estramustine and Breast-Neoplasms

Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy, Combination; Estramustine; Female; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Microtubules are one of the major filament of the cytoskelton and play a role in various biological functions such as mitosis, cell motility and intracellular transport. Therefore, microtubules are considered one of the most important molecular targets for cancer chemotherapy. Tubulin is one of the major microtubular components, and its polymerization and depolymerization regulate microtubular dynamics. Other microtubular components such as microtubule-associated protein (MAPs), actin, and intermediate and microfilaments have also been demonstrated to be involved in microtubular dynamics. Recent studies provide evidence that the functions of MAPs and filaments in microtubule assembly are regulated by phosphorylation, which is catalyzed by mitogenactivated protein kinase (MAP kinase) and cdc2 kinase. Antimitotic agents that disrupt microtubules can be classified in two categories according to the mechanism of action, vinca alkaloids and taxanes. Vinca alkoloids, estramustine, rhizoxin, and E7010 inhibit microtubule polymerization. In contrast, taxanes such as paclitaxel and docetaxel promote polymerization of microtubules and enhance microtubule stability. We have demonstrated that paclitaxel inhibits the catalytic activity of MAP kinase and cdc2 kinase in lung cancer cell lines. This biological effect may be responsible for the increased affinity between MAP2 and tubulins, resulting in promotion of microtubule assembly. Factors that contribute to the resistance to antimitotic agents include intracellular accumulation of the drugs, genetic or functional alternations in tubulin, and alternations in MAP kinase cascade. Antimitotic agents showed a broad spectrum of preclinical antitumor activity. Clinical trials of taxanes revealed that they were effective for several cancers which were advanced or resistant against other anticancer drugs, especially for breast cancers, ovarian cancers and non-small cell lung cancers.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma, Small Cell; Drosophila Proteins; Estramustine; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Lung Neoplasms; Mice; Microtubules; Ovarian Neoplasms; Paclitaxel; Vinca Alkaloids

Estramustine phosphate is approved by the Food and Drug Administration for oral use in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a conjugate of 17 beta-estradiol and the carbamate of nitrogen mustard. Although its therapeutic efficacy has been demonstrated, it is not clear to what extent each constituent contributes to estramustine's effectiveness. Estramustine phosphate therapy achieves objective response rates of 60-90 percent in advanced stage D prostatic cancer patients with no prior hormonal therapy. These results are consistent with those obtained with conventional hormonal therapy in similar patient populations. Therapeutic efficacy does not appear to increase when estramustine is used concurrently with other cytotoxic chemotherapeutic agents. An objective response rate of 20-30 percent can be anticipated in patients refractory to conventional hormonal therapy. It is in this group, the estrogen-resistant patients, that estramustine shows the most promise. Adverse effects of estramustine are similar to those of diethylstilbestrol. Gastrointestinal and cardiovascular side effects appear to be the most important and may be severe enough to require discontinuation of therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular System; Clinical Trials as Topic; Costs and Cost Analysis; Digestive System; Estramustine; Female; Humans; Kinetics; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC).. Thirty-six patients with MBC were treated with estramustine 900 mg/m(2) per day divided into 3 doses given on Days 1-3 and docetaxel 70 mg/m(2) given by intravenous administration over 1 hour on Day 3 after the first dose of estramustine, every 21 days. Patients may have received any number of prior chemotherapy regimens for MBC.. Nine partial responses were observed in 31 assessable patients, for an objective response rate of 29% (95% confidence interval, 14-48%). The median progression free survival was 4 months (range, 1-41 months), and the median overall survival was 17 months (range, 2-45 months). Severe toxicities (Grade 3 or 4) were neutropenia, hypophosphatemia, and thrombosis. Seventy-five percent of patients experienced either an improvement or no change in quality of life.. The combination of docetaxel and estramustine produced responses in heavily pretreated women with MBC while maintaining quality of life.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Estramustine; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Quality of Life; Remission Induction; Survival Analysis; Taxoids

Docetaxel and estramustine exert anti-tumor effects by inhibiting microtubule function. In vitro data suggest synergism with this combination. This phase II study evaluated the response rate and toxicity of docetaxel and estramustine in patients with metastatic breast cancer (MBC).. Patients were treated with docetaxel 35 mg/m(2) on day 2 and estramustine phosphate 280 mg p.o. tds days 1-3 weekly for 3 of 4 weeks, for a maximum of six treatment cycles.. Thirty-nine patients were enrolled between August 1999 and March 2001; 36 were eligible. Of 31 evaluable patients, responses were observed in 15 patients (47%); two patients (6%) obtained a complete response. Median time to treatment failure was 6 months; median survival was 1 year. Thromboembolic toxicity occurred in 11% of patients: three experienced deep venous thromboses and one had a fatal pulmonary embolism. Myelosuppression was minimal with this regimen.. Despite modest activity in metastatic breast cancer, the toxicity observed with the combination of estramustine and docetaxel precludes the routine use of this combination in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Drug Administration Schedule; Estramustine; Female; Humans; Microtubules; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival; Taxoids; Treatment Outcome; Venous Thrombosis

