1-DEHYDRO-MELENGESTROL ACETATE INHIBITS THE GROWTH AND PROTEIN-KINASE-C ACTIVITY OF ANDROGEN-INDEPENDENT DUNNING RAT PROSTATIC TUMORS

Androgen-independent Dunning R3327-AT3 rat prostate tumors are considered an appropriate model of advanced prostate cancer in humans. We recently reported that the progestational steroid melengestrol acetate (MGA) inhibited growth of these tumors on oral administration but also induced a marked involution of adrenals and androgen target organs (prostate, seminal vesicles, and testes). We report herein that the 1-dehydro derivative of melengestrol acetate (dMGA) fed to rats for 21 days also inhibited the growth of Dunning AT3 tumors by approximately 55% without causing a significant regression of adrenals or androgen-dependent tissues. Thus, tumor-growth inhibition was induced by dMGA in the absence of glucocorticoid activity. Cytosolic AT3 tumor fractions obtained by diethylaminoethyl (DEAE)-Sephacel batch chromatography were assayed for lipid- and Ca2+-dependent (PKC) and -independent protein kinase activities. Prostatic cytosols had equivalent activity levels of both types of kinases (approximately 2 nmol gamma-[P-32]-adenosine 5'-triphosphate (ATP) incorporated mg protein-1 min-1. The PKC activity recovered from the cytosol of untreated AT3 tumors was approximately 4 times higher. Oral administration of dMGA reduced this activity by >95%. The relationship between protein-kinase activity levels and dMGA-induced growth inhibition of androgen-independent tumors in this animal model is discussed.