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PubMed1978

Blood coagulation studies in patients with advanced carcinoma of the prostate treated with 2,6-cis-diphenylhexamethylcyclotetrasiloxane or estramustine-17-phosphate.

Two drugs, 2,6-cis-diphenylhexamethylcyclotetrasiloxane (Cisobitan) and estramustine-17-phosphate (Estracyt) were given to patients with poorly differentiated metastatic carcinoma of the prostate. The effect of the drugs on blood coagulation was investigated. Some parameters showed changes during the treatment: Antithrombin III decreased in the Estracyt treated patients to a level which might imply a thrombogenic effect. Fibrinogen decreased, whereas factor VIII showed no consistent change. Normotest changes appeared to correlate with liver damage whereas antithrombin III showed no change. Increased levels of fibrinogen degradation products and fibrinopeptide A (FPA) were more frequent in the group of deteriorating patients. However, the number of FPA analyses were too small for any definite conclusions regarding possible disseminated intravascular coagulation.

Afibrinogenemia↗
PubMed1988

Estramustine phosphate (estracyt) following androgens in men with refractory stage D2 prostate cancer.

Twenty-two orchiectomized men with progressive stage D2 prostate cancer were treated with a 3-week cycle of estramustine phosphate (EMP: from day 3 to day 21) and androgen priming (from day 1 to day 4). A partial response according to the NPCP-USA criteria was shown in 4 of 20 evaluable patients. Median progression-free survival of all patients was 24 weeks (range, 4-48) and median survival, 42 weeks (range, 4-112). Although in two cases treatment had to be stopped due to a marked increase in bone pain, no life-threatening side effects were observed. The androgen sensitivity of tumors was supported by the occurrence of increase in prostatic phosphatase and in bone pain in most patients. In this group of patients, androgen priming did not seem to potentiate the effectiveness of EMP, our results being comparable to those previously reported using EMP alone.

Aged↗
PubMed1990

Estramustine phosphate reversibly inhibits an early stage during adenovirus replication.

Estramustine phosphate, an estradiol-mustard conjugate, was shown to reversibly inhibit a stage during the first hour of productive adenovirus 2 infection of HeLa cells. This drug, employed in the therapy of advanced prostatic cancer, specifically interacts with microtubule-associated proteins (MAPs) of the cytoskeleton. The results obtained under physiological conditions in vivo suggest a MAPs-interference with the microtubule-mediated vectorial migration of the virus inoculum to the nucleus. Virus attachment, uncoating kinetics and the appearance of established uncoating intermediates were not affected.

Adenoviridae Infections↗
PubMed1975

Treatment of prostatic cancer with Estracyt (estramustine phosphate).

The experience gained with Estracyt, kindly supplied by AB LEO, Sweden, is reported. On the basis of former data in the literature we only used the drug in estrogen resistant and advanced cases. Estracyt (estramustine phosphate) is a nitrogen mustard derivative of the urethan type, attached to oestradiol-17-phosphate. In histologically verified cases, it was administered in daily doses of 300 mg intravenously for three weeks, followed by maintenance doses of 300 mg a week in tablets for three months. During treatment, liver and bone marrow function was checked systematically. The changes in morphological picture were studied by means of biopsies during and at the end of treatment. In agreement with the data in the literature a favourable effect was observed in estrogen resistant patients, with no toxic effect whatever on the bone marrow. At the same time GOT and GPT and BSP retention examinations demonstrated a hepatotoxic side effect. The pathological values returned to normal after withdrawal of the drug. Histological examinations showed that the tumour cells had changed but failed to disappear after treatment.

Clinical Trials as Topic↗
PubMed1991

Effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate on some proteins related to haemostasis in prostatic carcinoma patients.

