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PubMed1978

Estramustine phosphate: metabolic aspects related to its action in prostatic cancer.

Estramustine phosphate, a drug effective in a substantial number of patients with cancer of the prostate who had failed on other forms of therapy, has been shown to be split into its constituents, that is estradiol-17beta and the carbamate nitrogen mustard by non-cancerous and cancerous human prostatic tissues. This fact may explain, in part, the mechanism of action and efficacy of the drug in patients with cancer of the prostate. In addition to presenting results on the hydrolysis and its products accomplished by human prostatic tissues we discuss the limitations of extrapolating animal results with estramustine phosphate to the human condition and possible parameters that bear upon the insignificant toxic and estrogenic effects observed in patients given estramustine phosphate.

Adenocarcinoma↗
PubMed1983

Estramustine phosphate versus stilbestrol as primary treatment for metastatic cancer of the prostate.

A controlled, randomized trial of estramustine phosphate versus stilbestrol has been conducted in patients with previously untreated adenocarcinoma of the prostate. Both drugs were equally effective in decreasing serum testosterone and acid phosphatase levels. No therapeutic advantage of estramustine over stilbestrol was noted. At 3 months, 50% of tumours treated with stilbestrol had regressed compared with 36% treated with estramustine, at 1 year the rates were 50% and 21% respectively and at 2 years 50% and 9%. However, there was no difference in objective stabilization and regression rates between the two groups or in therapeutic failure rates.

Acid Phosphatase↗
PubMed1995

Immediate estrogen or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicenter study with 15 years of followup. The South Sweden Prostate Cancer Study Group.

From November 1978 to July 1984, 285 men with previously untreated, localized prostate cancer were consecutively randomized in an open multicenter study. The main objective was to determine if early endocrine treatment prolongs the interval to metastasis and/or cancer related or overall survival. Patients were randomized to receive either 80 mg. polyestradiol phosphate by intramuscular injection every 4 weeks plus 50 micrograms ethinylestradiol 3 times daily or 280 mg. estramustine phosphate 2 times daily, or for surveillance only but with deferred endocrine treatment at progression to metastatic disease. From 1983 further inclusion into the polyestradiol phosphate plus ethinylestradiol group was closed because of a high frequency of cardiovascular complications and thereafter 13 patients were instead randomized to a new treatment group with 80 mg. polyestradiol phosphate only by intramuscular injection every 4 weeks. Mean age was 70 years for 228 evaluable patients: 66 in the polyestradiol phosphate plus ethinylestradiol group, 74 in the estramustine phosphate group and 88 in the deferred treatment group, respectively. Mean followup for 100 patients alive on August 31, 1993 was 144 months (range 111 to 180). During the observation period 51 patients had metastasis. There was no difference in interval to metastasis (p = 0.07) among the 3 groups, although there was a tendency for a higher probability of metastases in the deferred treatment group. A total of 128 patients (56%) died during the observation period and prostatic cancer was considered to be the cause of death in 46 (20%). There was a significant difference (p = 0.03) among the 3 groups in the probability of dying of prostatic cancer, with the highest risk in the surveillance group but we found no significant difference in overall survival. The relevance of different prognostic factors and their interaction with treatment was also evaluated. These analyses were applied to the entire patient group as well as to the different subgroups. We found that patients with moderately well differentiated cancer (stage greater than T0a) who received early treatment with estramustine phosphate had the lowest risk of metastases or death from prostatic cancer, while those with well differentiated cancer (stage greater than T0a) did best on early polyestradiol phosphate plus ethinylestradiol treatment.

Adenocarcinoma↗
PubMed1994

Interaction of an estramustine photoaffinity analogue with cytoskeletal proteins in prostate carcinoma cells.

