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PubMed1984

Estramustine phosphate sodium.

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.

Animals↗

PubMed1985

Effect of estramustine phosphate on the assembly of isolated bovine brain microtubules and fast axonal transport in the frog sciatic nerve.

Estramustine phosphate (0.01 to 0.5 mM), an estradiol mustard derivative used in the therapy of prostatic carcinoma, inhibited the assembly of brain microtubules proteins in vitro and disassembled preformed microtubules. In the presence of estramustine phosphate, the minimum microtubule-protein concentration sufficient for the assembly of microtubules was increased. Low concentrations of taxol (20 microM) completely reversed the inhibition of assembly by estramustine phosphate. The effects were specific to estramustine phosphate since neither estradiol 17 beta-phosphate, the hormonal moiety of the drug, nor nornitrogen mustard, the alkylating moiety, had any effect on assembly. Estramustine phosphate (0.1 to 0.5 mM) was also found to reversibly inhibit fast axonal transport in the frog sciatic nerve. The nerve content of adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate was not significantly affected by estramustine phosphate. Our results suggest that the cytotoxic action of estramustine phosphate could be dependent partially on an interaction with microtubules, probably via the microtubule-associated proteins.

Animals↗

PubMedDate not supplied

Uptake, metabolism and antiproliferative effect of estramustine phosphate in human glioma cell lines.

The uptake, metabolism and antiproliferative effects of estramustine phosphate, a cytotoxic agent used in prostatic cancer, were investigated in the two human malignant glioma cell lines U-105 MG and U-251 MG. The primary metabolite estramustine had a dose-dependent inhibitory effect on cell proliferation within the concentration range 5-20 micrograms/ml. After incubation with 3H-estramustine phosphate in both cell lines, a progressive uptake of radioactivity was recorded during 24 hours. A significant metabolism of parent estramustine phosphate into estramustine and estramustine, which is a well known part of the metabolic pathway in man, was also demonstrated. In conclusion, certain cultured malignant glioma cells display significant uptake, retention and metabolism of estramustine phosphate and further studies are indicated to assess the clinical implications of these findings.

Biological Transport↗

PubMed1980

Estramustine phosphate: plasma concentrations of its metabolites following oral administration to man, rat and dog.

Estramustine phosphate, a nitrogen mustard derivative of estradiol used for the treatment of advanced prostatic cancer, was administered orally to man, rat and dog and the plasma concentrations of its unconjugated metabolites were determined by high performance liquid chromatography. In all species the drug was rapidly and completely dephosphorylated prior to reaching the peripheral circulation. In man and the rat, the 17-keto analogue of estramustine (estromustine) was the mamor metabolite found in plasma with considerably lesser amounts of estramustine itself. In the dog, significant concentrations of both estramustine and estromustine were present. Highly elevated levels of both estrone and estradiol, as a result of cleavage of the nitrogen mustard from the steroid, were observed in all species. Chronic administration of therapeutic doses of estramustine phosphate to man did not result in any apparent accumulation of circulating metabolites. The study suggests that the metabolite, estromustine, in addition to estramustine, may play an important role in the therapeutic efficacy of estramustine phosphate.

Administration, Oral↗

PubMed1994

Estramustine sensitizes human glioblastoma cells to irradiation.

Estramustine is an estradiol-based antimicrotubule agent that accumulates in malignant glioma cells, resulting in a concentration-dependent inhibition of proliferation. This agent has been shown to synchronize human glioma cells at G2-M consistent with its known effects on the mitotic spindle and potentially could be used as a radiation enhancer. We determined the effects of estramustine on the cell cycle of glioblastoma cells by flow cytometry. These findings were compared with clonogenic survival in cells pretreated with varying concentrations of estramustine prior to irradiation. These experiments indicated that 24 h treatment with 1 microM estramustine had no effect on the percentage of G2-M cells and did not enhance the cytotoxic effects of radiation while 10 microM estramustine increased the G2-M fraction by 100% associated with a potentiation factor as high as 8.5 and a relative radiation sensitivity at 70% cytotoxicity of 5.2 compared with 15.4 for control cells. Estramustine can be administered p.o. on a daily schedule with minimal systemic toxicity. These data suggest that estramustine may be an effective radiation enhancer for glioblastoma.