Twenty-four previously untreated patients with carcinoma of the prostate were prospectively randomized to one of the following treatments: (1) ethinyl oestradiol combined with polyoestradiol phosphate (EE/EP); (2) estramustine phosphate (EM); (3) bilateral orchiectomy. The effects on some plasma proteins related to haemostasis were studied by measuring the concentrations of alpha-1-antitrypsin, orosomucoid, haptoglobin, antithrombin III, C1-inhibitor and von Willebrand's factor before and 3 months after the start of treatment. Orchiectomy induced a reduction of alpha-1-antitrypsin and haptoglobin, while the other studied proteins were unaffected. It was found that both EE/EP and EM treatment induced significant decreases of orosomucoid, haptoglobin, antithrombin III and C1-inhibitor, while the same treatment increased the plasma concentration of alpha-1-antitrypsin. None of these treatments showed any influence on the plasma concentration of the von Willebrand factor. No differences were observed between EE/EP and EM for any of the studied proteins, suggesting comparable oestrogenic effects of these forms of treatment in patients with prostatic carcinoma. The findings are discussed in relation to the proposed difference in thromboembolic complications between EE/EP and EM treatments of prostatic carcinoma patients.

Aged↗
PubMed1989

Estramustine phosphate (Estracyt) in the treatment of prostatic carcinoma.

This review presents the most important hormonal, cytotoxic and pharmacokinetic properties of estramustine phosphate. Furthermore the results of randomized Phase III trials are described in patients with hormone refractory prostatic cancer with and without previous irradiation. Several randomized studies are reported with Estracyt also in the primary treatment of this disease.

Estramustine↗
PubMed2002

Estramustine phosphate enhances the effects of hyperthermia and induces the small heat shock protein HSP27 in the human prostate carcinoma cell line PC-3.

The antimicrotubule drug estramustine phosphate (EMP) has been shown to sensitize prostate carcinoma cells to radiation via synchronization at the G2/M phase of the cell cycle. This synchronization may also render cells more sensitive to hyperthermia, providing a rationale for multimodal treatment approaches. We have investigated the effects of EMP and hyperthermia, as well as the regulation of heat shock proteins (HSP) in the PC-3 prostatic carcinoma cell line. Cells were incubated with four doses of EMP for 48 h followed by a 1-h hyperthermia treatment ranging from 41 degrees C to 44 degrees C. Cell cycle distribution at the end of the EMP incubation was investigated by flow cytometry. Cytotoxicity was assessed by colony formation assays. HSP accumulation was investigated by Western immunoblotting. Doses of 1, 5, 10 and 15 microM EMP synchronized 27, 28, 46, and 68% of PC-3 cells at G2/M. With 5, 10 and 15 microM, a sensitizing effect of EMP was assessed at hyperthermic temperatures of 42, 43 and 44 degrees C. EMP did not alter the expression of HSP72, but substantially induced the synthesis of HSP27 in PC-3 cells. Our data show that EMP sensitizes PC-3 cells to hyperthermia induced cytotoxicity. This observation supports the rationale for multimodal treatment approaches in locally advanced prostate cancer.

Antineoplastic Agents↗
PubMed1998

Distribution of estramustine in the BT4C rat glioma model.

Estramustine (EaM), a carbamate ester of 17beta-estradiol and nor-nitrogen mustard, is a cytotoxic compound with antitumoral effect in malignant glioma in vitro and in vivo . However, knowledge of the pharmacokinetics of EaM in experimental glioma is limited. The objective of this study was therefore to investigate further the distribution of EaM in the BT4C rat glioma model. Assessment of EaM uptake and distribution was performed by quantitative whole-body autoradiography. In addition, the uptake of EaM and its metabolites estromustine (EoM), estradiol, and estrone were analyzed by gas chromatography. EaM was taken up from the circulation and was found to be the main product in glioma tissue. Whole-body autoradiography after [14C]-EaM administration revealed a strong 14C label simultaneously in tumor and normal brain tissue at 0.5 h after drug administration. In tumor tissue, sustained high levels of 14C label were detected at 12 h after drug administration. In contrast to the tumor, radioactivity in normal brain tissue rapidly leveled off, indicating a retention of radioactivity in the tumor. The tumor/brain radioactivity ratio reached a peak of 4.5 at 12 h after drug administration. High levels of 14C label were also found in pulmonary tissue. By gas chromatography, EoM was found to be the main metabolite in plasma. However, EaM reached higher levels in tumor tissue, with the mean tumor/plasma ratio being 11.7 as compared with 2.0 for EoM. Only low plasma levels of the estrogen metabolites were detected. In conclusion, EaM is taken up in the BT4C rat glioma tissue and is retained in the tumor as compared with normal brain tissue and plasma. EaM showed a greater selectivity for tumor tissue, exhibiting a high tumor/plasma ratio as compared with EoM. The distribution pattern after administration of EaM, as evaluated by both whole-body autoradiography and gas chromatography, supports the earlier suggestion that the uptake is related to a protein with EaM-binding characteristics.

