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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Droloxifene (3-hydroxytamoxifen), is a triphenylethylene derivative recently developed for the treatment of breast cancer. Droloxifene was found to exhibit a membrane antioxidant ability in that it inhibited Fe(III)-ascorbate dependent lipid peroxidation in rat liver microsomes and ox-brain phospholipid liposomes. It also inhibited microsomal lipid peroxidation induced by Fe(III)-ADP/NADPH. Droloxifene was a better inhibitor of lipid peroxidation than tamoxifen, but was less effective than 17 beta-oestradiol in the two microsomal systems and in the preformed liposomal system. When introduced into ox-brain phospholipid liposomes, droloxifene inhibited Fe(III)-ascorbate induced lipid peroxidation to approximately the same extent as similarly introduced cholesterol and tamoxifen, although to a lesser extent than 17 beta-oestradiol. This inhibition of lipid peroxidation by droloxifene may result from a membrane stabilization that could be associated in cancer cells with decreased plasma membrane fluidity. This mechanism may be related to the clinically important antiproliferative action of droloxifene on cancer cells.
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PMID:Droloxifene (3-hydroxytamoxifen) has membrane antioxidant ability: potential relevance to its mechanism of therapeutic action in breast cancer. 145 Oct 97

Droloxifene (3-OH-tamoxifen citrate) is a novel anti-oestrogen with a higher affinity for oestrogen receptors (ER), a lower oestrogenic to anti-oestrogenic activity ratio and faster pharmacokinetics compared with tamoxifen. From May 1988 to April 1991, 369 postmenopausal women with metastatic or locally unresectable breast cancer of which the ER or progesterone receptor status was positive or unknown, were randomised to receive an oral dose of 20, 40 or 100 mg droloxifene once daily. 43 Brazilian, Canadian and European centres took part in this double-blind phase II trial. 60 women were ineligible for violation of entry criteria; 20 were inevaluable and 15 still await definitive response evaluation. 234 patients have been evaluated for response. The over-all objective response rate (complete plus partial) was 92/234 (39.3%): 23/74 (31.1%) for 20 mg, 33/74 (44.6%) for 40 mg and 36/86 (41.9%) for 100 mg (not significantly different within this dose range). There was no significant difference in time to tumour progression between the three doses. Toxicity was minimal at all doses. These preliminary results show that droloxifene is active against advanced breast cancer. Because of its outstanding preclinical characteristics, the drug warrants large-scale clinical investigation.
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PMID:Droloxifene, a new anti-oestrogen in postmenopausal advanced breast cancer: preliminary results of a double-blind dose-finding phase II trial. 151 58

Twenty-six patients with advanced breast cancer were treated with a new anti-estrogen, Droloxifene (3-hydroxy-tamoxifen). They had all used tamoxifen either in the adjuvant or the advanced situation. The dose schedule was 100 mg orally daily. Partial remissions were observed in 4 (15%) of the patients, and in another 5 patients stable disease (greater than 24 weeks of duration) was observed. Three of the responders were resistant to tamoxifen. Fourteen of the 26 patients had no side-effect. In 2 patients therapy had to be stopped due to fatigue. Droloxifene seems to be an interesting new anti-estrogen which should be further exploited.
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PMID:Droloxifene--a new anti-estrogen. A phase II study in advanced breast cancer. 163 78

We have previously shown that transforming growth factor beta (TGF beta) is a hormonally regulated negative growth factor in estrogen responsive MCF-7 human breast cancer cells. We have now compared the antiestrogens tamoxifen, droloxifene (3-hydroxytamoxifen), and toremifene in their ability to induce the secretion of autoinhibitory TGF beta by MCF-7 cells. The main results are as follows: induction of TGF beta secretion by droloxifene is about two to three times higher than by identical concentrations of tamoxifen or toremifene. A 5-10 times higher concentration of tamoxifen or toremifene than droloxifene is necessary to reach a similar induction of TGF beta secretion. In contrast to tamoxifen, intermittent application of droloxifene is as effective as continuous treatment in inducing TGF beta secretion. We conclude from these data that TGF beta proteins represent markers of antiestrogen action and might also play a pivotal role in their mechanism of action. Droloxifene is a more effective inducer of TGF beta and a more potent growth inhibitor for estrogen responsive human breast cancer cells than tamoxifen and toremifene in vitro. Therefore, droloxifene might also possess a higher antiestrogenic potential in treatment of human breast cancer.
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PMID:Induction of transforming growth factor beta by the antiestrogens droloxifene, tamoxifen, and toremifene in MCF-7 cells. 183 18

