Estrogen synthesis in human breast tumor and its inhibition by testololactone and bromoandrostenedione.
A total of 53 tumors have been examined for estrogen synthesis from androstenedione and assayed for estradiol receptors. It was found that of the 40 tumors that metabolized androstenedione to estrogens, 17 tumors were estradiol receptor negative and 23 tumors were estradiol receptor positive. Of the 13 tumors that did not synthesize estrogens, 7 tumors were receptor negative and 6 tumors were receptor positive. No correlation was found between the ability of the tumor to synthesize estrogens and the presence or absence of estradiol receptors. The inhibition of aromatase enzyme in human breast tumors by delta 1-testololactone, testololactone, and 6 alpha- and 6 beta-bromoandrostenedione was investigated. Estrone and estradiol synthesis from androstenedione was reduced in five tumor incubations by the presence of 0.2 mM delta 1-testololactone and testololactone, 6 alpha- and 6 beta-bromoandrostenedione (2.0 microM) were also shown to block estrogen synthesis in 5 tumors. Furthermore, Lineweaver-Burk plots revealed that all four compounds were competitive inhibitors of androstenedione aromatization. An apparent Km of the aromatase enzyme for androstenedione of 0.08 microM and a Vmax of 23 pmol of estrone synthesized per g tumor per hr were determined for one human breast tumor specimen. The use of an aromatase inhibitor such as delta 1-testololactone in the treatment of breast cancer should be reconsidered. Data from one patient with advanced cancer of the breast, responding to previous oophorectomy and adrenalectomy and treated with large doses of delta 1-testololactone, are presented to illustrate the significance of successful treatment by scientific approaches.
D000315:Adrenalectomy; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000601:surgery; D002369:Castration; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007700:Kinetics; D009364:Neoplasm Recurrence, Local; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000032:analysis; D013738:Testolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
D047072:Aromatase Inhibitors; D004967:Estrogens; D011960:Receptors, Estrogen; C025177:6-bromoandrostenedione; C018155:testololactone; D000735:Androstenedione; D013738:Testolactone; D010088:Oxidoreductases