Brain Neoplasms↗

PubMed1986

[Studies on estramustine-binding protein in the human prostate].

In the present study, size exclusion HPLC was used to analyse the properties of Estramustine-binding protein (EMBP) in the cytosol of human benign prostatic hypertrophy (BPH). The typical size exclusion HPLC separation profile of 3H-Estramustine-labelled cytosol of BPH showed four radioactive peaks that corresponded to the V0, 250K, 68K and 45K protein regions. The specific binding protein for Estramustine is contained mainly in the 250K protein region and in part in the V0 region. In the presence of sodium molybdate, the specific Estramustine binding to a 250K protein was increased to a level which was about 2.5 times as much as the value in the absence of sodium molybdate. The specific Estramustine binding to a 250K protein under the condition of no DCC treatment and the addition of sodium molybdate was 600% of the value obtained under the condition of DCC treatment and no addition of sodium molybdate. These results suggested that sodium molybdate stabilized the specific Estramustine-binding activity to a 250K protein and that specific Estramustine binding to a 250K protein seemed to be weaker than the binding of androgen to androgen receptor.

Carrier Proteins↗

PubMed1991

Estramustine binding protein (EMBP) in rat R3327 Dunning tumors: partial characterization and effect of hormonal withdrawal, hormonal replacement, and cytotoxic treatment on its expression.

Expression of estramustine-binding protein (EMBP) was determined in eight variants of the Dunning R3327 rat prostate adenocarcinoma. This secretory protein was previously isolated from the normal rat prostate and binds estramustine and estromustine, the metabolites exerting anti-mitotic and anti-proliferative activity of the anticancer agent estramustine phosphate (EstracytR). EMBP was found in relatively high amounts only in the androgen-responsive G and H tumors from intact hosts, whereas low (AT-1, HI-F) or nondetectable levels (HI-S, AT-3, MAT-LyLu, MAT-Lu) were obtained in the androgen-independent tumors. Castration decreased EMBP expression in both G and H tumors, as did estradiol and estramustine when given separately to intact rats. Supplementation of castrates with exogenous androgen stimulated EMBP expression above the pre-castration level and was further enhanced when combined with estradiol and in particular estramustine. Partial physicochemical characterization of EMBP in G and H tumors was performed by using ligand-based and immunoblotting techniques. [3H]Estromustine was bound to cytosols and salt extracts from tumors with the same affinity and displayed similar surface-charge distribution, sedimentation behavior, and subunit composition as found for ventral and dorsolateral prostatic tissue from tumor-bearing rats. This study indicates that the synthesis of EMBP is under androgenic control and that its expression may be correlated to androgen responsiveness, metastatic potential, and androgen receptor content but not to growth rate and morphology of the tumors. EMBP may therefore provide a mechanism for concentration of cytotoxic activity at the target site in EMBP-positive tumors and help in the evaluation of antitumor effects obtained when administering estramustine.

Adenocarcinoma↗

PubMed1992

Evidence for a non-estrogenic cytostatic effect of estramustine on human prostatic carcinoma cells in vivo.

Estramustine is one of the main metabolites of estramustine phosphate (EstracytR), a drug used in the treatment of advanced prostatic cancer. In the present study the hormone independent human prostatic carcinoma cell line DU 145 implanted subcutaneously in nude mice (NMRI) was used to investigate the mode of action of estramustine in vivo. Metaphase arrest was found in mice treated with estramustine intraperitoneally, 200 and 400 micrograms daily for 2 weeks, 5 days a week. A significant dose dependent decrease in the number of anaphase figures was found. A 7 to 8 fold increase in the number of abnormal metaphases, i.e., highly contracted and unaligned chromosomes, was found. Uptake and retention of 3H-estramustine was found in tumour tissue. No increase in the mitotic index or the number of abnormal metaphases was found in animals treated with polyestradiol phosphate (EstradurinR). This is the first time evidence has been presented demonstrating the anti-mitotic effect of estramustine in vivo.

Animals↗

PubMed1987

Hormone-independent, non-alkylating mechanism of cytotoxicity for estramustine.

