4-OHA, a potent and selective inhibitor of estrogen biosynthesis, will be synthesized for use in the following studies. Evaluation of the effect of 4-OHA in breast cancer patients are proposed. In previous studies, 29% of patients responding to 4-OHA had not respond to previous antiestrogen treatment (tamoxifen) while a further 50% had relapsed for prior endocrine therapy. The significance of tumor aromatase to tumor growth will be determined by using the sensitive immunocytochemical peroxidase-antiperoxidase (PAP) technique with recently prepared polyclonal antibodies to aromatase. Antibodies to estrogen and progesterone receptors will be applied to the same tissue preparation for comparison. Concentrations of estrone, estradiol, estrone sulfate and androgen precursors will be measured in the tumor samples. The influences of c-ras/H oncogenic protein on hormone-dependent and hormone independent tumor growth will also be investigated by the above technique. The expression of the oncogenic protein (p21) will be determined in tumor samples from patients before and during treatment with aromatase inhibitor. Similar in vitro studies to the above will be carried out in tissue from patients with benign prostatic hypertrophy and prostatic cancer. Prostatic tissues will also be grown in nude mice and the effect of 4-OHA on the tumors determined.