Droloxifene, a new tamoxifen (TAM)-derived compound, has excellent antiestrogenic activity. This compound exhibits less endogenously estrogenic but higher antiestrogenic activity, with better tolerability than TAM in experimental models. Two phase II studies of droloxifene were performed in 47 Japanese institutions to assess the optimal dose. The first was a randomized comparative study using 20, 40, and 80 mg, respectively, once a day. The other was a pilot study using 120 mg once a day. The subjects of both studies were women with primary or recurrent advanced breast cancer, regardless of estrogen receptor status and menopausal status. Of 94 patients enrolled in the comparative study, 22, 26, and 23 were evaluable in the 20-, 40-, and 80-mg groups, respectively. Of the 71 evaluable patients, 14 (19.7%) were negative for estrogen receptor, and 36 (50.7%) had a previous history of TAM therapy. The response rate complete response + partial response (CR + PR) was 13.6% for 20 mg, 15.4% for 40 mg, and 17.4% for 80 mg. The rate of no change (NC) was 31.9%, 46.1%, and 47.8%, and that of progressive disease (PD) was 54.5%, 38.5% and 34.8%, respectively, in the 20-, 40-, and 80-mg groups. In the other study, 16 patients were enrolled in the pilot study with 120 mg of droloxifene, of whom 14 were evaluable. The response rate was slightly higher: four responders (28.6%) were assessed as CR + PR, six (42.9%) as NC, and four (28.6%) as PD. These results suggest that the response rate may be dose-dependent and that PD rates seem lower in the higher doses. No serious side effects were encountered, and droloxifene was well tolerated even in the higher doses. At present, a final randomized dose-finding study with 80 mg/day and 120 mg/day is being carried out.
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PMID:Japanese early phase II study of droloxifene in the treatment of advanced breast cancer. Preliminary dose-finding study. 196 96

To determine the optimal daily dose of the new antiestrogen droloxifene for the treatment of breast cancer, a multinational, multicenter, randomized, double-blind, phase II trial was initiated. Postmenopausal women with progressive advanced breast cancer (distant metastatic cancer, inoperable recurrent or primary tumor) with positive or unknown hormone receptor status (estrogen or progesterone) were entered in the study. Droloxifene was administered in a double-blind randomized design with daily doses of either 20, 40, or 100 mg once daily as first-line systemic therapy. None of the patients had received previous systemic antitumor therapy with the exception of adjuvant chemotherapy terminated at least one year before the patient's recruitment. Response was determined according to Union Internationale Contre le Cancer/World Health Organization criteria. Only patients with at least one measurable lesion were entered into the trial. The highest quality of data was achieved in two ways: source verification in the hospitals through monitors and peer review with subgroups of investigators determining the tumor response of each patient at adjudication meetings (evaluating parameters obtained from physical examination and reviewing X-rays and computer tomography scans). To date, 254 patients have been enrolled. Results from all these groups, without breaking the randomization code, based on 131 patients whose data have been verified are as follows: 10 complete responses (CR), 37 partial responses (PR), 47 no change, 29 progressive disease, 8 patients too early to evaluate. Thus, the overall response rate (CR + PR) was 38%. Droloxifene was well tolerated.
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PMID:Droloxifene, a new antiestrogen, in advanced breast cancer. A double-blind dose-finding study. The Droloxifene 002 International Study Group. 196 99

Droloxifene (DROL) is a new antiestrogen which is used for the treatment of endocrine-responsive breast cancer in humans. As Droloxifene exists in a Z- and E-isomer, we investigated the main pharmacological properties of both isomers. For both compounds the following tests were conducted: affinity for the estrogen receptor (ER); effect on the growth of rat uteri; influence on the growth of the ER + human breast cancer cell line ZR-75; and isomer interconversion in vitro. DROL-(Z) had binding affinity to the cytosolic ER approximately ten times lower than that of DROL-(E). Furthermore, the estrogenic effect of DROL-(Z) in the rat uterus is weak and there is no antiestrogenic activity. The lack of antiestrogenic activity of DROL-(Z) in contrast to DROL-(E) could also be shown in the human breast cancer cells ZR-75. Thus DROL-(Z) is, as far as investigated, without antiestrogenic and estrogenic activities. Of note is the stability of both DROL-isomers. There is no interconversion or metabolism of the parent compounds DROL-(E) and DROL-(Z) in vitro.
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PMID:Pharmacological activities of droloxifene isomers. 321 58

