`
`Alternate Antiestrogens and Approaches to the Prevention of
`Breast Cancer
`
`V. Craig Jordan, PhD, DSc
`
`Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, IL 60611
`
`Abstract The biological rationale and extensive clinical experience with the breast cancer drug
`tamoxifen make it the agent of choice for testing as a breast cancer preventive. However, concerns
`(Jordan and Morrow, Eur I Cancer, in press) about development of endometrial cancer in patients and
`liver tumors in rats with tamoxifen has encouraged the investigation of other antiestrogens. At present
`no compounds are available to replace tamoxifen, but two triphenylethylenes, toremifene and droloxi-
`fene, have been tested in postmenopausal women to treat advanced breast cancer. The response rates
`are similar to those observed with tamoxifen (i.e., approximately 35% [CR + PR] in unselected patients),
`although dosage regimens of the new antiestrogens are higher than the 20 mg tamoxifen required daily.
`Doses of up to 200 mg toremifene daily are being tested and studies use up to 100 mg droloxifene daily.
`Side effects appear comparable, but neither droloxifene nor toremifene produce liver tumors in rats.
`Tamoxifen produces DNA adducts, whereas toremifene and droloxifene appear to be only weakly
`active. A new tamoxifen analogue, idoxifene, is entering clinical trial. The drug is designed to be meta-
`bolically stable so that there will be low carcinogenic potential.
`In contrast, a novel strategy may be considered to be of value to protect women from developing
`breast cancer. It is known from laboratory and clinical studies that antiestrogens protect bone and
`prevent rat mammary cancer. One compound, raloxifene, is being tested as an agent to treat osteoporo-
`sis. If the drug becomes generally available to prevent osteoporosis in postmenopausal women, a
`beneficial side effect may be a reduction in breast cancer risk. This broad-based strategy may prove
`more effective than focusing on small groups of women with a high risk for breast cancer alone.
`Protection from breast cancer may be as an advantageous side effect from the successful treatment of
`other diseases in women.
`© 1995 Wiley-Liss, Inc.
`
`Key words: Breast cancer, droloxifene, endometrial cancer, liver cancer, raloxifene, tamoxifen, toremifene
`
`Tamoxifen (Fig. 1) is the endocrine therapy of
`choice for selected patients with all stages of
`breast cancer [1]. An overview analysis [2] dem—
`onstrates a survival advantage for both node—
`positive and node-negative patients who received
`adjuvant tamoxifen therapy. Tamoxifen can re—
`duce the incidence of fatal myocardial infarction
`[3,4] and stabilize bone density in postmeno—
`
`
`Address correspondence to V. Craig Jordan, PhD, DSc,
`Professor of Cancer Pharmacology, Director, Breast Cancer
`Research Program, Robert H. Lurie Cancer Center,
`Northwestern University Medical School, 303 E. Chicago
`Avenue, Olson Pavilion 8258, Chicago, IL 60611.
`© 1995 Wiley-Liss, Inc.
`
`its
`pausal patients [5—7], an incentive to test
`worth as a preventive in women who are only at
`risk for breast cancer [8,9].
`Tamoxifen has a low incidence of side effects
`
`[1], but its balance of estrogenic and antiestro-
`genic action that is considered an advantage [9]
`may result in more serious complications. Con-
`cerns about endometrial carcinoma [10—13] and
`developing liver tumors [14,15] have resulted in
`new drug development programs to produce
`novel therapeutic agents with improved toxico-
`logical profiles.
`This article will review progress in developing
`new antiestrogens and describe the rationale for
`each drug design. All of the compounds under
`
`AstraZeneca Exhibit 2011 p. 1
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`52
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`Jordan
`
`investigation have their genesis in pharmacologi—
`cal investigations of tamoxifen. For convenience,
`the drugs have been divided into three main
`groups—tamoxifen analogues, derivatives of
`tamoxifen metabolites, or novel antiestrogens.
