The long-term objective of this proposal is to develop selective inhibitors of aromatase, C17-20 lyase, and the cholesterol side chain cleavage enzyme for application to problems in endocrinology and oncology. Specific inhibitors of aromatase would block estrogen biosynthesis and thus provide potential agents for use in the management of estrogen-dependent mammary tumors. Specific inhibitors of C17-20 lyase would block androgen as well as estrogen biosynthesis and could thus be useful in the mangement of prostatic tumors. Specific inhibitors of the cholesterol side chain cleavage enzyme would block steroid hormone biosynthesis from cholesterol and could be useful in the management of cortisol hypersecretion due to autonomously functioning adrenal tumors. The types of inhibitors chosen for development are known as suicide substrates. Such compounds contain function groups which are in themselves not chemically reactive, but are capable of becoming chemically reactive after the target enzyme carries out its catalytic reaction.
The specific aims are: 1) to study the mechanism of action of known and newly prepared aromatase suicide substrates; 2) to demonstrate the feasibility of using a radiolabeled aromatase suicide substrate to localize tissue distribution of this enzyme; 3) to prepare a novel 14,15-secopregnene as a C17-20 lyase inhibitor and evaluate its effectiveness in microsomal preparations from rat testes; and 4) to prepare novel actylenic steroids as inhibitors of the cholesterol side chain cleavage enzyme and evaluate them using mitochondrial powders from bovine adrenal glands. The methodology involves organic synthesis, enzymology, analysis by gas chromatography-mass spectrometry, and autoradiography.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA023582-12
Application #
3166182
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1978-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1991-03-31
Support Year
12
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Berry, P E; Ward, S E (1995) Barriers to pain management in hospice: a study of family caregivers. Hosp J 10:19-33
Zimniski, S J; Brandt, M E; Covey, D F et al. (1993) Inhibition of growth and appearance of estrogen-dependent rat mammary tumors by 10-propargylestr-4-ene-3,17-dione, an aromatase inhibitor. Breast Cancer Res Treat 26:15-21
Brandt, M E; Covey, D F; Zimniski, S J (1990) The effects of in vivo administration of 10-propargylestr-4-ene-3,17-dione on rat ovarian aromatase and estrogen levels. J Enzyme Inhib 4:143-52
Sherwin, P F; McMullan, P C; Covey, D F (1989) Effects of steroid D-ring modification on suicide inactivation and competitive inhibition of aromatase by analogues of androsta-1,4-diene-3,17-dione. J Med Chem 32:651-8
Auchus, R J; Palmer, J O; Carrell, H L et al. (1989) Preparation of 14,15-secoestra-1,3,5(10)-trien-15-ynes, inhibitors of estradiol dehydrogenase. Steroids 53:77-96
Covey, D F; McMullan, P C; Wixler, L L et al. (1988) [19-14C]androstenedione: a new substrate for assaying aromatase and studying its reaction mechanism. Biochem Biophys Res Commun 157:81-6
Auchus, R J; Covey, D F; Bork, V et al. (1988) Solid-state NMR observation of cysteine and lysine Michael adducts of inactivated estradiol dehydrogenase. J Biol Chem 263:11640-5
Brandt, M E; Puett, D; Garola, R et al. (1988) Aromatase and aromatase inhibitors: from enzymology to selective chemotherapy. Prog Clin Biol Res 262:65-84
Brandt, M E; Puett, D; Covey, D F et al. (1988) Characterization of pregnant mare's serum gonadotropin-stimulated rat ovarian aromatase and its inhibition by 10-propargylestr-4-ene-3,17-dione. J Steroid Biochem 31:317-24
Covey, D F; Carrell, H L; Beusen, D D (1987) Metabolism of 19-methyl substituted steroids and a proposal for the third aromatase monooxygenation. Steroids 50:363-74

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