on two occasions 1 week apart (Method 2). Tumors appeared, with a relatively shorter latent period, in 98% of rats treated by Method 1 but in only 46% of those treated by Method 2. All of the 110 tumors produced by Method 1 examined histologically were carcinomas, with features indicative of a high degree of malignancy; 54.5% were classified as medullary carcinomas. In contrast, 56.5% of the tumors induced by Method 2 were well-differentiated cystic papillary adenocarcinomas; 4 were fibroadenomas. Carcinomas induced by Method 1 varied in their response to ovariectomy; of 21 biopsied tumors, 10 (48%) underwent a complete remission, and 7 (33%) underwent a partial remission, but progression was reestablished in 3 (14%) of these within 6 weeks. Similarly, 8 of 12 (67%) Method 1-induced carcinomas responded to tamoxifen, and 5 (42%) were still in remission after 6 weeks of treatment. All but 1 of 8 ovariectomized rats bearing carcinomas induced by Method 2 underwent a complete remission, which was maintained for 6 weeks or longer; tamoxifen produced complete remissions in 6 and arrested growth in 1 of 7 Method 2-induced carcinomas. Estrogen receptors were detected in all but 3% of 96 carcinomas induced by Method 1 and in 91% of 64 carcinomas induced by Method 2. No clear-cut relationship emerged between the receptor level and response to endocrine manipulation.

¹ Supported in part by USPHS Grant CA 14520 awarded to the Wisconsin Clinical Cancer Center by the National Cancer Institute and by Grants CA 11946, CA 17579, and CA 20432.

² To whom requests for reprints should be addressed.

Received 7/11/79. Accepted 10/18/79.

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