`
`TAMOXIFEN ANALOGS
`
`A current concern with the use of tamoxifen
`
`is development of endometrial carcinoma and
`the potential to induce hepatocellular carcinoma.
`Tamoxifen is a partial estrogen agonist; it has
`been suggested that hydroxylation, dealkylation
`of the side chain, and isomerization could pro-
`duce estrogenic metabolites that stimulate tumor
`growth [16—18]. However,
`this hypothesis has
`recently been found untenable; stable derivatives
`of tamoxifen that cannot isomerize after meta-
`
`bolic activation also provoke growth of tamoxi-
`fen-stimulated tumors under laboratory condi-
`tions [19,20]. Nevertheless, new analogs of tam-
`oxifen that may be metabolically resistant and
`reduce the potential for carcinogenicity are being
`evaluated in clinical trials.
`
`Toremifene
`
`Chlorination of the ethyl side chain of tamoxi»
`fen to produce toremifene (Fig. 1) reduces anti-
`estrogenicity and decreases potency as an anti-
`tumor agent. However,
`toremifene appears to
`possess an advantage over tamoxifen because it
`has a reduced ability to induce rat liver tumors
`[21,22]; unlike tamoxifen, toremifene does not
`produce DNA adducts in the rat liver [22—24].
`There is currently no evidence that tamoxifen
`does increase the incidence of hepatocellular car—
`cinoma (at least above the ten-fold increased risk
`
`observed with oral contraceptives [24]). How-
`ever, if hepatocarcinogenicity becomes an issue
`in humans, toremifene could replace tamoxifen
`in prevention studies. The issue of endometrial
`carcinoma is unresolved because there is no ex—
`
`perience with long-term toremifene therapy.
`Conversely,
`there is no reason to believe that
`toremifene will not produce an identical risk for
`endometrial carcinoma as tamoxifen, i.e., 2—3 fold
`[13].
`
`Toremifene has been extensively tested for the
`treatment of advanced breast cancer [25-28]. The
`
`dose range is between 60—280 mg daily, but the
`response rate is similar to tamoxifen, i.e., approx-
`
`imately 30% of unselected patients. Initial reports
`that high dose toremifene (>100 mg) will pro-
`duce responses in patients with tamoxifen-resist-
`ant disease [29] are unsupported; current clinical
`studies demonstrate cross-resistance. A cross-
`
`over study from Denmark that compared 40 mg
`tamoxifen daily with 240 mg toremifene daily
`found cross-resistance with both therapies [30].
`No subsequent responses were observed at cross-
`over. Similarly, an American study found only a
`5% response in 105 patients who had failed tam-
`oxifen but were then treated with 200 mg toremi—
`fene daily [31]. A major clinical trial of tamoxifen
`versus toremifene to treat advanced breast cancer
`
`in postmenopausal women has been completed
`in the United States. An analysis of the results is
`anticipated and FDA approval will be sought in
`1995.
`
`Idoxifene
`
`Hydroxylation of tamoxifen to produce 4-hy-
`droxytamoxifen increases antiestrogenic potency
`[32]. However, this metabolic activation is an ad-
`vantage, but not a requirement, for antiestrogenic
`activity. Blocking 4-hydroxylation with halogen
`substitutions results in compounds of weaker
`antiestrogenic potency [33], but does not reduce
`partial agonist activity. It has been reasoned that
`a compound with reduced 4-hydroxylation and
`a stable alkylaminoethoxy side chain may have
`less carcinogenic potential. Idoxifene (Fig. 1) is a
`weak antiestrogen in the rat but exhibits antitu-
`mor activity in rat mammary carcinoma models
`[34]. Idoxifene is resistant to metabolic degrada-
`tion in laboratory tests and is detected as the
`principal compound in the serum of treated pa-
`tients. The compound is currently undergoing
`Phase I/ II clinical trials in England.
