6-HYDROXIMINOANDROSTENEDIONE, A NEW SPECIFIC INHIBITOR OF ESTROGEN BIOSYNTHESIS AND ITS EFFECT ON T47D HUMAN BREAST-CANCER CELLS

A new male steroid hormone analogue, 6-hydroximinoandrostenedione, was obtained in 12% yield by an 8-step synthesis. The compound is cytochr ome P450 aromatase-specific, inducing a Type-1 optical difference spec trum with the human placental enzyme (K(s) 2.24 muM). It efficiently i nhibits human cytochrome P450 aromatase (K(i) 0.08 muM) in a time - an d concentration - dependent manner, but no conclusive evidence was fou nd that it also inactivates the placental enzyme. Cultured human T47D breast cancer cells have the unique capacity to convert de novo [C-14] androstenedione into radioactive estrone and estradiol, as we have est ablished by repetitive HPLC purifications of the biosynthetic products formed. A very small amount of an unidentifed radioactive metabolite was also formed. We conclude that an endogenous androgen - aromatizing enzyme is present in T47D cells; a fact not previously reported for t his human breast cancer cell line. Furthermore, the new aromatase inhi bitor was found to cause a significant decrease in the growth of these cells. Our results indicate that: 1) growth of T47D cancer cells is e strogen-dependent, 2) substitution at the C-6 <<front>> face of an and rost-4-ene-3-one molecule does not cause rejection of the modified C19 male steroidhormone by the aromatase enzyme, 3) the new 6-hydroximino androstenedione inhibitor has the potential to act as a highly specifi c anti-aromatase breast cancer agent.