This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Welsch, C. W. Articles by Aylsworth, C. F. Search for Related Content PubMed PubMed Citation Articles by Welsch, C. W. Articles by Aylsworth, C. F.

Retinoid Feeding, Hormone Inhibition, and/or Immune Stimulation and the Progression of N-Methyl-N-nitrosourea-induced Rat Mammary Carcinoma: Suppression by Retinoids of Peptide Hormone-induced Tumor Cell Proliferation in Vivo and in Vitro¹

Department of Anatomy, Michigan State University, East Lansing, Michigan 48824

Female Sprague-Dawley rats were treated at 50 and 57 days of age with 2.5 mg per 100 g body weight of N-methyl-N-nitrosourea (MNU). At 60 days of age, the animals were divided into eight groups (40 rats/group) and treated as follows: (a) controls; (b) immune stimulation (IS); (c) hormone inhibition (HI); (d) HI + IS; (e) retinyl acetate feeding (RA); (f) RA + IS; (g) RA + HI; and (h) RA + HI + IS. IS treatment was accomplished by three i.p. injections (at 1, 3, and 5 weeks after carcinogen treatment) of a mixture of cell particulate preparations from pooled MNU-induced rat mammary carcinomas and Freund's (complete) adjuvant. HI treatment consisted of daily s.c. injections of tamoxifen (12.5 to 25.0 µg/100 g body weight) and CB-154 (200 to 400 µg/100 g body weight), and RA treatment consisted of daily feeding of retinyl acetate (1.0 mM). Both RA alone and HI alone significantly (p < 0.01 to 0.001) reduced mammary carcinoma incidence; HI treatment was significantly (p < 0.01) more effective than RA treatment. The combination of RA + HI was significantly (p < 0.01) superior to either treatment alone; RA + HI treatment virtually completely blocked the development of mammary carcinomas at termination of study (a total of only 2 mammary carcinomas was observed in the RA + HI groups of rats at 1 year after carcinogen treatment). IS treatments did not significantly influence mammary carcinoma incidence, either alone or in combination with RA and/or HI.

Female Sprague-Dawley rats given MNU and subsequently treated daily for 4 weeks with the prolactin secretion-stimulating drug haloperidol (0.05 mg/100 g body weight) responded with a significant (p < 0.001) increase in mammary carcinoma development when compared with control rats. RA treatment of haloperidol-treated rats significantly (p < 0.001) blocked the stimulatory effect of haloperidol on mammary carcinoma development. The addition of insulin (5.0 µg/ml) to the culture media of 2-day organ cultures of MNU-induced rat mammary carcinomas resulted in a significant (p < 0.05) stimulation of [³H] thymidine incorporation into DNA of the cultured cells. Retinoic acid (1 x 10^-6 M) significantly (p < 0.05) blocked the stimulatory effect of insulin on [³H]thymidine incorporation into DNA; retinoic acid alone did not significantly affect [³H]thymidine incorporation into DNA.

The results of this study demonstrate a striking prevention of the development and progression of MNU-induced rat mammary carcinomas by a combination of two biological response modifier treatments, i.e., RA and HI. Retinoid-induced suppression of peptide hormone-induced stimulation of mammary carcinoma cells in vivo and in vitro has also been demonstrated, suggesting a mechanism by which retinoids may suppress the progression of rat mammary carcinomas.

¹ This research was supported by USPHS Contract NO1-CP-05717 from the Division of Cancer Cause and Prevention, National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 7/15/83. Accepted 10/ 6/83.