Journal of Cellular Biochemistry, Supplement 22:51 -57 (1995)
`
`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
`
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`52
`
`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.
`
`ldoxifene
`
`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 alkylarninoethoxy side chain may have
`less carcinogenic potential. ldoxifene (Fig. 1) is a
`Weak antiestrogen in the rat but exhibits antitu-
`mor activity in rat mammary carcinoma models
`[34]. ldoxifene 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 1/ 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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`Antiestrogens Prevent Breast Cancer
`
`-
`
`53
`
`
`
`IDOXIFENE
`(1993)
`
`
`
`TAMOXIFEN
`(1971)
`
`C1
`
`TOREMIFENE
`(1986)
`
`Fig. 1. Tamoxiten analogues that are in clinical trial. The date in parentheses indicate the year breast
`cancer studies were reported.
`
`ANIMAL STUDIES
`
`CLINICALLY USEFUL AGENTS
`
`r,/v‘<
`
`O
`....‘ O
`
`4-HYDROXYTAMOXIFEN
`
`metabolism ;
`/\/M0 \
`
`
`
`0
`
`3,4-DIHYDROXYTAMOXIFEN
`
`H0
`DROLOXIFENE
`
`Fig. 2.
`agent
`
`The derivatives of tamoxifen that have used metabolite mimicry to design an antibreast cancer
`
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`
`54
`
`Jordan
`
`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-I-Iydroxytamoxifen 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-hydroxytamoxiten.
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`Antiestrogens Prevent Breast Cancer
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`55
`
`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.
`
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