Droloxifene (3-hydroxytamoxifen) is a novel antiestrogen currently undergoing clinical investigations for treatment of breast cancer patients. We measured plasma levels of sex hormone binding globulin (SHBG) and the gonadotrophins (LH and FSH) at baseline and after 3 months on treatment in a group of fourteen postmenopausal women treated with droloxifene 40 mg daily. Plasma levels of estrone (E1), estradiol (E2) and estrone sulphate (E1S) were measured in a subgroup of eight patients. Plasma SHBG increased during treatment with droloxifene by a mean value of 16.6% (P < 0.05), while plasma levels of LH and FSH decreased by a mean value of 15.7% (n.s.) and 18.1% (P < 0.05), respectively. Plasma levels of E2 and E1 fell slightly (mean decrease 19.4 and 16.7% respectively, n.s.). On the contrary, plasma levels of E1S increased by a mean value of 23.5% (P = 0.068). The ratio of E1S to E1 and E1S to E2 increased by a mean value of 48.3% (P < 0.025) and 53.2% (P < 0.025), respectively. The effect of droloxifene 40 mg daily on plasma levels of SHBG resembles what is seen during treatment with tamoxifen but occurs to a smaller extent. Contrary to tamoxifen, droloxifene caused a minor suppression of plasma LH levels, suggesting droloxifene to have less estrogen agonistic effects on the pituitary.
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PMID:Influence of droloxifene (3-hydroxytamoxifen), 40 mg daily, on plasma gonadotrophins, sex hormone binding globulin and estrogen levels in postmenopausal breast cancer patients. 749 98

Plasma levels of oestradiol (Oe2), oestrone (Oe1) oestrone sulphate (Oe1S), androstenedione, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG) and the gonadotrophins (FSH and LH) were determined in 20 postmenopausal women with breast cancer treated with the anti-oestrogen droloxifene (3-hydroxytamoxifen). Plasma oestrogens were measured before and after 3, 6 and 12 months of therapy. The other hormones were measured before and after 6 months of therapy. Droloxifene treatment had no significant influence on plasma levels of Oe2. Plasma levels of Oe1 and Oe1S increased during treatment (mean increase of 11.9-15.9% and 24.5-69.4% respectively after different time-intervals on treatment). The Oe1S/Oe1 and Oe1S/Oe2 ratios increased by mean values of 13.8-45.2% and 25.9-52.4% respectively. Plasma SHBG increased significantly by a mean value of 73.9%, while FSH and LH fell non-significantly by 19.7% and 20.4% respectively. Plasma levels of testosterone, androstenedione, DHEA and DHEAS all increased during treatment, but none of these alterations were of statistical significance. While the influence of droloxifene on plasma SHBG resembled that which is seen during treatment with tamoxifen, its influence on plasma oestrogens and the gonadotrophins seems to be different. Possible explanations of such differences and the clinical implications of alterations in plasma hormones during treatment with droloxifene are discussed.
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PMID:Influence of treatment with the anti-oestrogen 3-hydroxytamoxifen (droloxifene) on plasma sex hormone levels in postmenopausal patients with breast cancer. 756 49

Droloxifene, a new antiestrogen, has theoretical advantages over tamoxifen based on preclinical data. These include higher affinity to the estrogen receptor, higher antiestrogenic to estrogenic ratio, and more effective inhibition of cell growth and division in ER positive cell lines, as well as less toxicity, including reduced carcinogenicity in animal models. Droloxifene also exhibits more rapid pharmacokinetics, reaching peak concentrations and being eliminated much more rapidly than tamoxifen. A phase II study compared droloxifene in dosages of 20, 40, and 100 mg daily in postmenopausal women with metastatic, or inoperable recurrent, or primary locoregional breast cancer who had not received prior hormonal therapy. Of 369 patients randomized, 292 were eligible and 268 evaluable for response. Response rates (CR + PR) were 30% in the 20 mg group, 47% in the 40 mg group, and 44% in the 100 mg group (40 mg vs 20 mg, p = 0.02; 100 mg vs 20 mg, p = 0.04; pooled 40 + 100 mg vs 20 mg, p = 0.01). Median response duration also favoured the higher dosages (20 mg group = 12 months; 40 mg group = 15 months; 100 mg group = 18 months). When adjusted for prognostic factors, time to progression was significantly better for the 100 mg (p = 0.01) and the 40 mg (p = 0.02) group compared to the 20 mg group. Droloxifene increased SHBG and suppressed FSH at all dosages and suppressed LH at the 40 and 100 mg dosages. These hormonal effects increased with increasing dosage. Short-term toxicity was generally mild, and similar to that seen with other antiestrogens. Droloxifene appears active and tolerable. It may have a particular role in situations in which rapid pharmacokinetics, or an increased antiestrogenic to estrogenic ratio, are required.
Breast Cancer Res Treat 1994
PMID:Droloxifene, a new antiestrogen: its role in metastatic breast cancer. 798 60


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