Over two decades, experience with estramustine has provided limited data which support an estrogenic mechanism of action and no data which indicate the nitrogen mustard involvement in the cytotoxic properties of the drug. Consideration of the carbamate-ester portion of estramustine supports the pharmacokinetic evidence that estramustine has a long half life since enzymatic hydrolysis of the carbamate is an uncommon event. Using a variety of immunocytochemical and cellular morphology procedures, estramustine per se has been found to express anti-cytoskeletal properties through non-covalent binding to microtubule associated proteins (MAP's). In both fish erythrophores and in dividing human prostatic carcinoma cells, estramustine exerts an antimicrotubule effect at micromolar concentrations. Thus, estramustine possesses unique pharmacology and protein binding specificity. As such, it should not be classified as an alkylating agent. The estrogenic effects, while possibly of relevance to clinical administration, are not the primary mechanism by which the drug exerts cytotoxicity.

Alkylation↗

PubMed1987

Clinical evaluation of flutamide and estramustine as initial treatment of metastatic carcinoma of prostate.

The efficacy and side effects of flutamide were compared with estramustine in patients with advanced prostatic carcinoma. Thirty patients with metastatic cancers but with no serious cardiovascular (CV) conditions were randomly assigned to receive treatment either with flutamide (250 mg X 3) or with estramustine (280 mg X 2). Clinical examination, bone scan, laboratory measurements, including coagulation studies were performed prior to randomization, every three months during year one, and at six-month intervals thereafter. The two groups were comparable with respect to age and tumor characteristics. However, more patients presented with skeletal pain among those later treated with flutamide. During an observation period of between one and two and one-half years, flutamide was discontinued in 1 case (7%) because of icterus, and estramustine in 3 cases (20%) because of CV complications. Of the remaining 14 flutamide-treated patients, 13 responded initially. Eleven of them relapsed, and 5 died of cancer. In the corresponding group of 12 estramustine-treated patients, there were 11 primary responders. Of these, only 2 relapsed and died as did the only nonresponder. The difference between the two groups with regard to relapse is significant (P less than 0.01), but not with regard to mortality. All estramustine-treated patients lost their libido, whereas only 20 per cent of the patients treated with flutamide did so. In the present limited material there was an initial favorable response to flutamide without signs of CV complications and with maintained libido in most cases. However, due to significantly increased risk for relapse compared with estramustine, flutamide cannot be recommended as single therapy except in cases where estrogens are contraindicated or when interference with libido and potency is unacceptable.

Adenocarcinoma↗

PubMed1995

DNA fragmentation induced by the antimitotic drug estramustine in malignant rat glioma but not in normal brain--suggesting an apoptotic cell death.

Estramustine, a combination of 17 beta-oestradiol and nor-nitrogen mustard, has been shown to be metabolised and to induce specific antiproliferative effects in malignant glioma, including arrest of glioma cells in the G2/M phase of the cell cycle, damage to cell membranes and DNA and induction of free oxygen radicals. To evaluate further the effects of estramustine, an in vivo rat glioma model using inbred BD-IX rats and the BT4C cell line was set up. In order to detect cells with fragmented DNA, tumour and brain specimens were, following fixation for histological examination, processed for in situ end labelling (ISEL) with biotin-labelled nucleotides. Fresh tissue fragments were also used for DNA integrity analysis on agarose gels. It was demonstrated that estramustine induced clusters of ISEL-positive cells and a pronounced typical fragmentation of DNA 0.5-8 h after treatment. In tumours examined 24 or 94 h after estramustine treatment, and in untreated tumours, only occasional single ISEL-positive cells were scattered in the tumour. DNA from normal brain tissue did not display any visible sign of fragmentation. These changes are indicative of programmed cell death induced by estramustine in glioma cells but not in normal brain tissue. Further studies are, however, needed to establish in detail the mechanism of cell death following treatment with the antimitotic drug estramustine.

Animals↗

PubMed1999

Effects of radiotherapy and estramustine on the microvasculature in malignant glioma.

