CONTROLLED-RELEASE LOW-DOSE MEDROXYPROGESTERONE ACETATE (MPA) INHIBITS THE DEVELOPMENT OF MAMMARY-TUMORS INDUCED BY DIMETHYL-BENZ(A) ANTHRACENE IN THE RAT

Medroxyprogesterone acetate (MPA) is well recognized to have beneficia l effects for the treatment of advanced breast cancer which are compar able to those achieved with other forms of endocrine therapy. Using ma mmary tumors induced in the rat by dimethylbenz(a)anthracene (DMBA) as a model, we have studied the possibility that low dose MPA could prev ent the development of these tumors. Single subcutaneous injection of Depo-Provera (crystalline suspension of MPA) or MPA encapsulated in bi odegradable microspheres of 50:50 poly[DL-lactide-co-glycolide] was gi ven 7 days before oral DMBA. While 63% of intact animals developed pal pable mammary tumors within 85 days after DMBA administration, tumor i ncidence decreased to 28% and 23% in animals who had received 30 mg an d 100 mg of Depo-Provera, respectively. The same amounts of MPA delive red in microspheres caused a further decrease in tumor incidence to re spective values of 7% and 6%. Average tumor area, on the other hand, d ecreased from 4.89 cm2 in intact rats to about 0.75 (0.57-0.88) cm2 an d approximately 0.20 (0.14-0.22) cm2 in the Depo-Provera and microsphe re-treated groups, respectively. Using the 50: 50 formulation of poly[ DL-lactide-co-glycolide] designed to release MPA at a constant rate fo r a 4-month period, the serum MPA concentration at 3 months was measur ed at 4.99 +/- 0.43 ng/ml. Such data suggest that administration of a low dose controlled-release formulation of MPA in 50: 50 poly[DL-lacti de-co-glycolide] microspheres could well be an efficient and well tole rated approach for the prevention of breast cancer in women.