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United States Patent (19) 11 Patent Number: 4859,585 Sonnenschein Et Al

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United States Patent (19) 11 Patent Number: 4859,585 Sonnenschein Et Al United States Patent (19) 11 Patent Number: 4859,585 Sonnenschein et al. 45 Date of Patent: Aug. 22, 1989 54 IN-VITRO METHODS FOR IDENTIFYING Schatz et al., Endocrinology, 115: 501-506 (1984). COMPOSITIONS WHICH ARE AGONSTS Paz et al., J. Cell Biol, 99: 339a, No. 1256 (1984). AND ANTAGONSTS OF ESTROGENS Sonnenschein & Soto, Proc. AACR, 26: 198, No. 783 (1985). (75 Inventors: Carlos Sonnenschein; Ana M. Soto, Soto et al., Proc. AACR, 26: 198, No. 784 (1985). both of Boston, Mass. Soto & Sonnenschein, Endo. Soc., 67th Annual Mtg., 73 Assignee: Trustees of Tufts College, Medford, No. 1152 (1985). Mass. Sonnenschein & Soto, Endo. Soc., 67th Annual Mtg., No. 663 (1985). 21 Appl. No.: 853,240 Sonnenschein et al., Life Sciences, 37:387-394 (1985). 22 Filed: Apr. 17, 1986 Soto & Sonnenschein, J. Steroid. Biochem., 23: 87-94 51) Int. Cl* ............................................... C12O 1/02 (1985). 52 U.S. Cl. ...................................................... 435/29 Schatz et al., J. Cell. Physiol., 124: 386-390 (1985). 58) Field of Search ............................... ... 435/29 Papendorp et al., J. Cell. Physiol, 125: 591-595 (1985). 56 References Cited Primary Examiner-Esther M. Kepplinger Assistant Examiner-David A. Saunders PUBLICATIONS Attorney, Agent, or Firm-David Prashken Coezy et al, Cancer Research, 42, 317-323, 1982. 57 ABSTRACT Reddeletal, Cancer Research, 43, 4618-4624, 1983. Soto et al, Biochem. Biophys. Res. Communic, 122, The present invention provides two general protocols 1097-1103, 1984. by which a substance may be identified and character Biotechnology, Fisher Scientific, 1983, p. 97. ized as an estrogen agonist and/or an estrogen antago Sonneschein et al., J. Cell Biol, 99, 3392, 1984. nist. The protocols are in-vitro methods which utilize Sonneschein et al, Biol. Abstr., 80, Abstr. No. 69567, estrogen dependent cells in culture and a medium com 1985. prising an inhibitor endogenous to the sera of adult Stack & Gorski, Endocrinology, 115: 1141-1150 (1984). humans which is able to prevent the proliferation of Sonnenschein & Pierce, Cancer Research, 41: 4742-4743 cultured cells in-vitro. The methodology is rapid, repro (1981). ducible, accurate and provides the major advantage of Laugier et al., Proc. Natl. Acad. Sci., USA, 80: 1621-1625 being able to screen large numbers of substances for (1983). their primary or secondary side effects in a large variety Soto & Sonneschein, J. Cell Biol, 97: 393a (1983). of medical and environmental applications. Soto & Sonnenschein, Proc. Am. Assoc. Can. Res., 25: 213 (1984). 13 Claims, 6 Drawing Sheets ---O-O-O---a : A to a - O Iol2O-ll IO-IOIO-9 O-8M CONCENTRATION PER WELL O is ESTRADIOL 8 a NACTIVE A a FULL ANTAGONST U.S. Patent Aug. 22, 1989 Sheet of 2 4859,585 A-A-A- IO S 9 8 7 6 a 5 4 3. O- - - - - - - - - - - - - - - - - p 2 ---O-O-O----a a - - - - f -- - - O IO-2 IO-ll IO-IO IO-9 O-8M O O-12 O-O-IOIO-9 O-8M CONCENTRATION PER WELL CONCENTRATION PER WELL O POSITIVE CONTROL (CELSESTRADIOL-CDHS) O a ESTRADIOL Or NEGATIVE CONTROL (CELLS+CDHSWITHOUTESTRADIOL) O = |NACTIVE &-PARTIAL ANTAGONIST (CELLS+ESTRADIOL+TEST SUBSTANCE) A - FULL ANTAGONIST Cy-FULLANTAGONIST (CELLS+ESTRADIOL+TEST SUBSTANCE) F G FG.2 - EMPERICAL DATA 5 ------- EXTRAPOLATED DATA 5 O 5 20 25 3O f M CONCENTRATION PERCENTAGE (PROCEDUREL) 3 6 9 O5 O 5 CALENDARDAYS MLLIGRAMS OF PROTEIN (PROCEDUREI) FG.3 F. G. 4 U.S. Patent Aug. 22, 1989 Sheet 2 of 2 4859,585 -O-O-O-O-O-O-O-O." O O.2 O4 O6 O.8 O .2 INHIBITOR CONCENTRATION (MILLIGRAMS PROTEIN) () = CELS-- INHIBITOR PREPARATION O = CELLS-- INHIBITOR PREPARATION+ESTRADIOL F.G. 5 10% CHARCOAL - 10% CHARCOAL - DEXTRAN STRIPPE) DEXTRAN STRIPPED MALE HUMAN FEMALE HUMAN SERA SERA NO ESTRADOL 3 x 10" ESTRADIOL 4,859,585 2 Macmillan Publishing Company, 1985, pages N-VITRO METHODS FOR IDENTIFYING 1421-1423. Accordingly, there has been increasing COMPOSITIONS WHICH AREAGONISTS AND interest in finding newly synthesized compositions and ANTAGONSTS OF ESTROGENS new uses for previously known compounds which are demonstrably estrogenic, that is, able to induce estrus. FIELD OF THE INVENTION Probably the best known examples are: ethinyl estradiol The present invention is concerned generally with (Estinyl); 3-methyl-ethinyl estradiol (Mestranol); and methods for identifying chemical compositions whose diethylstilbestrol (DES); methallenestril (Vallestril); pharmacological activities mimic or contradict the ac and doisynoestrol (Fenocylin). tion of naturally occuring estrogens and is particularly 10 Despite the apparent wide interest in compositions directed to in-vitro protocols which will classify phar said to be estrogenic, surprisingly few assay methods