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 vitro.

Abstract

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 micrograms/100 g body weight) and CB-154 (200 to 400 micrograms/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 less than 0.01 to 0.001) reduced mammary carcinoma incidence; HI treatment was significantly (p less than 0.01) more effective than RA treatment. The combination of RA + HI was significantly (p less than 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 less than 0.001) increase in mammary carcinoma development when compared with control rats. RA treatment of haloperidol-treated rats significantly (p less than 0.001) blocked the stimulatory effect of haloperidol on mammary carcinoma development. The addition of insulin (5.0 micrograms/ml) to the culture media of 2-day organ cultures of MNU-induced rat mammary carcinomas resulted in a significant (p less than 0.05) stimulation of [3H] thymidine incorporation into DNA of the cultured cells.(ABSTRACT TRUNCATED AT 400 WORDS)