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PubMed1985

Antimicrotubule effects of estramustine, an antiprostatic tumor drug.

Estramustine [17 beta-estradiol 3 N bis(2-chloroethyl)carbamate; EM] is a stable conjugate of estradiol and nor-nitrogen mustard that is used for the treatment of human prostatic carcinoma. We have studied the cytotoxic effects of EM on the cytoskeletal organization of squirrelfish pigment cells (erythrophores) and human prostatic tumor cells (DU 145) in culture. Light and whole-mount electron microscopy studies reveal that, at microM levels (60 to 120 microM), EM has a dose-dependent disruptive effect on cell shape, cytoskeletal organization, and intracellular transport. Upon removal of the drug, the cytological effects of EM are rapidly reversible in fish cells but not DU 145s. Immunofluorescent studies reveal that EM produces microtubule disassembly in fish erythrophores and DU 145 cells. A concomitant disruption of actin-microfilament arrays also occurs in DU 145 cells. These morphological data suggest that EM, in contradistinction to its constituent estradiol: nitrogen mustard species, induces cytotoxicity as an antimicrotubule drug. The observed disruption of the microtubules and cytomatrix of interphase cells is not reversible in the prostatic carcinoma cells. The disruptive action of EM on the cytoskeleton could ultimately produce a cytotoxic antimitotic effect in dividing cells.

Animals↗
PubMed1977

Treatment of oral estramustine phosphate (Estracyt) in prostatic carcinoma: influences on lipid and carbohydrate metabolism.

Estramustine phosphate (Estracyt), a combination of estradiol and nitrogen mustard given to males with prostatic carcinoma, had the same effect on serum lipids, lipoproteins, and serum phosphoglyceride fatty acid composition as ethynyl estradiol (Etivex). The characteristic effects on serum lipids caused by both drugs, i.e., a reduction in serum cholesterol and an increase in serum phospholipids, were apparently expressions for reduced low density lipoproteins and increased alpha-lipoproteins. Serum lecithin fatty acid composition revealed during the administration of both drugs a characteristic increase in palmitic acid (16:0) and a decrease in stearic acid (18:0), interpreted as evidence for a cholestatic, although subclinical, liver involvement. Similar changes have earlier been revealed in women given ethynyl estradiol; however, the increase in serum triglycerides and very low density lipoprotein cholesterol in young women was not duplicated in aged males with prostatic carcinoma. Furthermore, in aged males, the administration of these estrogens did not change carbohydrate metabolism but did produce an increase in adipose tissue lipoprotein lipase.

Adipose Tissue↗
PubMed1980

Estramustine versus conventional estrogenic hormones in the initial treatment of highly or moderately differentiated prostatic carcinoma. A randomized study.

In a prospective randomized multicenter trial patients with highly or moderately differentiated prostatic carcinoma, previously untreated, were allotted either to oral Estramustine phosphate or to intramuscular polyestradiol phosphate plus oral ethinyl estradiol. As regards frequency and duration of tumour remission there was no statistical difference between the two groups. Nor did they differ significantly with respect to adverse reactions. This is an interim report and will be followed later on by a final evaluation.

Bone Neoplasms↗
PubMed1984

Oral estramustine phosphate (Estracyt): a broad phase II study.

Thirty-five patients with advanced cancers were treated with estramustine phosphate tablets (Estracyt). Doses ranged between 420 mg and 700 mg daily. One partial response was documented in a hormone resistant prostatic cancer patient. Four minor responses (less than 50% responses, or less than one month more than 50% response) were obtained; one in a hormone resistant prostatic cancer, two in metastatic colorectal cancers; and another in a malignant melanoma. Toxicity phenomena included nausea (9/35 - 25%), water retention (4/35 - 11.5%) and mild elevation of alkaline phosphatase (2/35 - 6%). Other toxicity effects were vaginal bleeding in two women, acne in one woman and mild pruritus in another patient. Myelosuppression and immune suppression were not significantly detected.

Adult↗
PubMed1984

[Value of estramustine phosphate in the treatment of estrogen-resistant prostatic adenocarcinoma].

