The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary tumours.

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.

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

Differential centrifugation and gel-chromatography techniques have been employed to study the distribution and molecular forms of acid phosphatase in rat mammary tumours induced by 7,12-dimethylbenz[a]anthracene. With p-nitrophenylphosphate as substrate three distinct forms of acid phosphatase activity were separated on gel chromatography.



Enzyme I (Mr > 200000) and enzyme II (Mr 120000) were found to have similar biochemical properties and differential centrifugation indicated that both enzymes are present in a sedimentable fraction. Disruption of a mitochondrial-lysosomal fraction by freezing and thawing released 45% of the total acid phosphatase of the fraction into a soluble phase. Treatment with detergent solubilized the bound enzyme. The possibility of two forms of acid phosphatase, one bound and one freely soluble, in the lysosomes of the rat mammary tumour is discussed.



Enzyme III (Mr 30000) is localized in the soluble fraction of the tumour cell and is biochemically distinct from enzymes I and II.



The overall findings are examined in relation to the properties and distribution of acid phosphatase in other tissues.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1974.tb03454.x

Distribution and Some Properties of Acid Phosphatase in the 7,12-Dimethylbenz[a]anthraccne-Induced Rat-Mammary Carcinoma

The mechanism of the antitumor activity of 3,4-bis(3'-hydroxyphenyl)hexane (I) [71953-72-5] was studied in rats with DMBA-induced mammary tumors. Changes in the tumor enzyme levels and histol. characteristics during I treatment were examd. and compared with those induced by hexestrol, tamoxifen, and ovariectomy. It was not possible to conclude whether the estrogenic or antiestrogenic activity of I was responsible for its antitumor activity.

3,4-bis(3'-hydroxyphenyl)hexane--a new mammary tumor-inhibiting compound. Studies on the mechanism of action on the DMBA-induced, hormone-dependent mammary tumor of the rat.

Irene Bagnall

Papers

Lysosomal enzymes in 7, 12-dimethylbenz[a]anthracene-induced mammary carcinomas after ovariectomy