To identify specific drug targets of the antimitotic drug estramustine, a photoaffinity analogue, 17-O-[[2-[3-(4-azido-3-[125I] iodophenyl)propionamido]ethyl]carbamyl]estradiol-3-N-bis(2- chloroethyl)carbamate, was synthesized and reacted in competition assays with cytoskeletal protein preparations. By attaching the photoaffinity ligand to the 17 beta-position of the steroid D-ring, the cytotoxic properties of the drug were maintained. In cytoskeletal protein preparations from human prostate carcinoma cells (DU 145) or a clonally selected, estramustine-resistant cell line (E4), the major microtubule-associated protein (MAP) present was MAP4. In both cytoskeletal fractions and reconstituted microtubules, 17-O-[[2-[3-(4-azido-3-[125I]iodophenyl)propionamido] ethyl]carbamyl]estradiol-3-N-bis(2-chloroethyl)carbamate bound to both MAP4 and tubulin. From competition assays, the apparent binding constant for MAP4 from DU 145 cells was 15 microM. Similar calculations for tubulin gave values of 13 microM (bovine brain), 19 microM (DU 145 wild-type cells), and 25 microM (E4 cells). The identification of these cytoskeletal proteins as specific drug targets provides a direct explanation for the antimicrotubule and antimitotic effects of estramustine.

Affinity Labels↗
PubMed1997

Estramustine-based chemotherapy.

Long misclassified as an alkylating agent, estramustine phosphate is a stable conjugate of estradiol and nornitrogen mustard with antimitotic properties. Binding of the drug to microtubule-associated proteins, tubulin, and proteins of the nuclear matrix are presently considered to be the most likely mechanisms underlying the cytotoxicity of estramustine in androgen-independent prostatic carcinoma. Identification of these mechanisms of action has led to clinical reevaluation of estramustine phosphate (EMP) in several rationally designed drug combinations. Combination of EMP with either vinblastine, paclitaxel or etoposide has produced antitumor responses in 30% to 60% of patients with metastatic hormone-refractory prostate carcinoma as determined by reduction in bidimensionally measurable soft tissue disease, pain, and serum prostate-specific antigen. Whereas the antitumor activity of the combinations has been greater than additive for the single agents, the toxicities of treatment have not been greater than predicted for the individual drugs. The promising results of EMP-based chemotherapy encourage additional laboratory and clinical investigations to develop more effective therapy for hormone-refractory disease and for selected patients with earlier stages of prostate cancer.

Antineoplastic Agents, Hormonal↗
PubMed1987

Mouse monoclonal antibodies against rat estramustine binding protein.

Hybridomas producing antibodies against rat prostatic estramustine binding protein (rEMBP) have been obtained by fusion of spleen lymphocytes from Balb/c mice, immunized with rEMBP, and SP2/0 Ag 14 mouse myeloma cells. Anti-rEMBP IgG producing cultures were identified in a solid phase ELISA using alkaline phosphatase conjugated sheep antimouse IgG. Cultures producing specific antibodies were subcloned and expanded. The produced immunoglobulins were characterized according to interaction with subunits of rEMBP. No interaction was found with [3H]estramustine-human estramustine binding protein. Following development of a radioimmunoassay, tissue distribution of rEMBP in the rat was studied. Despite high specificity, shown by selective interaction with rEMBP (F and S subunits), macromolecules interacting with anti-rEMBP were found in high concentrations in the prostrate and also in low concentrations, in other tissues of the male genital tract, and further in the adrenals, pancreas and submaxillary gland. The high specificity also makes it possible to study the F and S subunit selectively. These results show that macromolecules very similar to rEMBP are present in hormone-sensitive tissues in the rat.

Animals↗
PubMed1999

Estramustine in combination with vinblastine and mitomycin-C for patients with progressive androgen independent adenocarcinoma of the prostate.

A phase II trial was performed to assess the antitumor activity and toxicity of estramustine in combination with vinblastine and mitomycin-C in 46 consecutive patients with androgen independent prostate cancer. All patients presented with disease progression following castrate serum testosterone levels and were treated for six consecutive weeks with three daily 140 mg doses of oral estramustine, vinblastine at 5 mg/m(2) weekly by intravenous bolus and mitomycin-C at 15 mg/m(2) every six weeks by intravenous bolus. Prostate specific antigen levels decreased by greater than 50% from baseline in 16 (41%; 95% CI 25-58%) and normalized in 11 (28%; 95% CI 14-45%) of 39 evaluable patients. Patients who demonstrated a greater than 50% reduction in PSA had a longer delay in time to disease progression. Non-hematologic toxicity was mild, predominately gastrointestinal. Hematologic toxicity was apparent in five patients with Grade III granulocytopenia and in 21 patients with Grade IV granulocytopenia of 43 evaluable patients for toxicity. Three patients were admitted to the hospital for neutropenic fever. Eight patients had Grade III thrombocytopenia, four patients had Grade IV thrombocytopenia, no bleeding occurred. Estramustine in combination with vinblastine and mitomycin-C is an active regimen. The non-hematologic toxicity was tolerable, while the hematologic toxicity required individual dosage reduction. The combination and the clinical significance of the decline in the PSA warrants further investigation.