Animals↗
PubMed2002

Ondansetron but not granisetron affect cell volume regulation and potassium ion transport of glioma cells treated with estramustine phosphate.

PURPOSE: Highly 5-HT(3)-receptor-specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs. Cell volume regulation, which is dependent on potassium ion (K(+)) flux, is involved the control of cell growth, proliferation, and apoptosis. K(+)-flux response mechanisms to the antiemetics ondansetron and granisetron were therefore correlated to malignant glioma cell (Mg251) volume response to estramustine phosphate (EMP) in vitro. METHODS: We quantified the influx and efflux of potassium ions (using the K(+) analogue (86)Rb(+)) as well as cell volume changes (with image analysis) of glioma cells incubated with the 5-HT(3)-receptor antagonists ondansetron and granisetron (0.1 micro mol/l) combined with 40 mg/l EMP. RESULTS: The EMP-induced cell volume increase was fully inhibited by ondansetron but not affected by granisetron. Ondansetron retained high cellular K(+)-efflux and reduced Na(+), K(+), 2Cl(-)-cotransport activity, whereas granisetron (0.1 micro mol/l) reduced K(+)-efflux and retained an augmented Na(+), K(+), 2Cl(-)-cotransport activity in the presence of 40 mg/l EMP. CONCLUSIONS: Ondansetron affects K(+) transport with ensuing effects on cell volume of tumour cells treated with EMP, whereas granisetron does not. Since ondansetron and other 5-HT(3)-receptor antagonists are used routinely to prevent nausea during anticancer treatment, an increased awareness of possible interactions with the antitumour efficacy of anticancer drugs seems warranted.

Antineoplastic Agents, Alkylating↗
PubMed2006

A randomized comparative study of endocrine monotherapy and a combination of estramustine phosphate with the endocrine therapy in patients with untreated stage D prostate cancer.

BACKGROUND: We investigated the clinical efficacy and the prolongation of survival with combination therapy of estramustine phosphate (EMP) and endocrine therapy in untreated patients with progressive prostate cancer. METHODS: We randomly divided 57 patients with untreated stage D prostate cancer into two groups, an endocrine monotherapy group and a group receiving combination treatment, consisting of endocrine therapy plus EMP. Treatment was continued until deterioration. RESULTS: There were no significant differences in the improvement rating for subjective/objective symptoms or in progression-free survival between the two groups. However, overall survival was significantly prolonged in the combination therapy group (log-rank test, P = 0.0394; generalized Wilcoxon's test, P = 0.0145). In particular, overall survival was significantly prolonged, compared to that in the endocrine monotherapy group, in patients in the combination therapy group who were less than 74 years old, those with a performance status (PS) of 1 to 3, a pretreatment prostate-specific antigen (PSA) level of more than 20 ng/ml, moderately or poorly differentiated carcinoma, or a partial response (PR) based on the PSA level 12 weeks after the start of treatment. There was no significant difference in the incidence of side effects between the combination therapy and the endocrine monotherapy groups. CONCLUSION: A combination of EMP with endocrine therapy may be useful for initial treatment in younger patients (aged 73 or younger) and in patients at high risk of progressive prostate cancer.

Aged↗
PubMed1981

Estramustine phosphate (Emcyt) as treatment for metastatic renal carcinoma.

Sixteen patients completed an adequate trial of estramustine phosphate for the management of metastatic renal cell carcinoma. Although no patient showed a complete or partial response, 9 (56 per cent) had stabilization of disease for a median of 44 weeks. Toxicity was not severe, but intolerance to the drug may limit its widespread use.