`
`DERIVATIVES OF
`TAMOXIFEN METABOLITES
`
`TAT 59
`
`This antiestrogen is a derivative of 4—hydroxy—
`tamoxifen. Although 4-hydroxytamoxifen is a
`potent antiestrogen in vitro [35,36] and can ex-
`hibit antitumor activity in both carcinogen-in-
`duced rat mammary carcinoma models [37] and
`athymic mice inoculated with MCF-7 breast tu-
`mors [38], higher doses are required to produce
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`53
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`
`
`IDOXIFENE
`(1993)
`
`TAMOXIFEN
`(1971)
`
`
`
`TOREMIFENE
`(1986)
`
`Fig. 1. Tamoxifen analogues that are in clinical trial. The date in parentheses indicate the year breast
`cancer studies were reported.
`
`ANIMAL STUDIES
`
` MU
`
`4-HYDROXYTAMOXIFEN
`
`metabolism *
`
`H0
`
`3,4-DIHYDROXYTAMOXIFEN
`
`H0
`DROLOXIFENE
`
`Fig. 2. The derivatives of tamoxifen that have used metabolite mimicry to design an antibreast cancer
`agent.
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`54
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`Jordan
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`equivalent effects because the drug is vulnerable
`to phase II metabolism. TAT 59 is phosphory-
`lated (Fig. 2) at the 4—hydroxy position, which
`could protect it from phase II metabolism, but
`the drug probably needs to be dephosphorylated
`to produce the active agent. Animal studies dem-
`onstrate antitumor activity [39]; the drug is in
`clinical trial in Japan.
`
`Droloxifene
`
`4—Hydroxytamoxifen and 3,4-dihydroxytamox—
`ifen are metabolites of tamoxifen [40]. Both have
`
`high binding affinity for the estrogen receptor
`and both exhibit antiestrogenic activity in rats
`[40]. Interestingly, 3,4-dihydroxytamoxifen has
`only weak estrogen agonist properties and is an
`antiestrogen in mouse uterine weight—tests [32,
`40]. This contrasts with tamoxifen and 4-hydro-
`xytamoxifen, both estrogens in mouse assays.
`Droloxifene (Fig. 2), the 3-hydroxylated analog of
`tamoxifen, has a high binding affinity for the
`estrogen receptor and blocks the growth of
`MCF-7 breast cancer cells in culture [41,42]. It
`
`does not produce DNA adducts in laboratory
`models of genotoxicity [23].
`
`Droloxifene has had extensive clinical testing
`throughout the world. Phase I testing found few
`side effects [43], but as anticipated, human phar-
`macokinetics demonstrate a rapid excretion, with
`low circulating blood levels [44]. Droloxifene has
`been used at daily doses up to 100 mg; response
`rates for unselected postmenopausal patients are
`between 30—40% [45]. Clinical trials in postmeno-
`pausal women with advanced disease are being
`planned in the United States.
`
`A NOVEL ANTIESTROGEN: RALOXIFENE
`
`The initial report [46] that raloxifene (origin—
`ally named keoxifene) preserves bone density in
`laboratory animals has been confirmed [47], and
`studies are being set up to evaluate the worth of
`raloxifene as an agent to prevent osteoporosis.
`Raloxifene has almost complete antiestrogenic
`activity in high doses in the rat and mouse uter-
`us [48] and exhibits antitumor action in the rat
`
`[49]. In contrast, it has an estrogen-like action to
`lower circulating cholesterol and preserves bone
`density in the rat [47].
`Large doses will be used in clinical trials be-
`cause raloxifene is rapidly cleared from the circu-
`
`
`
`4-HYDROXYTAMOXIFEN
`
`HIGH AFFINITY FOR ER
`(1977)
`
`RALOXIFENE
`HIGH AFFINITY FOR ER
`(1983/94)
`
`Fig. 3. A new clinical concept that is being developed to exploit the high affinity binding of antiestrogens
`to the estrogen receptor (ER) to produce a compound targeted to maintain bone density but block breast
`tumor development. Raloxifene is a high affinity antiestrogen that employs the principle first discovered with
`4—hyd roxytamoxifen.