Tumour angiogenesis is essential for progression of solid tumours and constitutes an interesting target for therapy. However, impaired tumour blood supply may also be an important obstacle for treatment by radiotherapy and chemotherapy. Estramustine has been shown to increase tumour blood flow and potentiate the effect of radiotherapy in experimental glioma. This study investigated the effects of fractionated radiotherapy and estramustine on angiogenesis in malignant glioma. The intracerebral BT4C rat glioma model was used and the animals were given whole brain radiotherapy 4 Gy x 5 days alone or in combination with estramustine 20 mg kg(-1) i.p. daily. Tumour microvascular density (MVD) was assessed by manual and computerized morphometrical analysis. Expression of vascular endothelial growth factor (VEGF) was studied by in situ hybridization. Radiotherapy decreased MVD to 157 vessels per mm2 compared to 217 vessels per mm2 in controls. Estramustine counteracted this anti-angiogenic effect and potentiated the anti-tumoural effect of radiotherapy. In addition, vessel size increased after estramustine treatment. Five days after completion of radiotherapy the expression of VEGF was increased in the centre of the tumours. In conclusion, fractionated radiotherapy decreases microvascular density in experimental malignant glioma. This effect was abolished by estramustine. The anti-vascular effect of irradiation is important to recognize when combining radiotherapy with cytotoxic drugs.

Animals↗

PubMed2005

Evaluation of lipophilins as determinants of tumor cell response to estramustine.

Estramustine administered orally as estramustine phosphate (EMP) remains a major tool in hormone refractory prostate cancer chemotherapy. The presence of estramustine binding protein, prostatin, in prostate tissue may be a determinant of response to treatment. Lipophilins are secretory proteins with homology to prostatin. Reverse transcription-polymerase chain reaction was performed to estimate expression patterns of lipophilins A to C in human biopsies and cell lines resistant to estramustine. Although lipophilin A was not expressed in prostate tissue, both lipophilins B and C were expressed in normal and tumor prostate without significant differences. For lipophilin C, a somatic mutation (T to C transition at positions 409 and 412) was found in human tumor samples and absent in normal prostate tissue. No consistent response to EMP was observed in enhanced green fluorescent protein (EGFP)-tagged lipophilin C-transfected PC3 cells compared with parental controls. Among these EGFP-lipophilin C clones, no direct correlation between response to EMP treatment (IC50 values) and EGFP expression was observed (p = 0.73). Lipophilin C mRNA levels did not vary significantly between wild-type and estramustine-resistant cells in prostate (DU145 and PC3) and ovarian (SKOV3) cancer cell lines. Overall, these results suggest that lipophilins are not specific determinants of estramustine efficacy.

Antineoplastic Agents, Hormonal↗

PubMed1988

Estramustine binds MAP-2 to inhibit microtubule assembly in vitro.

We have investigated the ability of estramustine to bind to rat brain microtubule-associated proteins (MAPs) and purified MAP-2 in vitro. [3H]estramustine's relative affinity for tubulin and MAPs was assessed by gel filtration chromatography, immunoprecipitation and binding assays. Scatchard analysis demonstrated a specific affinity of the drug for MAP-2. Calculations from kinetic parameters and non-linear regression analysis gave a Kd of 15 microM, and a Bmax of 3.4 x 10(-7)M ml-1. Extrapolation of this value suggested that each MAP-2 molecule binds approximately 20 molecules of estramustine. Microtubule assembly studies and SDS-polyacrylamide gel electrophoresis revealed that at 20-60 microM levels, estramustine inhibited the association of MAPs with taxol microtubules. Turbidity (A350) studies further demonstrated that 20-60 microM-estramustine inhibited MAP-2-driven tubulin assembly and produced microtubule disassembly. Electron-microscopic studies confirmed the centrifugation and turbidity results. The data demonstrated that estramustine can bind MAPs and MAP-2 specifically, thereby inhibiting microtubule assembly.

Animals↗

PubMed1998

Pharmacokinetics and pharmacodynamics of estramustine phosphate.

Estramustine phosphate (estramustine phosphate sodium), a carbamate ester combining 17 beta-estradiol and nor-nitrogen mustard, is a cytotoxic drug used in the treatment of advanced prostatic carcinoma. Because of the radiosensitising effect of this drug there has been a recent increase in interest concerning estramustine phosphate and its clinical use. It has also been found that the early recommendations of drug administration together with food or milk were inappropriate, since calcium containing food and antacids hamper drug uptake. This may have obscured results from earlier clinical studies with estramustine phosphate. Estramustine phosphate is currently being re-evaluated for the treatment of other tumours such as glioma and mammary carcinoma. This review summarises the present relatively limited knowledge concerning the pharmacokinetic and pharmacodynamic aspects of estramustine phosphate and its metabolites.

