EFFECTS OF PROGESTAGENS AND ORG-OD14 IN IN-VITRO AND IN-VIVO TUMOR-MODELS

Sex steroids, in particular estradiol(E2) and progesterone (P4), play, together with other hormones and growth factors, a role in the develo pment of normal breast tissue. The effect of four progestagens (noreth isterone, 3-ketodesogestrel, gestodene and P4) and Org OD14, a steroid with weak estrogenic, progestagenic and androgenic properties were st udied on growth of breast tumor cells in vitro using two subclones of MCF-7 (H and A) and T47D (S and A) cells. In addition, we investigated the effects of 3-ketodesogestrel, gestodene and Org OD14 on the growt h of 7,12-dimethyl-benz(a)anthracene(DMBA)-induced mammary tumors in r ats. In the in vitro assays with MCF-7 cells norethisterone, 3-ketodes ogestrel and gestodene stimulated growth only at high doses (greater t han or equal to 10(-7)M), whereas P4 had no effect. Gestodene was more potent than 3-ketodesogestrel and norethisterone. Org OD14, stimulate d cell growth at a dose of 10(-8)M, while E2 is active at 10(-10)M. In T47D-A cells similar effects were found, but the subclone S did not r espond to the progestagens and Org OD14. The two T47D-S the progestage ns and Org OD14 inhibited, while in T47D-A these compounds did not mod ulate the effect of E2. In the DMBA model we found that gestodene and 3-ketodesogestrel were able to inhibit tumor growth to the same extent . Surprisingly, Ord OD14 was even more effective in the DMBA model usi ng the therapeutic approach. Using the prophylaxic approach tumor deve lopment was delayed and tumor growth was strongly suppressed. The inhi bitory effects of Org OD14 on tumor growth in the DMBA model may be at tributed to its mixed hormonal profile. From these studies we conclude that different cell lines and even subclones thereof respond quite di fferently to steroids. Both in vitro and in vivo studies are required to judge whether synthetic steroids might be involved in an increased risk for the development of breast tumors.