EFFECTS OF 2 CLASSES OF PROGESTAGENS, PREGNANE AND 19-NORTESTOSTERONEDERIVATIVES, ON CELL-GROWTH OF HUMAN BREAST-TUMOR CELLS .1. MCF-7 CELL-LINES

The effects of two classes of progestagens, e.g. pregnane [Org 2058, m edroxyprogesterone acetate (MPA), R5020, progesterone (PROG)] and 19-n ortestosterone derived progestagens [3-ketodesogestrel (KDG), levonorg estrel (LNG), gestodene (GES), norethisterone (NE), Org 30659] on prol iferation of three estradiol (E(2))-dependent human breast tumor MCF-7 cell lines of different origin [Van der Burg (B), Litton bionetics (L ) and McGrath (M)] were studied. The pregnane derivatives hardly stimu lated cell growth at 10(-6) M in MCF-7 B and L cells except for Org 20 58 in B cells, whereas in M cells a statistically significant growth i nduction was observed except for FROG. The 19-nortestosterone derivati ves induced cell growth at doses at 10(-7) M or higher in all three ce ll lines. NE, GES and Org 30659 were more potent stimulators than KDG and LNG at 10(-7) M. E(2) already showed maximal stimulation at 10(-10 ) M. For all three cell lines, the effects and ranking of the individu al progestagens were similar. Antiprogestagens, like RU 38486 and Org 31710 could not block these stimulatory effects while antiestrogens li ke 4-hydroxytamoxifen and ICI 164,384 could. This suggests that cell g rowth by the above-mentioned progestagens occurs via an interaction wi th the estrogen receptor. Indeed, displacement studies with cytosol fr om MCF-7 M cells revealed that at very high concentrations NE, GES and Org 30659 were able to displace 50% of the radiolabelled E(2), while KDG and LNG could not. Relative binding affinities (RBAs) were 0.010, 0.025 and 0.015% for NE, GES and Org 30659, respectively. The effect o f the two classes of progestagens on cell proliferation was also inves tigated at several dose levels in combination with E(2) (10(-10) M) in the MCF-7 B cell line. This resulted in a statistically significant i nhibition of cell growth with R5020, MFA and most of the 19-nortestost erone derivatives at concentrations of 10(-8) M. Org 2058 and NE did n ot have any influence on E(2)-induced growth. The inhibitory effects c ould not be blocked by antiprogestagens. In summary these studies with 3 subclones of MCF-7 cells show that the pregnane derived progestagen s stimulate growth only in one subclone, whereas the 19-nortestosteron e derived progestagens do so in all three subclones. The progestagens possess estrogenic activity only at high pharmacological doses, being 10,000 times weaker than estradiol. In combination with estrogens most progestagens gave a reduction of E(2)-stimulated growth in the B subc lone.