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`lation. The hydroxyl groups make raloxifene
`(Fig. 3) vulnerable to phase II metabolism. Pre-
`liminary clinical studies using 200 and 600 mg
`raloxifene daily in several hundred postmeno-
`pausal women demonstrate that the higher daily
`dose will effectively lower cholesterol and reduce
`circulating osteocalcin levels [50].
`The novel use of raloxifene opens up an excit-
`ing therapeutic opportunity. Rather than select-
`ing women to treat With an antiestrogen to pre-
`vent breast cancer (with the added advantage of
`reducing their risk for osteoporosis and coronary
`heart disease), it is now possible to consider us-
`ing safe agents to treat all postmenopausal
`women to prevent osteoporosis and coronary
`heart disease, but with the added advantage of
`preventing breast cancer [cf review 51]. The na-
`tional impact of the new strategy on women's
`health may ultimately be greater than defining a
`narrow targeted population of women at risk
`only for breast cancer.
`
`SUMMARY
`
`The development of tamoxifen during the past
`25 years has revolutionized the treatment of
`breast cancer. There are now an estimated six
`
`million woman-years of experience worldwide
`with tamoxifen, and each year in the United
`States an estimated 80,000 women diagnosed
`with breast cancer plan to start a course of long-
`term tamoxifen therapy.
`The clinical evaluation of tamoxifen as a
`
`breast cancer preventive in high—risk women has
`opened the door to new therapeutic opportuni-
`ties. Pharmacological studies over the past two
`decades have predicted not only the value of
`tamoxifen as a therapeutic agent with positive
`effects on bones and lipids, but also predicted
`concerns with endometrial carcinoma and the
`
`potential for hepatocellular carcinoma. Numer-
`ous compounds have been screened, and several
`agents with improved toxicology are waiting for
`extensive clinical testing. A new range of anti-
`estrogens with different properties and poten-
`tially different applications will soon be available
`to treat estrogen-regulated diseases in women.
`
`REFERENCES
`
`1.
`
`Jordan VC (ed): "Long-term Tamoxifen Treatment for
`Breast Cancer." Madison: University of Wisconsin
`
`Press, 1994, pp 1—289.
`Early Breast Cancer Trialists' Collaborative Group:
`Systemic treatment of early breast cancer by hor-
`monal, cytotoxic or immune therapy. 133 Random-
`ized trials involving 31,000 recurrences and 24,000
`deaths among 75,000 women. Lancet 339:1—15, 1992.
`McDonald CC, Stewart H]: Fatal myocardial
`infarction in the Scottish adjuvant tamoxifen trial. Br
`Med ] 303:435—437, 1991.
`Stewart H], Everington D: Treatment of elderly
`patients with breast cancer. Br Med ] 304:1569—1570,
`1992.
`
`Love RR, Mazess RB, Barden HS, Epstein S,
`Newcomb PA, Jordan VC, Carbone PP, DeMets DC:
`Effects of tamoxifen on bone mineral density in post-
`menopausal women with breast cancer. N Eng] Med
`326:852—856, 1992.
`Kristensen B, Ejlertsen B, Dalgaard P, Larsen L,
`Holmegaard SN, Transbol I, Mouridsen HT: Tam-
`oxifen and bone metabolism in postmenopausal low
`risk breast cancer patients: A randomized study.
`] Clin Oncol 12:992—997, 1994.
`Ward RL, Morgan G, Dalley D, Kelly P]: Tamoxifen
`reduces bone turnover and prevents lumbar spine
`and proximal femoral bone loss in early postmeno-
`pausal women. Bone and Mineral 22:87—94, 1993.
`Nayfield SG, Karp IE, Ford LG, Dorr FA, Kramer BS:
`Potential role of tamoxifen in prevention of breast
`cancer. ] Natl Cancer Inst 83:1450—1459, 1991.
