The major objective of these studies is to examine the effects of 10-propargylestr-4-ene-3,17-dione (PED) and its 17 propionated derivative (PEDP) on the growth and hormone-responsiveness of several hormone-dependent tumors. Although PED is a potent inhibitor of the aromatase enzyme and an equally potent antitumor agent, many questions remain as to its effects on endocrine and non-endocrine tissues. Therefore, to attain the primary objective we intend to examine the actions of both PED and PEDP on the metabolism of steroids in vitro in microsomal preparations of selected tissues of female rats. We hope to identify specific steroids whose production is altered in the presence of PED by GC/mass spectrometry. In addition, we would like to determine whether the altered steroidogenesis is due to direct actions of PED or is secondary to the inhibition of estradiol (or perhaps another steroid) production. Secondly, we propose to examine the effects of these compounds following their in vivo metabolism of labeled steroid precursor in tissues obtained from preinjected rats, and also by examining serum levels of estradiol, progesterone and corticosterone. Furthermore, we intend to monitor serum levels of gonadotropin and prolactin to again investigate the levels at which these agents act. As another measure of the effects of these agents, we will also monitor the relative amount and degree of occupancy of estrogen and progesterone receptors in mammary tumor and hormone-responsive tissues in both tumor-bearing and normal cycling rats. We will also assess the efficacy of various doses of PED and PEDP, both in DMBA-induced mammary tumors, and also on human mammary and endometrial tumor cell line established in nude mice. These will be the first experiments to examine the in vivo effects of these agents in human tumors. The response of these tumors to therapy will be determined not only by monitoring tumor growth, but also by measuring the level of steroid receptors in these tumors. We feel that these studies will evaluate the potential of PED and PEDP as antitumor agents. Moreover, the delineation of actions and effects of these agents both in vivo and in vitro will give us a better understanding of how these compounds act. These studies should provide valuable information to determine whether these drugs will be active as anti-tumor agents in humans.
