Antiestrogen therapy for breast cancer: Current strategies and potential causes for therapeutic failure

Iino, Y; Gibson, David F.; Jordan, V. Craig

doi:10.1007/978-1-4615-3940-7_10

Cited by 2 publications

(3 citation statements)

References 61 publications

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“…Inhibition of Human Placental Aromatase byPyridyl-Substituted Tetrah^drocyclopropanaphthalenes[1][2][3][4][5][6][7][8][9][10] …”

mentioning

confidence: 99%

Pyridyl-Substituted Tetrahydrocyclopropa[a]naphthalenes: Highly Active and Selective Inhibitors of P450 arom

Rw¹,

Bayer²,

Grün³

et al. 1995

J. Med. Chem.

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The synthesis and biological evaluation of substituted exo-1-(4-pyridyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene s as inhibitors of estrogen biosynthesis is described [H (1); 4-OCH3 (2); 5-OCH3 (3); 6-OCH3 (4); 1-CH3, 6-OCH3 (5); 4-OCH3, 7-Br (6); 6-OCH3, 5-Br (7); 4-OH (8); 5-OH (9); 6-OH (10)]. The synthetic key step--the formation of the cyclopropyl ring--was accomplished using the conditions of a modified Wolff-Kishner reduction (N2H5OH/KOH; delta T) and yielded exclusively the exo-configurated diastereomers. The racemic compounds 1-10 showed an inhibition of human placental aromatase (P450 arom) exhibiting relative potencies (rp) from 3.7 to 303 (compounds 8 and 4, respectively; rp of aminoglutethimide (AG) identical to 1, fadrozole = 359). The enantiomers of 4 and 7 were separated by LPLC on tribenzoyl cellulose and by crystallization of the diastereomeric tartrates (4). (1aS,2S,7bS)-(+)-4 (absolute configuration determined by X-ray crystallographic analysis) is the active P450 arom inhibiting enantiomer of 4 and shows a rp value of 617. Compound 4 is a reversible inhibitor showing a competitive type of inhibition and a type II difference spectrum. In vitro 4 influenced other steroidogenic P450 enzymes either not at all (bovine adrenal P450 scc) or only marginally (rat testicular P450 17, bovine adrenal P450 18). In ACTH-stimulated rat adrenal tissue, 4 was less active, inhibiting corticosterone and aldosterone formation compared to AG and fadrozole, respectively. In vivo 4 was not superior to AG as far as the inhibition of the uterotrophic activity of androstenedione (juvenile SD rats) and the reduction of the plasma estradiol concentration (pregnant mares' serum gonadotropin-primed SD rats) are concerned. Compound 4 shows marked antitumor activity in the dimethylbenzanthracene-induced mammary carcinoma of the SD rat: in the postmenopausal model it is at least as active as AG; in the premenopausal experiment it is clearly superior to AG. No induction of hepatic P450 enzymes was observed in the latter experiment. The rp value of 4 toward rat ovarian P450 arom, i.e., 23 (rp of AG identical to 1), is markedly decreased compared to the human enzyme (rp value of 303). From this fact it must be concluded that 4 should be more active in the human than in the rat.

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“…Inhibition of Human Placental Aromatase byPyridyl-Substituted Tetrah^drocyclopropanaphthalenes[1][2][3][4][5][6][7][8][9][10] …”

mentioning

confidence: 99%

Pyridyl-Substituted Tetrahydrocyclopropa[a]naphthalenes: Highly Active and Selective Inhibitors of P450 arom

Rw¹,

Bayer²,

Grün³

et al. 1995

J. Med. Chem.

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“…Third, non-endocrine mechanisms resulting in tumor cytotoxicity may occur [16,17]. Finally, even in patients whose tumors are ERand PR-negative by cytosol analysis, immunohistochemical methods frequently demonstrate small numbers of receptor-positive cells.…”

Section: Selecting Patients For Endocrine Therapymentioning

confidence: 96%

“…Finally, even in patients whose tumors are ERand PR-negative by cytosol analysis, immunohistochemical methods frequently demonstrate small numbers of receptor-positive cells. Such cells when stimulated by hormonal agents may secrete transforming growth factors (TGF's) such as TGF-f3 which may suppress growth and division of surrounding receptor-negative tumor cells [16,17].…”

Section: Selecting Patients For Endocrine Therapymentioning

confidence: 99%

Endocrine therapy for advanced breast cancer: A review

Muss

1992

Breast Cancer Res Tr

125

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More than 45,000 women will die of metastatic breast cancer in the United States in 1991. Endocrine therapy remains a major option for treatment of such patients, and results in complete plus partial response rates of 30% with a median duration of approximately one year. Postmenopausal status, increased age, a prolonged disease-free interval, bone and soft tissue metastases, and positive estrogen and progesterone receptors are all associated with an increased response to endocrine therapy. The use of additive hormonal therapy, specifically antiestrogens, progestins, and aromatase inhibitors, have replaced surgical ablative procedures in the majority of patients; response rates to antiestrogen therapy, progestin therapy, and aromatase inhibitors are similar, but antiestrogens have generally been associated with the most favorable therapeutic index. At present, there is no convincing evidence that either combinations of endocrine therapies or endocrine therapy combined with chemotherapy are associated with an improvement in survival for patients with metastatic disease. Future research efforts directed at defining the molecular mechanisms of endocrine activity should facilitate clinical trials of newer and potentially more effective agents. All patients with metastatic breast cancer should be considered for at least one trial of endocrine therapy provided their metastatic disease is not rapidly progressive or life-threatening.

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Antiestrogen therapy for breast cancer: Current strategies and potential causes for therapeutic failure

Cited by 2 publications

References 61 publications

Pyridyl-Substituted Tetrahydrocyclopropa[a]naphthalenes: Highly Active and Selective Inhibitors of P450 arom

Pyridyl-Substituted Tetrahydrocyclopropa[a]naphthalenes: Highly Active and Selective Inhibitors of P450 arom

Endocrine therapy for advanced breast cancer: A review

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