`Jordan VC: Gaddum Memorial Lecture: A current
`View of tamoxifen for the treatment and prevention
`of breast cancer. Br] Pharmacol 110:507—517, 1993.
`Fomander T, Rutqvist LE, Cedermark B, Glas U,
`Mattsson A, Silfversward C, Skoog L, Somell A,
`Theve T, Wilking N, Askergren ], Hjalmar ML:
`Adjuvant tamoxifen in early breast cancer: Occur-
`rence of new primary cancers. Lancet :117—120, 1989.
`Magriples U, Naftolin F, Schwartz PE, Carcangium
`]L: High grade endometrial carcinoma in tamoxifen-
`treated breast cancer patients. ] Clin Oncol 11:485—
`490, 1993.
`J, Coebergh JWW,
`van Leeuwen FE, Benraadt
`Kiemeney LALM, Gimbrere CHE, Otter R, Schouten
`L], Damhius RAM, Bontenbal M, Diepenhorst FW,
`van den Belt-Dusebout AW, van Tinteren H: Risk of
`endometrial cancer after tamoxifen treatment of
`breast cancer. Lancet 343:448—452, 1994.
`Fried] A, Jordan VC: What do we know and what
`don't we know about tamoxifen and the human
`uterus? Breast Cancer Res Treat 31:27—40, 1994.
`Greaves P, Goonetilleke R, Nunn G, Topham ], Orton
`T: Two-year carcinogenicity study of tamoxifen in
`Alderly Park Wistar derived—rats. Cancer Res 53:
`3919—3924, 1993.
`Iatropoulos M], Djordjevic MV,
`Williams GM,
`Kaltenberg OP: The triphenylethylene drug tamoxi-
`fen is a strong liver carcinogen in the rat. Carcino-
`genesis 14:315—317, 1993.
`Osborne CK, Coronado E, Allred DC, Wiebe V,
`DeGregorio M: Acquired tamoxifen resistance:
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`AstraZeneca Exhibit 2011 p. 5
`
`
`
`56
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`Jordan
`
`Correlation with reduced breast tumor levels of tam-
`
`oxifen and isomerization of transA—hydroxytamoxi-
`fen. ] Natl Cancer Inst 83:1477—1482, 1991.
`Osborne CK, Wiebe V], McGuire WL, Ciocca DR,
`DeGregorio M: Tamoxifen and the isomers of 4-hy-
`droxytamoxifen in tamoxifen—resistant tumors from
`breast cancer patients. ] Clin Oncol 10:304—310, 1992.
`Wiebe V], Osborne CK, McGuire WL, DeGregorio M:
`Identification of estrogenic tamoxifen metabolite(s) in
`tamoxifen-resistant human breast
`tumors.
`] Clin
`Oncol 10:990~994, 1992.
`Wolf DM, Langan-Fahey SM, Parker C], McCague R,
`]0rdan VC: Investigation of the mechanism of tam-
`oxifen-stimulated breast tumor growth with non-iso—
`merizable analogues of tamoxifen and metabolites.
`] Natl Cancer Inst 85:806—812, 1993.
`Osborne CK, ]arman M, McCague R, Coronado EB,
`Hilsenbeck SG, Wakeling AB: The importance of
`tamoxifen metabolism in tamoxifen-stimulated breast
`
`tumor growth. Cancer Chemother Pharmacol 34:89—
`95, 1994.
`Hirsimaki P, Hirsimake Y, Nieminen L, Bayne B]:
`Tamoxifen induces hepatocellular carcinoma in rat
`liver: A 1 year study with two antiestrogens. Arch
`Toxicol 67:49—54, 1993.
`]0rdan K, Radi L,
`Hard GC,
`Iatropoulos M],
`Kaltenberg OP, Imordi AR, Williams GM: Major dif-
`ferences in the hepatocarcinogenicity and DNA ad-
`duct forming ability between toremifene and tamoxi'
`fen in female CrlzCD (BR) rats. Cancer Res 53:4534—
`4541, 1993.