Journal Article↗
PubMed1992

The expression of estramustine-binding protein in the human prostatic cancer cell line DU 145 is not androgen dependent.

Estramustine-binding protein (EMBP) constitutes one of the major proteins in the prostatic gland, it binds estramustine and estromustine, the active metabolites of estramustine phosphate (Estracyt). Previous studies in rats have indicated that the expression of EMBP is androgen dependent, with diminishing quantities following castration and estrogen treatment as well as restored pre-castration production upon administration of androgens. In this study, we have used the human prostatic cancer cell line DU 145 transplanted in female and male nude mice. This cell line, which is sex hormone independent, gave rise to subcutaneous tumors in the rats with no difference in growth characteristics between the males and females. The expression of EMBP was analysed by radioimmunoassay, immunohistochemical and Western blot techniques. No difference was seen between the two sexes with respect to EMBP content, demonstrating that the expression of EMBP, in contrast to that reported for the normal prostate, is neither androgen- nor estrogen-dependent in tumor tissues.

Animals↗
PubMed1981

The effect of estramustine phosphate on prostatic cancer estimated by transrectal ultrasonotomography.

Transrectal ultrasonotomography was performed in 44 patients with prostatic cancer before, during, and after estramustine phosphate (Estracyt) administration. In 75.7% of 37 previously untreated patients, the deformity of the horizontal section of the prostate with prostatic cancer was corrected considerably, while in 89.2%, prostatic weight was remarkably reduced. In 57.1% of seven previously treated patients, appreciable changes were also observed in the shape and weight of the prostate. We concluded that estramustine phosphate was effective not only for untreated prostatic cancer, but also, at least in some degree, for relapsed cases.

Aged↗
PubMed1982

Estramustine phosphate (Estracyt) treatment of T3-T4 prostatic carcinoma.

From September, 1978, to November, 1980, 69 consecutive patients with locally advanced (T3-T4) prostatic adenocarcinoma, with or without distant metastases, were treated with oral estramustine phosphate. Dosage was 15 mg/kg/day for 2 months, followed by 5 mg/kg/day until progression. In the 48 evaluable patients with progressive disease that entry in the study, 1 complete response, 7 partial responses, 31 disease stabilizations, and 9 progressions were encountered (81.2% NPCP response rate). Karnofsky performance status equal to or less than 50 was predictive of poor response to estramustine phosphate. In the 10 evaluable patients with stabilized disease at entry in the study after orchiectomy, 2 complete responses, 4 partial responses, 3 disease stabilization, and 1 progression were noted. The major side effects observed were gynecomastia, nausea, and vomiting.

Adenocarcinoma↗
PubMed1992

Radiation sensitization by estramustine studies on cultured human prostatic cancer cells.

In low-stage prostatic carcinoma, local cure can be obtained with radiation therapy alone, while in locally advanced disease the chances for cure are less. In this study, we have addressed the question of whether estramustine (EM), the main cytostatic metabolite of estramustine phosphate (Estracyt), may act as a radiosensitizing agent. This drug accumulates in prostatic cancer and has also been shown to arrest cancer cells at metaphase both in vitro and in vivo. The human prostatic cancer cell line DU 145 was grown as cultures monolayer and incubated with EM in concentrations varying from 1 to 20 micrograms/ml. External beam irradiation was performed with doses ranging from 0 to 8 Gy using gamma rays from a 60Co source. Clonogenic cell survival (CS) was used to analyse the radiation sensitizing effect of EM. The radiation dose modifying factor (DMF) at the survival level 0.1 was found to be 0.77 in the presence of EM (5 micrograms/ml), i.e., 23% sensitization was obtained. When irradiating cells at the standard fraction dose of 2 Gy in the absence of EM, 22% of the cells lost their clonogenic ability. In presence of EM (5 micrograms/ml), 2 Gy caused 40% of the cells to lose their clonogenic ability. Thus a radiation sensitizing effect of EM was established in the CS assay. It was also of interest to determine if the radiosensitizing effect of EM could be confirmed in a rapid assay. The rapid fluorescence assay was used to observe early damage of the cells. Results showed that by 2 days after exposure to irradiation a weak tendency towards sensitization was seen, while a clear sensitization was obtained after 4 days. This indicates that the rapid assay might be developed to a predictive assay for detection of the response of primary prostate tumor cells to the radiation sensitizing effect of EM.

