Exogenous Hormones in the Aetiology of Cancer in Women

Mp, Vessey

doi:10.1177/014107688407700704

Cited by 36 publications

(16 citation statements)

References 67 publications

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“…Unfortunately, concerns regarding the increased incidence of breast and endometrial cancer and some other undesirable side effects, including breakthrough bleeding, are considerable drawbacks to the initiation and long-term use of estrogens (Vesey, 1984;Jacobs, 2000). Accordingly, a therapeutic agent that can mimic the protective effects of estrogen on nonreproductive tissues without inducing significant proliferative effect on the uterus and breast, would be highly desirable for postmenopausal women.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Actions of a Novel, Potent, Tissue-Selective Benzopyran Estrogen

Galbiati

Caruso²,

Amari³

et al. 2002

J Pharmacol Exp Ther

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We have identified a new benzopyran derivative, 3-(4-methoxy) phenyl-4- [[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-2H-1-benzopyran-7-ol hydrochloride (CHF 4227), with improved in vivo estrogen agonist/antagonist effects. CHF 4227 binds with high affinity to the human estrogen receptor-␣ and -␤ (dissociation constant K i ϭ 0.017 and 0.099 nM, respectively). In immature rats, oral administration of CHF 4227 for 3 days inhibited the uterotrophic action of 17␣-ethynyl estradiol (EE2) (ED 50 ϭ 0.016 mg/kg ⅐ day); raloxifene was 25 times less potent as estrogen antagonist (ED 50 ϭ 0.39 mg/kg ⅐ day), whereas both compounds were found to be devoid of uterotrophic activity. In line with its estrogen antagonist effect, CHF 4227 significantly prevented the development of dimethylbenz [a]anthracene (DMBA)-induced mammary tumors, the incidence being reduced from 87.5 to 26.3% 6 months after DMBA administration. In ovariectomized (OVX) rats treated orally for 4 weeks, CHF 4227 completely inhibited OVX effects on bone density (ED 50 ϭ 0.003 mg/kg ⅐ day) and on serum osteocalcin levels. The protective effects on bone were comparable with those achieved with EE2, whereas raloxifene was less efficacious and 100 times less potent. CHF 4227 reduced serum cholesterol (ED 50 ϭ 0.007 mg/kg ⅐ day) and had little to no stimulatory effects on uterine weight, uterine peroxidase activity, and endometrium epithelial thickness. In conclusion, CHF 4227 compares favorably in efficacy and potency with raloxifene in preventing bone loss and in antagonizing EE2 stimulation of the uterus. This profile along with the minimal uterine stimulation suggests a therapeutic advantage to CHF 4227 over EE2 or raloxifene for the treatment of postmenopausal women.Compounds that can bind to and activate the estrogen receptors (ERs) but cause differential estrogenic or antiestrogenic responses in specific tissue are currently being investigated as alternatives to estrogens for the prevention and treatment of chronic postmenopausal pathologies.Estrogen replacement therapy has been used primarily to prevent perimenopausal symptoms in addition to preventing and treating osteoporosis (Kiel et al., 1987). Although many other beneficial activities of estrogens have been described, including improvements in cognitive functions and decreases in the risk of coronary disease through their effect on lipids profile (Cumming, 1991;Stampfer and Colditz, 1991), there are several undesirable side effects associated with chronic estrogen therapy that create difficulties in compliance.In particular, the return of withdrawal bleeding is one of the major reasons for a woman stopping estrogen therapy. In addition, estrogens when administered without progestin, substantially increase the incidence but not the mortality of endometrial cancer (Ziel and Finkle, 1975;Vesey, 1984); furthermore, concerns about the increased risk of breast cancer associated with estrogen replacement therapy have been raised (Cauley et al., 1999;Jacobs, 2000).These adverse effects of estrogens have...