`White INH, de Mattheis F, Davis A, Smith LL,
`Croften-Sleigh C, Venitt S, Hewer A, Phillips DH:
`Genotoxic potential of tamoxifen and analogues in
`female Fisher F344 /n rats, DBA / 2 and C57BL/6 mice
`and in human MCL-5 cells. Carcinogenesis 13:2197—
`2203, 1992.
`Prentice RL: Epidemiologic data on exogenous hor-
`mones and hepatocellular carcinoma and selected
`other cancers. Prev Med 20:38—46, 1991.
`Valavaara R, Pyrhonen S, Heikkinen M, Risisanen P,
`Blanco G, Tholix E, Nordman E, Tuskiner P, Holsti
`L, Hajba A: Toremifene, a new antioestrogenic com-
`pound for treatment of advanced breast cancer Phase
`II study. Eur ] Cancer Clin Oncol 24:785-790, 1988.
`Gunderson S: Toremifene, a new antiestrogenic com-
`pound in the treatment of metastatic mammary
`cancer. ] Steroid Biochem 36:233—234, 1990.
`
`llliger H], Schmid H,
`Kaufman M, Possinger K,
`Hietanen T, ]ohansson R, Pyrhonen S, Valavaara R,
`Sinderman H: Toremifene clinical Phase II/III trials
`of a new antiestrogen in patients with advanced
`breast cancer. Contrib Oncol 37:50—57, 1989.
`Pyrhonen S: Phase III studies of
`toremifene in
`metastatic breast cancer. Breast Cancer Res Treat
`16:41—46, 1990.
`Pyrht‘jnen S, Valavaara R, Hajba A: Highdose toremi-
`fene therapy in tamoxifen failed patients with breast
`cancer. Breast Cancer Res Treat 14:138, 1989.
`Sterbygaard LE, Hemstedt ], Thomsen ]F: Toremifene
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`37.
`
`38.
`
`39.
`
`40.
`
`41.
`
`42.
`
`43.
`
`44.
`
`and tamoxifen in advanced breast cancer—a double
`blind crossover trial. Breast Cancer Res Treat 25:57—
`63, 1993.
`Vogel CL, Shemano I, Shoenfelder L, Gams RA,
`Green MR: Multicentre Phase II efficacy trial of tore-
`mifene in tamoxifen-refractory patients with advanc-
`ed breast cancer. J Clin Oncol 11:345—350, 1993.
`Jordan VC, Collins MM, Rowsby L, Prestwich G: A
`monohydroxylated metabolite of
`tamoxifen with
`potent antioestrogenic activity. ] Endocrinol 75:305—
`316, 1977.
`Allen KE, Clark ER, ]ordan VC: Evidence for the
`metabolic activation of non-steroidal antioestrogens:
`A study of structure-activity relationships. Br] Phar-
`macol 71:83—91, 1980.
`Chander SK, McCague R, Lugmani Y, Newton C,
`Dowsett M, ]arman M, Coombes RC: Pyrrolidino—4-
`iodotamoxifen and 4—iodotamoxifen, new analogues
`of the antiestrogen tamoxifen for the treatment of
`breast cancer. Cancer Res 51:5851—5858, 1990.
`Coezy E, Borgna ]L, Rochefort H: Tamoxifen and
`metabolites in MCF-7 cells: Correlation between
`
`binding to estrogen receptors and cell growth inhibi-
`tion. Cancer Res 42:317—323, 1982.
`Lieberman ME, Gorski ], ]ordan VC: An estrogen
`receptor model to describe the regulation of prolactin
`synthesis by antiestrogens in vitro.
`] Biol Chem
`258:4741-4745, 1983.