Estramustine phosphate (EMP) is an oral cytotoxic agent that depolymerizes tubuline, a mechanism of action that has been revisited during the last decade. Because of its lack of haematological toxicity and favourable tolerance profile, EMP is a good candidate for palliative chemotherapy. The aim of the study was to assess its tolerance and efficacy in advanced breast cancer after failure with usual regimens.. Patients with a life expectancy of at least 12 weeks and bi-dimensionally measurable disease having received at least 1 line of chemotherapy (including taxanes and/or anthracyclines) for advanced breast cancer (ABC) were eligible. EMP was given daily at a dose of 10 mg/kg until disease progression, unacceptable toxicity or patient refusal to continue chemotherapy.. Forty patients were included between June 1998 and December 1999. Patients had previously received one to eight chemotherapy regimens (median is two) for ABC. Twenty-two patients (55%) had visceral involvement and eighteen patients (45%) had osseous, chest wall or soft tissue metastases. Adverse events leading to early interruption of EMP were grade 2 allergy (n = 1), grade 2-3 nausea (n = 6), deep-vein thrombosis (n = 1), grade 3 sepsis (n = 1). One patient died at twenty-four weeks from pulmonary embolism, and another at fourteen weeks from unknown cause. Seven objective responses were observed (17.5%; 95% confidence interval (CI): 6%-30%). Median time to failure was 24 weeks (14-52+) in responding patients. All objective responses but one were observed in patients with visceral metastases. In 10 other patients (25%), disease remained stable with a median time to failure of 27 weeks (16-50); 6 of these experienced a decrease of consumption of analgesics or an improvement of performance status.. EMP is an active drug in ABC after failure with taxanes and anthracyclines, whose tolerance profile appears favourable.

Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents, Hormonal; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Drug Resistance, Neoplasm; Estramustine; Female; Humans; Middle Aged; Salvage Therapy; Taxoids; Treatment Outcome

Estramustine phosphate (EMP) is thought to form a chemical link between estradiol and non-nitrogen mustard. An estramustine-binding protein has been isolated in prostate, breast, and brain cancers as well as in malignant melanoma cells. Estramustine phosphate's ability to bind to microtubular-associated proteins and to interfere with mdr-mediated drug efflux are thought to result in its enhancement of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) activity in cell lines and in its ability to affect hormone-resistant prostate cancer. This phase I study administered combined paclitaxel and EMP to 25 women with ovarian, breast, and other tumors and assessed efficacy and toxicity. Estramustine phosphate was administered at two dose levels, 900 or 1,200 mg/m2 daily on days 1, 2, and 3 in 3-week cycles. On day 3, paclitaxel (150, 180, 210, or 225 mg/m2) was given concomitantly by 3-hour infusion. Therapeutic effects were noted in all patients. Partial responses were noted in three of eight patients with breast cancer who had failed to improve on paclitaxel alone. Three other patients experienced prolonged stable disease. Only moderate toxicities were noted until EMP levels of 1,200 mg/m2 were reached. At these dose levels, gastrointestinal toxicities became more prominent. The addition of EMP to paclitaxel allowed patients to receive paclitaxel for longer periods, and may have enhanced the therapeutic effects of paclitaxel. If so, the mechanisms of such enhancement warrant investigation. The two drugs may work on different aspects of microtubular function, for example, or may reduce efflux of paclitaxel in P-glycoprotein overexpressed tumors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Estramustine; Fatigue; Female; Humans; Middle Aged; Nausea; Ovarian Neoplasms; Paclitaxel; Treatment Outcome; Vomiting

