Advances in Brief Induction of Tamoxifen-dependent Rat Mammary

We have observed previously that animals given tamoxifen (TAM) and the carcinogen dimethylbenzanthracene develop exclusively hormone-in dependent tumors. Since our data implied that the TAM-associated tu mors were different from control tumors, we undertook studies to examine the role of TAM in the induction and growth of these tumors. Following cessation of TAM administration, almost one-third [29.0 Â±1.7% (SEM)] of the tumors regressed and more tumors appeared. Resumption of TAM administration resulted in regrowth of some tumors and regression of the new tumors. These studies demonstrate that some of the TAM-associated tumors are actually dependent upon TAM for growth, while the appear ance of new tumors suggests that TAM does not totally prevent tumor formation but may only delay it. Introduction While TAM' has repeatedly been shown to be an effective anticancer agent in both animal and clinical studies (1â€”4),several studies have reported that human tumors may develop resistance to this agent (5-7). Previous work from this laboratory has also demonstrated that tumors induced in the presence of TAM are exclusively hormone independent and possess characteristics distinct from those of control hormone-dependent and independent tumors (8). These TAM-associ ated tumors possessed significantly lower levels of the estrogen re ceptor and grew at a rate that was more than 3 times faster than that of hormone-independent tumors in control animals (8). For these reasons, we undertook studies to examine the role of tamoxifen in the induction and growth of these hormone-independent tumors. Materials and Methods Chemicals. The carcinogen DMBA and tamoxifen citrate were purchased from Sigma Chemical Co. (St. Louis, MO). Animals. Adult female Sprague-Dawley rats (55 days old) were obtained from HarÃ-anSprague Dawley. Inc. (Indianapolis. IN). Animals were main tained in a temperature-controlled room on a 12 h: 12 h day:night cycle with free access to food and water. The reproductive cycles of the animals were monitored by daily vaginal smears. Administration of carcinogen and all sur gery were performed under light ether anesthesia. Animals were sacrificed by COi asphyxiation. Tumor Induction. The carcinogen DMBA was dissolved in sesame oil and administered by gavage under light ether anesthesia once a week for 4 weeks (5 mg/rat/week; total dose, 20 mg) as modified from Isaacs (9). This protocol results in a greater number of tumors with characteristics identical to those of the original Huggins model (10, 11). TAM (10 mg/kg body weight in sesame oil) was injected s.c. coincident with DMBA administration. Tumor number and volume were determined weekly starting at week 3 following the last coadministration of carcinogen and TAM. Tumor volume was calculated ac cording to: Received 3/22/93; accepted 5/28/93. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ' Supported by the Kansas Health Foundation, the Women's Research Institute, and The Wesley Medical Research Institute. 2 To whom requests for reprints should be addressed, at Women's Research Institute, Department of Obstetrics and Gynecology, University of Kansas School of Medicine, 2903 E. Central. Wichita, KS 67214. 3 The abbreviations used are: TAM, tamoxifen; DMBA, 7,12-dimethylbenzanthracene. 4 V=-T (radius RÂ¡< r? 2). In some experiments selected animals received additional periodic administrations of TAM (10 mg/kg body weight) and monitoring of tumor growth and number was continued. Each experiment had 10 animals/ group. In total these experiments were conducted with 60 rats possessing 183 tumors (46 tumors were found in animals receiving tamoxifen). Experiments were performed at least twice and all data are reponed as mean Â±SEM.