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

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.