Estramustine phosphate is approved by the Food and Drug Administration for oral use in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a conjugate of 17 beta-estradiol and the carbamate of nitrogen mustard. Although its therapeutic efficacy has been demonstrated, it is not clear to what extent each constituent contributes to estramustine's effectiveness. Estramustine phosphate therapy achieves objective response rates of 60-90 percent in advanced stage D prostatic cancer patients with no prior hormonal therapy. These results are consistent with those obtained with conventional hormonal therapy in similar patient populations. Therapeutic efficacy does not appear to increase when estramustine is used concurrently with other cytotoxic chemotherapeutic agents. An objective response rate of 20-30 percent can be anticipated in patients refractory to conventional hormonal therapy. It is in this group, the estrogen-resistant patients, that estramustine shows the most promise. Adverse effects of estramustine are similar to those of diethylstilbestrol. Gastrointestinal and cardiovascular side effects appear to be the most important and may be severe enough to require discontinuation of therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular System; Clinical Trials as Topic; Costs and Cost Analysis; Digestive System; Estramustine; Female; Humans; Kinetics; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estramustine phosphate sodium (EMP) is an oral agent poorly developed--although active--in patients with metastatic breast cancer (MBC). To resume interest in EMP in MBC, we analyzed a retrospective series of consecutive patients with estrogen receptor-positive disease.. EMP was given orally at a dose of 140 mg daily. Treatment discontinuation rates due to progressive disease/toxicity and response rates were assessed.. Twenty postmenopausal patients with mainly visceral disease were treated with EMP, in five cases in combination with other anticancer drugs. Median numbers of previous chemotherapies and hormonal treatments were six and four, respectively. From the entire cohort, one complete response and four partial responses were observed. The proportions of patients free of progression at 6 and 12 months were 39 and 8 %, respectively. Six patients discontinued EMP, three each for toxicity and adverse events.. Good disease control was obtained in heavily pretreated MBC patients receiving EMP. Toxicity was manageable and reversible although treatment discontinuation has to be considered. A prospective study should be encouraged to identify the optimal use of the drug.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease Progression; Estramustine; Female; Humans; Middle Aged; Postmenopause; Receptors, Estrogen; Retrospective Studies

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Colitis; Diarrhea; Docetaxel; Estramustine; Female; Humans; Male; Paclitaxel; Prostatic Neoplasms; Taxoids; Vinblastine; Vinorelbine

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Drug Synergism; Estramustine; Female; Humans; Neoplasms; Ovarian Neoplasms; Paclitaxel; Taxoids

Estramustine previously has been shown to interact with P-glycoprotein and to restore intracellular accumulation of vinblastine and paclitaxel in cells overexpressing this drug transporter. However, the ability of estramustine to potentiate the cytotoxicities of several drugs was less than that expected. To resolve this apparent discordance, the authors examined the effects of serum on the actions of estramustine.. The cytotoxicities of anticancer drugs with or without estramustine or verapamil toward MCF-7 breast carcinoma cells and a P-glycoprotein-overexpressing subline MCF-7/ADR were determined using the sulforhodamine-binding assay. The extent of intracellular accumulation of [3H]vinblastine and [3H]paclitaxel was determined for each using standard methods, and the binding of radiolabeled drugs to plasma proteins was characterized by equilibrium dialysis.. Without serum, the sensitivities of MCF-7/ADR cells to several P-glycoprotein-transported drugs were increased by estramustine and verapamil. Conversely, when the cells were treated with a 10% serum, the cytotoxicities of these drugs were increased by verapamil, but not by estramustine. Without serum, intracellular accumulation of [3H]vinblastine and [3H]paclitaxel by MCF-7/ADR cells was increased markedly by verapamil and estramustine; however, serum suppressed the effects of estramustine much more strongly than those of verapamil. Equilibrium dialysis experiments demonstrated that [3H]estramustine binds to plasma proteins, predominantly albumin, whereas [3H]paclitaxel binds to albumin and alpha 1-acid-glycoprotein, and [3H]vinblastine binds predominantly to alpha 1-acid-glycoprotein.. Although estramustine can bind to P-glycoprotein, its effectiveness as a reversing agent in vivo likely is limited by binding to plasma proteins.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood Proteins; Breast Neoplasms; Carcinoma; Dialysis; Drug Resistance, Multiple; Estramustine; Gene Expression Regulation, Neoplastic; Humans; Orosomucoid; Paclitaxel; Protein Binding; Serum Albumin; Tritium; Tumor Cells, Cultured; Verapamil; Vinblastine

Estramustine (EM), an antimicrotubule agent, binds microtubule-associated proteins, causes spindle disassembly, and arrests cells at the late G2/M phase of the cell cycle. Since cells in the G2/M phase are the most radiosensitive and some human cancer cells contain high level of EM-binding protein, experiments were carried out to determine whether radiation sensitization could be obtained in human carcinoma cells.. Cells containing a high level of EM-binding protein such as prostate carcinoma (DU-145), breast carcinoma (MCF-7), and malignant glioma (U-251) were used to demonstrate radiosensitization. Cervical carcinoma (HeLa-S3) and colon carcinoma (HT-29) cells which are not known to contain EM-binding protein were also employed. Cell survival was assayed by the colony forming ability of single plated cells in culture to obtain dose-survival curves.. Pretreatment of DU-145, MCF-7, and U-251 cells to a nontoxic concentration (5 microM) of EM for more than one cell cycle time, substantially enhanced the radiation-induced cytotoxicity. The sensitizer enhancement ratio of these cells ranged from 1.35-1.52. The magnitude of the enhancement was dependent on the drug concentration and exposure time. The rate of cell accumulation in G2/M phase, as determined by flow cytometry, increased with longer treatment time in the cell lines which showed radiosensitization. Other antimicrotubule agents such as taxol and vinblastine caused minimal or no radiosensitization at nontoxic concentrations.. The data provide a radiobiological basis for using EM as a novel radiation enhancer, with the property of tissue selectivity.

