OHA inhibits conversion of both androgen precursors to their respective estrogens with equal effi ciency in human placenta microsomes.Aminoglutethimide which is an aromatase inhibitor by virtue of its interaction with cytochrome P. The lack of estrone suppression in this study is unlikely to be due to crossreaction of OHA in the assay since the column chromatography system used prior to the estrone assay was designed specifically to avoid this poten tial problem.HYDROXYANDROSTENEDIONE IN BREAST CANCER analysis.The validity of the result is supported by previous observations in rats where suppression of estradiol synthesis by OHA was markedly greater than that of estrone. This nonparallel suppression of the estrogens by OHA might be expected to occur if the drug caused inhibition of SOHSDH.Although the drug appears to interact with that enzyme, the inhibition of OHSDH by OHA in vitro is about fold less effective than that of aromatase. Al though the explanation for the result remains unknown, these results indicate that inhibition of estradiol but not estrone synthesis is important for successful endocrine treatment of postmenopausal breast cancer.Plasma DHAS levels are a relatively stable marker of adrenal activity and are closely related to urinary free cortisol levels. Since OHA therapy did not affect DHAS it is unlikely that it has a significant effect on adrenal function.Gonadotrophin levels were unaffected by OHA treatment in patients although in ovariectomized rats levels of LH and FSH were suppressed after administration of OHA. Higher doses of OHA in patients may suppress gonadotrophins; however, peripheral aromatase is not under gonadotrophin control in postmenopausal women.These re sults indicate that at the dose used in this study this is unlikely to be a significant mechanism of action in these patients.Lack of significant androgenic activity is confirmed by our observa tion that therapy does not alter SHBG binding capacity.Measurable OHA plasma concentrations week after the previous injection suggest that a depot of drug is formed at the injection site.Slow release of the compound from this site together with its rapid metabolism and clearance rate that OHA is both a competitive, reversible inhibitor of aromatase as well as a slower irreversible suicide inhibitor.This latter effect together with the depot formed at the injection site may account for the sustained suppression of estradiol despite low drug levels.In conclusion, OHA, a potent new aromatase inhibitor, is capable of markedly reducing plasma estradiol levels and pro ducing tumor regression in postmenopausal patients with ad vanced breast cancer.This is the first direct evidence that selective inhibition of estradiol synthesis is important in the endocrine treatment of postmenopausal breast cancer.A major advantage of its use over other forms of endocrine therapy is the XY1 apparent absence of significant systemic toxicity.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on April. American Association for Cancer Research. Human colorectal tumors also express the ckit protooncogene.The present study focuses on the anticancer activity of STI in human colorectal tumor cells in vitro and in vivo.Cellular invasion induced by ngml stem cell factor and pharmacological inhibitors of several oncogenic signaling pathways, namely, phosphatidylinositol kinase.