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Section: Discussionmentioning

confidence: 99%

“…In addition, estrogens when administered without progestin, substantially increase the incidence but not the mortality of endometrial cancer (Ziel and Finkle, 1975;Vesey, 1984); furthermore, concerns about the increased risk of breast cancer associated with estrogen replacement therapy have been raised (Cauley et al, 1999;Jacobs, 2000).…”

mentioning

confidence: 99%

Pharmacological Actions of a Novel, Potent, Tissue-Selective Benzopyran Estrogen

Galbiati

Caruso²,

Amari³

et al. 2002

J Pharmacol Exp Ther

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“…However, there are several undesirable side effects associated with chronic estrogen therapy that create difficulties in compliance. In this respect, estrogens, when administered without progestin, substantially increase the incidence but not the mortality of endometrial cancer (Ziel and Finkle, 1975;Vesey, 1984); furthermore, concerns about the increased risk of breast cancer associated with estrogen replacement therapy have been raised (Cauley et al, 1999;Jacobs, 2000). Accordingly, an ideal therapy should prevent bone loss and improve the serum lipid profile as estrogen does, without inducing proliferate effects on reproductive tissues.…”

mentioning

confidence: 99%

Effects of 3-Phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]- 2H-1-benzopyran-7-ol (CHF 4056), a Novel Nonsteroidal Estrogen Agonist/Antagonist, on Reproductive and Nonreproductive Tissue

Galbiati

Caruso²,

Amari³

et al. 2002

J Pharmacol Exp Ther

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We have discovered a new, nonsteroidal, estrogen agonist/ antagonist, 3-phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl] methyl]-2H-1-benzopyran-7-ol (CHF 4056). The aim of this study was to determine the effects of CHF 4056 on a series of parameters (body weight, uteri, serum cholesterol, and bones) that were previously shown to be sensitive to estrogens and to selective estrogen receptor modulators (SERMs). CHF 4056 is a benzopyran derivative that binds with high affinity to the human estrogen receptors ␣ and ␤ (dissociation constant K i of 0.041 and 0.157 nM, respectively). In immature rats, CHF 4056 induced a full estrogen antagonism (half-maximal efficacious dose ϭ 0.33 mg/kg⅐day p.o.) coupled with a lack of uterine stimulatory activity, whereas the structurally related SERM levormeloxifene demonstrated a maximal partial agonist effect of ϳ65% that of 17␣-ethynyl estradiol (EE2). In ovariectomized (OVX) rats, CHF 4056 (0.1-1 mg/kg⅐day p.o. for 4 weeks) significantly reduced OVX-induced bone loss in the lumbar spine L1-4 and OVX-induced increase in serum osteocalcin. These protective effects on bone tissue were comparable with those of 0.1 mg/kg⅐day EE2. In the same experimental conditions, serum cholesterol was significantly lower in the CHF 4056-treated animals, compared with vehicle-treated OVX rats. In line with the results observed in immature rats, also in OVX rats CHF 4056 diverged dramatically from EE2 and levormeloxifene in its lack of significant estrogenic effects on uterine tissue. In conclusion, CHF 4056 is a new SERM that produces beneficial effects on bone and cholesterol levels, while maintaining antagonist effects on the uterus.

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“…Estrogenic hormones are often used for the treatment of postmenopausal osteoporosis. However, several side effects of estrogens, such as abnormal vaginal bleeding (8) and carcinogenicity (9), have been reported. Therefore, we have been searching for compounds that stimulate bone formation without having estrogenic activity.…”

mentioning

confidence: 99%

“…*P < 0.05 and **P < 0.01 vs the control value. nal bleeding (8) and tumors in the breast and sexual organs (9).…”

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confidence: 99%

Effects of KCA-012 on Bone Metabolism in Organ Culture

Tsutsumi

Kawashima

Nagata

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-3,9-Dihydroxy-5H-benzofuro[3,2-c]quinoline-6-one (KCA-012), the chemical structure of which is closely similar to that of the phytoestrogen coumestrol, inhibited parathyroid hormone-, 1a,25-dihydroxyvitamin D3-and prostaglandin E2-induced bone resorption of cultured fetal rat bones. KCA-012 also increased the calcium content of 9-day chick embryonic femur cultured in vitro. KCA-012 did not show any estrogenic activity as determined by an increase in the uterine weight of ovariectomized rats, whereas coumestrol did. These results indicate that KCA-012 has no estrogenic activity and has unique effects of inhibiting bone resorption and stimulating bone mineralization.

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Exogenous Hormones in the Aetiology of Cancer in Women

Cited by 36 publications

References 67 publications

Pharmacological Actions of a Novel, Potent, Tissue-Selective Benzopyran Estrogen

Pharmacological Actions of a Novel, Potent, Tissue-Selective Benzopyran Estrogen

Effects of 3-Phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]- 2H-1-benzopyran-7-ol (CHF 4056), a Novel Nonsteroidal Estrogen Agonist/Antagonist, on Reproductive and Nonreproductive Tissue

Effects of KCA-012 on Bone Metabolism in Organ Culture

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