Topics: Breast Neoplasms; Cell Cycle; Cell Survival; Colonic Neoplasms; Combined Modality Therapy; Estramustine; Female; Flow Cytometry; Glioma; HeLa Cells; Humans; Male; Microtubules; Neoplasms; Paclitaxel; Prostatic Neoplasms; Radiation-Sensitizing Agents; Tumor Cells, Cultured; Vinblastine

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Chlorambucil; Drug Screening Assays, Antitumor; Estradiol; Estramustine; Humans; Receptors, Estrogen; Tumor Cells, Cultured

Estramustine phosphate, an anti-prostatic cancer agent, was investigated on eleven patients to evaluate the efficacy in a treatment of advanced breast cancers. The daily dose of medication was 840 mg. According to criteria of Japan Society for Cancer Therapy, none was assessed as CR, three as PR, four as NC and PD. The response rate was 27.3%. There was no differences in response rates among estrogen receptor status. A favourable response was observed in postmenopausal patients but no response in premenopausal, as well as a good response in lesions of soft tissue and lung, a poor response in lesions of liver and bone. As to toxicity of estramustine phosphate, gastrointestinal disorders such as nausea, vomiting and diarrhea were noted frequently during the treatment, and a long term administration was not able to perform in premenopausal patients because of vaginal bleeding and discharge, and pain in breast. The estramustine phosphate therapy for advanced breast cancers was regarded as one of modalities for a treatment of postmenopausal patients as a second line therapy. This is the first report in Japan discussing the efficacy of estramustine phosphate for a treatment of breast cancer.

Topics: Administration, Oral; Adult; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Drug Evaluation; Estramustine; Female; Humans; Leukorrhea; Menopause; Middle Aged; Nausea; Nitrogen Mustard Compounds; Receptors, Estrogen; Vomiting

Estramustine is a cytotoxic metabolite of estramustine phosphate (Estracyt), which is used in the treatment of prostatic carcinoma. An estramustine binding site (EMBS) at pH 4.8-4.9 was demonstrated in 74 of 306 (24%) breast cancer biopsy samples using isoelectric focusing in polyacrylamide gels. The presence of EMBS was significantly (P less than 0.001) correlated with negative or low estrogen and progesterone receptor values. EMBS positivity was found in 31% of the samples from pre- and perimenopausal patients and in 22% of the samples from postmenopausals. If patients were instead divided into different age groups, EMBS positivity was most frequent in samples from patients between 50 and 59 years of age (42%). With increasing age the percentage of EMBS positivity fell successively. For patients under 50 years, no difference with respect to EMBS positivity between age groups could be demonstrated. The possible value of EMBS determinations in breast cancer tissue specimens for the selection of those patients that will respond to Estracyt therapy should be evaluated.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Binding Sites; Biopsy; Breast Neoplasms; Estramustine; Female; Humans; Isoelectric Focusing; Menopause; Middle Aged; Nitrogen Mustard Compounds; Receptors, Estrogen; Receptors, Progesterone

Topics: Breast Neoplasms; Estramustine; Female; Humans; Menopause; Nitrogen Mustard Compounds; Pilot Projects

Estracyt, a conjugate of an alkylating agent with an oestrogenic sterol, was given in a dose of 420 mg daily to a group of 44 postmenopausal patients with very advanced breast carcinoma. Thirty-eight of these were in relapse following chemotherapy and 32 had evidence of distant metastases. Seventeen patients had an objective response and marked or complete alleviation of symptoms, four others had a useful symptomatic response but no beneficial effect was observed in the remainder. Three who had shown no response to previous oestrogen therapy also failed to respond to Estracyt as did all nine patients with hepatic metastases. Oestrogen receptor status and age within the postmenopausal group seemed to have no bearing on the result. Side-effects were minimal with nausea in 18 patients but in only two did this necessitate withdrawal of the drug. Bone marrow depression did not occur. Changes in acute-phase reactant proteins suggested that part of the Estracyt was de-esterified in the liver liberating oestrone but the low incidence of vaginal haemorrhage and the recalcification of bony metastases suggested that on the whole Estracyt behaves as an anti-oestrogen as well as an antimitotic.

Topics: Aged; Breast Neoplasms; Estramustine; Female; Humans; Menopause; Middle Aged; Nausea; Neoplasm Metastasis; Palliative Care; Receptors, Estrogen; Time Factors