G. Kranzfelder

Entwicklung neuer Antiöstrogene vom Typ des 3,3′-Dihydroxy-α,β-diäthylstilbens und ihre Prüfung am DMBA-induzierten, hormonabhängigen Mammacarcinom der SD-Ratte

SummaryThe displacement of the phenolic OH-group of diethylstilbestrol into the 3,3′-position (trans-3,3′-dihydroxy-α,β-diethylstilbene compd. III) leads to a strong decrease of the estrogenic effect under conservation of the receptor affinity. In vitro, III inhibits the estradiol-receptor-interaction competitively and, in vivo, antagonises the uterotropic effect of estrone in the mouse. In tests with the DMBA-induced, hormone-dependent mammary carcinoma of the rat a dose-dependent strong decrease of tumor size and yield is achieved under the influence of III, due to the antiestrogenic, properties of III. The replacement of the α,β-bound ethyl groups in III by other alkyl chains leads to no further increase of the antiestrogenic and antitumor activity.ZusammenfassungDie Verlagerung der phenolischen OH-Gruppen des Diäthylstilböstrols in die 3,3′-position (trans-3,3′-Dihydroxy-α,β-diäthylstilben, Verb. Nr. III) führt unter Erhaltung der Rezeptoraffinität zu einer starken Abnhme der östrogenen Wirkung. III hemmt in vitro die östradiol-Rezeptor-Wechselbeziehung kompetitiv und antagonisiert in vivo bei der Maus die uterotrope Wirkung des Östrons. In Versuchen am DMBA-induzierten, hormonabhängigen Mammacarcinom der Ratte kommt es, unter III-Einwirkung dosisabhägig zu einer starken Abnahme von Tumorgröße und-zahl, die durch die antiöstrogenen Eigenschaften von III bedingt, ist. Der Austausch der α,β-ständigen Äthylreste in III durch andere Alkylketten führt zu keiner weiteren, Steigerung der antiöstrogenen und tumorhemmenden, Wirkung.

3,4-Bis(3′-hydroxyphenyl)hexane — A new mammary tumor-inhibiting compound

SummaryThe syntheses of the hexestrol derivatives 3,4-bis-(3′-hydroxyphenyl)hexane (4a), 3,4-bis(4′-fluoro-3′-hydroxyphenyl)hexane (4b), 3,4-bis(3′, 4′dihydroxyphenyl)hexane (4c), and 3,4-bis(3′,4′-diacetoxyphenyl)hexane (4d) are described. All compounds showed a marked, competitive inhibition of the estradiol receptor interaction (Ka4c>Ka4a>Ka4d>Ka4b). Evaluated in the mouse uterine weight test compounds 4c and 4d almost reached the estrone effect, whereas 4a and 4b did not produce full uterotrophic response. Compounds 4a-d antagonized the estrone stimulated uterine growth of the immature mouse. Compound 4a (NSC-297170) exhibited a specific, dose-related growth inhibition of the estrogen responsive MCF-7 human breast tumor cell line. Tested on the 9,10-dimethyl-1,2-benzanthracene-induced hormonedependent mammary adenocarcinoma of the Sprague-Dawley rat all compounds showed marked inhibition of tumor growth. As in all experiments compounds 4a and 4b, which is resistant to hydroxylation in 4′position exhibited an identical pattern of action, which is different from that shown by compound 4c, the effect of compound 4a cannot be explained by its possible catechol metabolite 4c.

The tumor-inhibiting effect of diethylstilbestrol-3,4-oxide

SummaryDiethylstilbestrol-3,4-oxide (DES-3,4-oxide), one of the possible cancerogenic metabolites of the well-known estrogen diethylstilbestrol (DES), is a potential estrophilic cytostatic compound. It shows a very good affinity to the estrogen receptor. The uterotrophic activity determined in the mouse uterine weight bioassay is nearly identical with that of DES. Potential alkylating properties could neither be detected in the p-NBP test nor in the prophage induction test. DES-3,4-oxide [0.01–1.0 mg/kg body weight (b. wt.)] markedly inhibited the growth of the DMBA-induced hormone-dependent mammary carcinoma of the SD rat, as well as the growth of a hormone-dependent postmenopausal (but not of a premenopausal) human mammary carcinoma serially transplanted in nude mice. However, DES-3,4-oxide had not significantly better effect on the DMBA-induced mammary carcinoma of the SD rat than DES.

Anti-proliferative effects of 1,2-diphenylethane oestrogens and anti-oestrogens on human breast cancer cells.

SummaryThe anti-tumour activities of 1,2-diphenylethane oestrogens (hexoestrol and orthohexoestrol) and anti-oestrogens (metahexoestrol, tetramethylHES, and metatetramethylHES) were studied on the human MCF-7 and MDA-MB-231 breast cancer cell lines. On the E2R-positive MCF-7 cell line, all test compounds exhibited a dose-dependent inhibition of cell proliferation, but no correlation between anti-proliferative activity and binding affinity for the E2R was found. Tested on the E2R-negative MDA-MB-231 cell line, metahexoestrol also showed dose-dependent inhibitory effects, but higher concentrations were necessary than on the MCF-7 cell line. From this it is concluded that the anti-proliferative effect is specific and at least partially mediated via the E2R. Combination of metahexoestrol (10−6M) with E2 (10−9 to 10−7M) gave no rescue effect. It is therefore suggested that this compound might be useful for therapy in the presence of high oestrogen levels, i.e. in pre-menopausal patients. The test compounds (10−8 to 10−6M) could rescue the inhibitory effect of tamoxifen (10−6M) in a dose-dependent manner, except in the cases of metahexoestrol (10−6M) and tetramethylHES (10−6M). The latter compound exhibited a strongly additive effect at this concentration.