macologically active compositions as being either full are available to detect and identify those compositions or partial agonists and/or full or partial antagonists of which have the pharmacological ability to initiate es estrogens. trus. To date, only three are recognized: the cornifica 15 tion of vaginal cells in the spayed rodent; the change in BACKGROUND OF THE INVENTION weight of excised wet uterine tissue; and the ability of Naturally occurring or endogeneous estrogens con the composition to bind competitively with radiola stitute one class of steroid sex hormones which are beled estradiol in cytosol preparations, and homoge produced in the ovaries and other tissues in the body mates of immature uterine cells. Each of these will be and which stimulate the growth and development of the 20 briefly summarized. secondary sex characteristics in female animals. The The cornification of vaginal cells is the classical naturally occurring estrogens are estrone (also known methodology by which the naturally occurring endoge as E), estradiol-17B (also known as E2), and estriol nous estrogens were discovered. The assay methodol (also known as E3) The secretion of such estrogens ogy has remained substantially unaltered since its first controls in major part the normal sexual cycle in hu 25 use Allen and Doisy, J. Am. Med. Assoc. 81:819 (1923). mans and animals which appears characteristically as The assay is based upon the ability of a substance to the changes of estrus, a period of mating activity produce the typical estrus response in-vivo when in marked by intense sexual urge (sexual heat). Historically, it has been demonstrated that removal of jected into castrated rats or mice. A positive reaction is both ovaries from an adult normal female mammal abol 30 characterized by the distinct change in the structure of ishes estrus, that is the period of intense sexual urge and the cells lining the vagina in which the cells acquire a mating activity; equally important, it was found that unique, cornified appearance easily distinguishable from entering into the state of estrus is accompanied and cells in the resting state. Microscopic examination of characterized by visually identifiable and distinct vaginal smears provides empirical evaluation of the changes in the cell structure of the cells lining the va 35 estrus condition of the living animal. Traditionally, the gina. At the height of estrus, the cell lining acquires a activity of a substance under test is expressed in terms of unique, cornified character easily distinguishable from mouse or rat units. A mouse unit is the quantity of en those cells present when the animal is resting, in a non dogenous estrogen that just suffices to produce estrus in estrus condition, in an immature animal which does not a castrated animal. Typically, the mouse unit varies display full sexual activity of an adult, or has been cas 40 from about 0.04-0.1 microgram (hereinafter "ug”) of trated. On this historical and technical basis, the natu pure estrone; the international unit of activity has been rally occurring estrogens were first isolated and puri set as 0.1 ug of estrone. fied. Concomittantly, the term "estrogen' is defined The uterine wet weight assay identifies substances only in operational form as-any substance able to in which induce estrus by measuring the increase in the duce estrus in a living animal. In consequence, all other 45 mass weight of uterine tissues, the increase in weight pharmacologically active compositions, steroidal and being directly attributable to the interaction between nonsteroidal which were subsequently synthesized and those substances and the secondary sex organs. The test which were demonstrably able to induce estrus or to utilizes immature and/or adult ovariectomized mice and mimic the induction of estrus have been conventionally rats which are administered a test substance subcutane classified as "estrogenic' regardless of their chemical 50 ously using an inert fluid such as corn oil. Groups of six structure or their mechanism of action. to ten animals are typically injected daily for three days The value of naturally occuring estrogens and syn with the putative estrogenic substance and sacrificed on thetic compositions demonstrating "estrogenic' activ the fourth day. The uteri are removed, dissected free of ity has been in their medical and therapeutic uses, many extraneous tissue and the fluid contents expelled. Each of which continue to be the subject of considerable 55 excised uterine tissue is then blotted and the wet weight controversy. A traditional listing of the therapeutic determined individually. The increased wet weight of applications for estrogens alone or in combination with the uterine tissue in comparison to those from control other active agents includes: oral contraception; relief animals receiving only the inert fluid identifies
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