Animals↗

PubMedDate not supplied

Radiation sensitizing effect of estramustine is not dependent on apoptosis.

BACKGROUND: Estramustine is an anti-mitotic cytostatic drug that also enhances the effect of radiotherapy. The mechanism of radiosensitization is not thoroughly known. Since both radiotherapy and estramustine induce apoptosis in prostate cancer cells, we conducted an experiment to show whether radiosensitization is mediated by apoptosis. MATERIALS AND METHODS: DU-145 human prostate cancer cells were xenografted to nude mice and treated with estramustine for 2 weeks and external radiation for 3 to 6 days (18 to 36 Gy). Tumor regression was measured mechanically and the rate of apoptosis defined by the amount of low molecular weight DNA fragmentation. Follow-up time was 1 to 18 days. RESULTS: The tumor size regressed in the group of mice receiving both radiotherapy and estramustine. Four weeks after the treatment, apoptosis was accentuated in the tumors treated with estramustine or radiation but not with their combination. CONCLUSION: Estramustine potentiates radiotherapy, but not by enhancing radiation-induced apoptosis.

Animals↗

PubMed1988

Blocking of collagenase secretion by estramustine during in vitro tumor cell invasion.

The effects of the antitumorigenic drug estramustine on tumor cell membrane penetration (invasion) were investigated in vitro by utilizing a synthetic basement membrane system (a modified Boyden chamber). Tumor cells were plated on a "partition barrier," consisting of a porous filter (8-micron pores) which was coated with a reconstituted basement membrane matrix (Matrigel), and induced to migrate across the barrier with conditioned medium obtained from 9DU 145 human prostatic tumor cells (passage 9). Quantitative radiolabeling studies demonstrated that specially isolated lines (isolated by several passages through the Matrigel) of DU 145 cells, A2058 melanoma, and B16-F10 melanoma cells were highly invasive such that 15 to 20% migrated across a 1-mm-thick Matrigel layer within 5 h at 37 degrees C. NIH-3T3 cells, mouse fibroblasts, and 20DU 145 cells (passage 20) exhibited little or no membrane invasive behavior. Micromolar concentrations of estramustine (30 to 120 microM) inhibited invasion by the invasive cell lines in a dosage-dependent fashion. Quantitative enzymatic assays and radioimmune assays demonstrated that estramustine inhibited membrane invasion by blocking type IV collagenase secretion. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blots confirmed that 30 to 60 microM estramustine blocked secretion of a Mr 105,000 collagenase protein. Indirect studies showed that a collagenase antibody raised against the Mr 105,000 protein and inhibitors of proteinase activity, including a metalloproteinase inhibitor, and 1,10-phenanthroline, blocked invasion. Because the antibodies inhibited type IV collagenase digestion of 3H-mouse type IV collagen, and invasion simultaneously, it is proposed that collagenolytic activity is involved in invasion. These data demonstrate that estramustine blocks proteinase secretion, and suggest that estramustine may be a useful therapeutic drug for the prevention of metastasis.

Cell Division↗

PubMedDate not supplied

Estrogen receptor and binding site for estramustine in metastatic malignant melanoma.

Enzyme immuno assay (EIA) of estrogen receptor (ER) has confirmed the results of earlier investigations using steroid binding techniques, namely that ER is present at very low concentrations in samples from metastatic melanoma. Thirty-four of 61 samples (56%) were ER positive with EIA. The corresponding figures using isoelectric focusing (IF) for the steroid binding assay were 16 of these 61 samples (26%). The difference between the methods may be due to difficulties in the interpretation of analytical results for IF at low ER concentration levels or to interference from other 3H-estradiol binding components. Estramustine binding site (EMBS) has been found in samples from 15 of 77 patients (20%) with IF in polyacrylamide gels. Estramustine is, together with estramustine, the cytotoxic metabolite of estramustine phosphate (Estracyt). In analogy to the previously suggested therapeutic significance of estramustine binding protein in the treatment of prostatic cancer, the clinical importance of estramustine phosphate should also be studied in metastatic malignant melanoma in correlation with EMBS status.

Adolescent↗