Development of new anti-estrogens and their effects on DMBA-induced hormone dependent mammary tumors of the rat

3,4-di(3'-hydroxyphenyl)-hexane (I) [68266-24-0], 3,3'-dihydroxy-alpha ,beta -diethylstilbene (II) [80149-87-7], 3,4-epoxy-3,4-di(4'-hydroxyphenyl)-hexane (III) [6052-82-0], and 3,4-epoxy-3,4-di(3'-hydroxyphenyl)-hexane (IV) [80149-95-7] all inhibited DMBA [57-97-6]-induced, hormone-dependent, mammary carcinoma in rats. I was also prophylactic against DMBA induction of mammary carcinoma. estradiol [50-28-2] Antagonized the effect of I on a human breast cancer cell line (MCF-7), indicating that I acts as an antiestrogen in inhibiting mammary tumors. The marked superiority of IV over that of II as an antitumor agent suggests a contribution to the antitumor action of the epoxide group

Entwicklung neuer Antiostrogene vom Typ des 3,3'-Dihydroxy-alpha, beta-diathylstilbens und ihre Prufung am DMBA-induzierten, hormonabhangigen Mammacarcinom der SD-Ratte

Development of new antiestrogens of the 3,3'-dihydroxy-alpha, beta-diethylstilbene-type and their evaluation on the DMBA-induced hormone dependent mammary carcinoma of the SD-rat (author's transl). The displacement of the phenolic OH-group of diethylstilbestrol into the 3,3'-position (trans-3,3'-dihydroxy-alpha, beta-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-induces, 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 alpha, beta-bound ethyl groups in III by other alkyl chains leads to no further increase of the antiestrogenic and antitumor activity

N,N'-Dialkylbis(dichlorophenyl)ethylenediamines and -imidazolidines: relationship between structure and estradiol receptor affinity

Diastereomeric N,N'-dialkylbis(dichlorophenyl)ethylenediamines and the corresponding imidazolidines with chlorine in the 2,4, 2,6, 3,4, and 3,5 positions were synthesized. Only the stereoisomers of the 2,6-dichloro-substituted compounds exhibit for N-CH3 (2e, 3e), N-C2H5 (2f, 3f), and N-C3H7 (2g, 3g) an affinity to the estradiol receptor (Ka values ranging from 9.1 X 10(4) to 9.1 X 10(6)), because the nitrogen atoms are shielded by the ortho-located chlorine atoms; therefore, a binding interaction with hydrophobic receptor areas is possible. These substances show weak uterotrophic activity and no significant effect on the growth of the DMBA-induced hormone-dependent mammary adenocarcinoma of the rat

Experimental chemotherapy of the breast cancer

A review with 82 refs

3,4-bis(3'-hydroxyphenyl)hexane--a new mammary tumor-inhibiting compound

The 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 greater than Ka4a greater than Ka4d greater than 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 hormone-dependent 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

Diethylstilbestrol-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 not 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 no significantly better effect on the DMBA-induced mammary carcinoma of the SD rat than DES