Adult↗
PubMed1981

Estramustine phosphate with multiple cytotoxic agents in treatment of advanced prostatic cancer.

Twenty-five patients with histologically proved adenocarcinoma of the prostate were divided into two groups and submitted to combination therapy with estramustine (Estracyt), cyclophosphamide (Cytoxan), 5-fluorouracil, and Cisplatin. Group A consisted of 10 patients newly diagnosed Stage D disease with no prior treatment. Group B consisted of 15 Stage D patients who had become hormonally unresponsive. Group A patients demonstrated an initial 100 per cent response rate including 70 per cent partial objective responses and 30 per cent stabilizations. Group B patients had a 46 per cent response with 39 per cent complete and partial responses and 6 per cent as stabilized. Toxicity was tolerable judged by the NPCP criteria. Both groups of patients are still under study for up to two years to determine if this therapy is superior to other traditional therapies.

Adenocarcinoma↗
PubMed1982

Effects of estramustine and megestrol on ultrastructure of rat ventral prostate.

The effects of estramustine phosphate on the ultrastructure of the rat ventral prostate closely resemble postcastration events, i.e., a decrease in cell size and secretory activities. The fibromuscular stroma, especially collagen fibers, appear to lose their adherence to adjoining muscle cells and fibroblasts. An infiltration of lymphocytes was noted in dilated regions of the fibromuscular stroma. There was an increase in cellular activity in the ventral prostate of rats treated with megestrol acetate with varying degrees of cellular atrophy and cytoplasmic disorganization. Squamous metaplasia was evident in one experimental group of MA-treated animals. Particles resembling mature C-type viruses were observed in several prostates from control and experimental animals.

Animals↗
PubMed1985

Clinical relevance of plasma testosterone and prolactin changes in advanced cancer of prostate treated with diethylstilbestrol or estramustine phosphate.

We have investigated a group of 30 patients with newly diagnosed metastatic carcinoma of the prostate who were randomly assigned to receive, as primary treatment, either diethylstilbestrol (DES) or estramustine phosphate (Emcyt). Clinical response was assessed following the guidelines of the National Prostatic Cancer Project and the Eastern Cooperative Oncology Group. Effective reduction in the levels of androgens was noted in all patients in both groups regardless of response. During the follow-up period (ranging between 2-5 years) relapses were noted despite the presence of androgen levels at or below castrate values. The most relevant endocrine observation was the detection of early elevations in serum prolactin in a majority of patients. It was noted, however, that those patients in whom hyperprolactinemia did not occur or appeared only briefly at the beginning of therapy, experienced a prolonged, symptom-free survival. Persistent hyperprolactinemia, on the other hand, carried an ominous prognosis. The differences in survival between normoprolactinemic and hyperprolactinemic groups carried statistical significance.

Carcinoma↗
PubMed1994

Experience in advanced prostatic cancer: orchiectomy and flutamide versus orchiectomy and estramustine phosphate.

OBJECTIVE: To compare pure hormonal treatment (orchiectomy plus flutamide) versus hormonal plus cytostatic treatment (orchiectomy plus estramustine phosphate [EMP]) as first-line therapy for advanced prostatic cancer. METHODS: From October 1985 to December 1991 a total of 99 patients were enrolled: 49 received orchiectomy plus EMP, 2 x 280 mg/day; 50 received orchiectomy plus flutamide, 3 x 250 mg/day. RESULTS: Of the 99 enrolled patients, 93 were evaluable for toxicity and 82 for efficacy. The median time to progression was 161 weeks for EMP versus 120 weeks for flutamide (p = 0.75, not significant). For distant metastases, bone pain, and poor performance status, treatment with EMP showed significantly better results than the flutamide group. The most frequent side effects were gastrointestinal for EMP and hot flushes for flutamide. CONCLUSIONS: For patients with advanced undifferentiated prostatic cancer and poor prognostic factors, treatment with EMP seems to show significant benefit.