`Jordan VC, Allen KE: Evaluation of the antitumour
`activity of
`the nonsteroidal antioestrogen mono—
`hydroxytamoxifen in the DMBA-induced rat mam-
`mary cancer model. Eur] Cancer 16:239—251, 1980.
`Gottardis MM, Robinson SP, ]0rdan VC: Estradiol-
`stimulated growth of MCF—7 tumors implanted in
`athymic mice: A model
`to study the tumoristatic
`action of tamoxifen. ] Steroid Biochem 30:311—314,
`1988.
`
`Toko T, Sigimoto Y, Matsuo KI: TAT59, a new tri-
`phenylethylene derivative with antitumor activity
`against hormone-dependent tumors. Eur J Cancer
`26:397—404, 1990.
`Jordan VC, Dix C], Naylor KE, Rowsby L, Prestwich
`G: Nonsteroidal antiestrogens: Their biological effects
`and potential mechanisms of action.
`J Toxicol
`Environ Health 4:364—390, 1978.
`Loser R, Seibel K, Roos WK, Eppenberger U: In vivo
`and in vitro antiestrogenic action of 3-hydr0xytam~
`oxifen,
`tamoxifen and 4-hydroxytamoxifen. Eur ]
`Cancer Clin Oncol 21:985—990, 1985.
`Epperberger U, Wosikowski K, Kiing W: Pharmaco‘
`logic and biologic properties of droloxifene, a new
`antiestrogen. Am ] Clin Oncol 14 (Suppl):SSvSI4,
`1991.
`
`Buzdar AU, Kau S, Hortobagyi G, Holmes F, Theriau
`HR, Bower D, Krakoff 1: Phase I trial of droloxifene
`in patients with metastatic breast cancer. Cancer
`Chemother Pharmacol 33:313—316, 1994.
`Grill H], Pollow K: Pharmacokinetics of droloxifene
`and its metabolites in breast cancer patients. Am ]
`Clin Oncol 14 (Suppl):S21—SZ9, 1991.
`
`AstraZeneca Exhibit 2011 p. 6
`
`
`
`Antiestrogens Prevent Breast Cancer
`
`57
`
`45.
`
`46.
`
`47.
`
`48.
`
`Bruning PF: Droloxifene, a new antioestrogen in
`postmenopausal advanced breast cancer: Preliminary
`results of a double-blind dose finding Phase II study.
`Eur J Cancer 28Azl404—1407, 1992.
`Jordan, VC, Phelps E, Lindgren IU: Effects of anti-
`estrogens on bone in castrated and intact female rats.
`Breast Cancer Res Treat 10:31—35, 1987.
`Black L], Sato M, Rowley ER, Magee DE, Bekele A,
`Williams DC, Cullinan GL, Bendele R, Kauffman RF,
`Bensch WR, Frolik CA, Termine JD, Bryant HU: Ral-
`oxifene (LY139481HC1) prevents bone loss and
`reduces serum cholesterol without causing uterine
`hypertrophy in ovariectomized rats. J Clin Invest
`93:63—69, 1994.
`Black L], Jones CD, Falcone IF: Antagonism of
`
`49.
`
`50.
`
`51.
`
`estrogen action with a new benzothiophene derived
`antiestrogen. Life Sci 32:1031—1036, 1983.
`Gottardis MM, Jordan VC: Antitumor actions of
`keoxifene and tamoxifen in the N-nitrosomethylurea-
`induced rat mammary carcinoma model. Cancer Res
`47:4020—4024, 1987.
`Draper MW, Flowers DE, Huster WI, Nield IA:
`Effects of raloxifene (LY139481HC1) on biochemical
`markers of bone and lipid metabolism in healthy
`postmenopausal women. Proceedings of the Fourth
`International Symposium on Osteoporosis. Hong
`Kong (in press).
`Lerner L], Jordan VC: Development of antiestrogens
`and their use in breast cancer: Eighth Cain Memorial
`Award Lecture. Cancer Res 50:4177—4189, 1990.
`
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