Cell Survival↗
PubMed1977

Estramustine phosphate therapy in carcinoma of the prostate.

Estramustine phosphate, a nor nitrogen mustard derivative of estradiol 17-beta-phosphate, was introduced in the treatment of prostatic carcinoma in 1966. Until March 1975, 466 patients have been reported on this treatment in open clinical trials: 82% of the patients were in stage IV. In 402 patients, nonresponsive to previous estrogen therapy, signigicant improvement occurred in 55%. In 64 previously untreated patients there was a favourable response in 83%. Side-effects were mainly bone marrow suppression. liver disturbance, thrombophlebitis following intravenous injection, and gastrointestinal troubles, mainly following oral administration. A prospective, randomized study comparing oral estramustine phosphate and conventional estrogen therapy in carcinoma of the prostate is in progress.

Administration, Oral↗
PubMed1991

Dependency of microtubule-associated proteins (MAPs) for tubulin stability and assembly; use of estramustine phosphate in the study of microtubules.

Microtubule-associated proteins (MAPs) were separated from tubulin with several different methods. The ability of the isolated MAPs to reinduce assembly of phosphocellulose purified tubulin differed markedly between the different methods. MAPs isolated by addition of 0.35 M NaCl to taxol-stabilized microtubules stimulated tubulin assembly most effectively, while addition of 0.6 M NaCl produced MAPs with a substantially lower ability to stimulate tubulin assembly. The second best preparation was achieved with phosphocellulose chromatographic separation of MAPs with 0.6 M NaCl elution. The addition of estramustine phosphate to microtubules reconstituted of MAPs prepared by 0.35 M NaCl or phosphocellulose chromatography, induced less disassembly than for microtubules assembled from unseparated proteins, and was almost without effect on microtubules reconstituted from MAPs prepared by taxol and 0.6 M NaCl. Estramustine phosphate binds to the tubulin binding part of the MAPs, and the results do therefore indicate that the MAPs are altered by the separation methods. Since the MAPs are regarded as highly stable molecules, one probable alteration could be aggregation of the MAPs, as also indicated by the results. The purified tubulin itself seemed not to be affected by the phosphocellulose purification, since the microtubule proteins were unchanged by the low buffer strenght used during the cromatography. However, the assembly competence after a prolonged incubation of the microtubule proteins at 4 degrees C was dependent on intact bindings between the tubulin and MAPs.

Alkaloids↗
PubMed1988

Growth inhibiting effect of estramustine on two prostatic carcinoma cell lines, LNCaP and LNCaP-r.

The effect of estramustine (EM), estradiol-17 beta (E2) or 5 alpha-dihydrotestosterone (DHT) on the growth of two human prostatic carcinoma cell lines, LNCaP and LNCaP-r was investigated. The hormone resistant subline LNCaP-r was derived in our laboratory, from the hormone sensitive LNCaP cell line. E2, 10(-8) or 10(-5) M inhibited the growth of the LNCaP cells, but did not affect the LNCaP-r. DHT, 10(-8) M, had a stabilizing effect at the stationary phase on the growth of the LNCaP cells whereas at higher concentrations, 10(-5) M, the growth rate was decreased. The LNCaP-r cell line was previously reported to be unaffected by DHT. EM inhibited the growth of both cell lines but LNCaP was more sensitive than LNCaP-r. E2 and DHT modulated the effect of EM. When treated with 10(-7) M EM, addition of E2 or DHT (10(-7)-10(-5) M) further inhibited the growth. When EM was used at a higher concentration (10(-5) M), the enhanced effect of growth inhibition by hormone addition was lost. Based on these results it is suggested that the presence of endogenous hormones, or estrogens released from EM on hydrolysis, may play a contributory role in the cytotoxicity of estramustine.