Aged↗
PubMed1991

Early morphological detection of estramustine cytotoxicity measured as alteration in cell size and shape by a new technique of microperifusion.

The present study describes a new microscopic perifusion technique for detecting momentary alterations in cell volume and shape. The method has been applied for evaluating early signs of cytotoxicity following chemotherapeutic treatments. The effects of estramustine phosphate (EMP) have been evaluated. EMP is a complex between oestradiol-17 beta and the alkylating agent nor-nitrogen mustard and has recently demonstrated a marked cytotoxicity against malignant glioma cells. The results showed a concentration-dependent increase in cell size and a concomitant decrease in shape factor following EMP-treatment of glioma cells. These changes correlated with cytotoxicity evaluated as cell proliferation and cell membrane alterations shown by 86Rb fluxes and ultrastructural visible membrane damage. The colon cancer line HT-29 displayed no reactions at all following EMP treatment. It is suggested that acute alterations in cell morphology and shape display a strong correlation to the cytotoxicity of EMP encountered by traditional cell culture systems. The findings are discussed with respect to cell membrane disturbances caused by EMP and its potential role as an early test of cytotoxicity.

Cell Line↗
PubMed1996

Binding of vinblastine and estramustine to isolated plasma membrane fractions from human prostate and prostatic tumors.

The binding of vinblastine (VLB) and estramustine (EM) to plasma membranes isolated from human prostate, prostatic tumors as well as from Dunning rat prostatic AT-1 tumors was studied. In addition, the uptake of these drugs in AT-1 tumor cells in culture was examined. Binding of VLB was six-fold lower than that of EM in membrane preparations from all three sources. The uptake of VLB in the intact AT-1 cells was nearly five-fold lower than that of EM. At concentrations comparable to those achieved clinically the binding of EM was 100-fold higher than that of VLB. The data suggest that, owing to a very high membrane concentration of EM relative to that of VLB, the active efflux VLB in drug resistant cells would be impeded. This in turn would lead to a higher accumulation of VLB in cells that actively transport cytotoxic drugs.

Animals↗
PubMed1994

Clinical and biological studies of estramustine phosphate as a novel radiation sensitizer.

PURPOSE: Estramustine phosphate (EMP), a nor-nitrogen mustard carbamate derivative of estradiol-17 beta-phosphate, causes G2/M phase arrest in treated cells through its specific binding to microtubule associated proteins. Since cells in the G2/M phase are the most radiosensitive, cell culture experiments were performed to determine whether EMP would enhance the radiosensitivity of related human tumor cells. Based on the cell culture findings and well known pharmacokinetic data in humans, a Phase II prospective study of concomitant radiotherapy (RT) and EMP plus Velban for locally advanced carcinoma of the prostate was carried out. METHODS AND MATERIALS: Three established human tumor cells, DU-145 cells (prostate), MCF-7 cells (breast), and U-251 cells (malignant glioma), were used to determine cell survival curves with and without the drug. Flow cytometry was used to obtain the cell cycle distribution of cells that were exposed to the drug for periods of 1 day to 1 week. Patients with locally advanced prostate cancer (Stages B2, C, D1) were entered into the Phase II study. All patients received a total tumor dose of 65-70 Gy over 7 weeks. Oral EMP was administered daily and Velban was administered weekly, concomitantly during the course of RT. RESULTS: Radiosensitization was dependent on the exposure time and the drug concentration prior to radiation. No radiosensitization was obtained when cells were exposed to the drug after irradiation. The enhancement ratios varied from 1.3-1.6 at the 10% survival level. All patients who received the combined RT and EMP plus Velban achieved complete response (n = 27). The rate of PSA (prostate specific antigen) reduction was very prompt compared to that of the RT alone group. There was not disproportionately enhanced side effects for the combined regimen. CONCLUSION: EMP enhances radiation induced cytotoxicity in several human tumor cells in culture. The effect is most significant after prolonged exposure to the drug before irradiation. Documented G2/M phase cell cycle block by EMP is the likely mechanism of radiosensitization. The preliminary clinical findings with the combined RT and drugs are highly encouraging.

Adenocarcinoma↗