Cell Division↗
PubMed1989

Difference in uptake of 3H-estramustine in two human prostatic carcinoma cell lines, LNCaP and LNCaP-r.

Estramustine, estradiol-3-N-bis(2-chloroethyl)carbamate (EM), has been shown to inhibit growth of the human prostatic carcinoma cell line LNCaP as well as its subline LNCaP-r. The hormone sensitive LNCaP showed greater sensitivity to the drug than the hormoneresistant LNCaP-r. LNCaP has also shown an increasing sensitivity to 10(-7) M EM, when incubated with different concentrations of steroid hormones. We studied whether the increasing sensitivity was caused by increased uptake of EM. 3H-estramustine was added to medium and the cells were incubated 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, and 4 h, or 2 h, 4 h, 6 h, and 8 h. No effect of steroids on the uptake of EM was noted, but LNCaP showed a higher uptake of EM compared to LNCaP-r. The uptake of EM in LNCaP increased for eight hours, whereas LNCaP-r reached its maximum uptake after six hours of incubation.

Biological Transport, Active↗
PubMed1994

Expression of estramustine-binding protein in ependymomas and in human and developing rat ependymal cells.

The mainstays of primary treatment of ependymoma are aggressive surgery followed by radiotherapy. Although spreading occasionally occurs in the cerebrospinal pathways, chemotherapy is still not established and no ultimate drug has so far been found. Estramustine-phosphate (EMP), with a demonstrated effect on astrocytoma in vitro, has been shown to penetrate the blood-tumor barrier and to accumulate in human brain tumor tissue including ependymoma. It has been proposed that the cytotoxic effect of EMP depends on the presence of a binding protein, estramustine-binding protein (EMBP). In the present paper we have, for the first time, immunohistochemically demonstrated an EMBP-like protein in a series of ependymomas. Immunoreactivity was found within the cytoplasm of the tumor cells with a tendency to increase with increasing malignancy of the tumor. In addition, the occurrence of EMBP-like protein was demonstrated in human ependymal cells. In the rat brain, a weak immunoreactivity was detected in early fetal neuroepithelial cells while the staining intensity was increased in mature ependymal cells in late fetal, neonatal, and adult rat. Thus; immunoreactivity for an EMBP-like protein was demonstrated in ependymoma tissue, normal human ependyma and in the developing rat ependymal cells.

Adolescent↗
PubMed1995

Radiosensitizing effect of estramustine in malignant glioma in vitro and in vivo.

Estramustine-phosphate (EMP), a combination of nornitrogen mustard and 17 beta-estradiol, has been demonstrated to exert specific antiproliferative effects on human glioma cells in vitro. The cytotoxic effect is, at least partially, mediated by inhibiting microtubule function. In this study the combined effect of EMP and radiation was evaluated in the human glioma cell-lines, 251-MG and 105-MG, in vitro, and in the rat glioma BT4C in vitro and in vivo. In all cell-lines an additive effect of EMP and radiation was obtained in vitro. Assuming equal effect of EMP is obtained in subsequent radiation fractions, the cell kill will be increased from 2-3 to 5-10 logs if delivering 30 fractions of 2 Gy combined with EMP. In the BT4C rat model the combined effect was found to be synergistic. Flow cytometry demonstrated an arrest in G2/M phase in all cell-lines after EMP treatment. This block in G2/M phase in addition to the previously demonstrated induction of free oxygen radicals, and the increase of blood flow with an assumed subsequent increase of oxygenation, might provide an explanation for the observed radiosensitizing effect of estramustine.

Animals↗
PubMed1991

Presence of oestrogen receptors on target cells and antiproliferative activity of estramustine phosphate: positive correlation for human tumours in vitro.

Incubation with estramustine phosphate for 24 h inhibited DNA, RNA and protein synthesis in primary cultures of human kidney, mammary, prostatic, cervical and endometrial carcinoma. Not only the presence, but also the concentration of oestrogen receptors correlated with estramustine phosphate effects on tumour cell proliferation.

Cell Division↗