Estramustine phosphate ( Estracyt ) was used in 32 patients with a mean age of 73 and a half years suffering from oestrogen-resistant carcinoma of the prostate. These carcinomas were advanced and were divided into 26 stage D and 6 stage C. Treatment was given orally at a dose of 600 mg per day. Results were assessed on the basis of reliable subjective and objective selected criteria. Objective responses were obtained in 28,1% of cases and subjective responses in 40.6%. All the patients in whom there was an objective response showed a subjective response. Objective action was more marked on the primary tumour than on metastases. There was a decrease in bone pain, an improvement in general condition and disappearance of dysuria in more than a third of all cases. When there was a response, it always occurred before the end of the 2nd month and was maximal at 3 months. The mean duration of a response was 29.1 months for objective responses and 27.7 months for subjective responses. Survival of patients responding to treatment was markedly longer (by 15 months on average) than in patients who failed to respond. The low level of toxicity of the compound, even after prolonged use, makes its use possible in all patients. Thus Estracyt is felt to have a role in the treatment of the severe forms represented by hormone-resistant carcinomas of the prostate.

Adenocarcinoma↗
PubMed1980

Cardiovascular complications to treatment of prostate cancer with estramustine phosphate (Estracyt) or conventional estrogen. A follow-up of 212 randomized patients.

Two hundred and twelve patients treated for prostatic cancer grade I or II were investigated for cardiovascular complications. The patients were part of a multicentre study in the Stockholm area and had been randomized to treatment with either estramustine phosphate (Estracyt) or polyestradiol phosphate and ethinyl estradiol. Cardiovascular complications categorized as impaired arterial circulation including ischemic heart disease, venous thromboembolism, cardiac incompensation and cerebral depression were found to be equally frequent following the two different forms of treatment. Among the patients getting cardiovascular complications, these occurred within two months after the start of treatment in 50% and within one year in 85% of them. There was a statistically significant correlation between the incidence of cardiovascular complications and a history of previous cardiovascular disease. This criterion was however in retrospect found to predict cardiovascular complications in only 67 of the 126 patients getting one or several of these complications.

Aged↗
PubMed1980

Estramustine phosphate therapy in poorly differentiated carcinoma of the prostate.

Ninety patients with poorly differentiated prostatic carcinoma have been treated with Estramustine phosphate (Estracyt). Seventeen of them had clinically metastases and had had no previous therapy. Seventy-three were initially given oestrogens and/or irradiation. Objective response was observed in 59%. The best effect was seen in patients primarily untreated.

Acid Phosphatase↗
PubMed1995

Paclitaxel plus estramustine in metastatic hormone-refractory prostate cancer.

Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases of > or = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased by > or = 50% in 15 (65.2%) and by > or = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.

Adenocarcinoma↗
PubMed1995

[Estramustine phosphate, estrogen conjugated with nitrogen mustard inhibits the growth of endometrial cancer cells in vitro].

Estra-1,3,5 (10)-triene-3,17-diol (17 beta)-, 3-[bis(2-chloroethyl) carbamate] (Estramustine EM) was tested for its anticancer effect on human endometrial cancer cell lines: Ishikawa and its estrogen (E) independent sub-clone EIIL (Estrogen Independent Ishikawa Line). The results showed: (1) EM inhibited growth of both cell lines in a dose dependent manner giving ID50 for Ishikawa as 12 microM and for EIIL as 65 microM. (2) The addition of EM to the culture medium caused cell detachment and death associated with a breakdown of DNA to approximately 90 base pair fragments. (3) Reverse transcription-polymerase chain reaction to examine expressions of c-erbB-2, nidogen and fas showed that EM completely abolished fas expression and resulted in a 40% decrease in nidogen expression in Ishikawa but not in EIIL. No change was seen in c-erbB-2 expression. The present data indicate that the E component of EM does not stimulate the growth of Ishikawa or EIIL. Since the growth of both cell lines was inhibited but apparently in an E receptor (ER) dependent manner, EM may be of value in an adjuvant therapy for endometrial cancer, especially an ER positive one.

Adenocarcinoma↗
PubMed1995

Studies of natural killer cell activity in a drug-free, healthy population. Response to a challenge with taxol, estramustine and lipopolysaccharide.

Preincubation of peripheral blood lymphocytes with the microtubule disturbing agents estramustine (ETMN; n = 7, final conc. 20 microM) or taxol (TX; n = 13, final conc. 10 microM), resulted in a statistically significant inhibition of natural killer cell activity [(NKCA); baseline (x +/- SD; expressed as percentage of specific chromium release) of 32.2 +/- 30.5 and 34.4 +/- 27.7 and drug treated samples of 13.9 +/- 19.9 and 12.5 +/- 20.8, respectively; Student's paired t-test p < 0.005]. Furthermore, most individual values for NKCA in the drug preincubated samples were at least 20% below the same subject baseline lytic function (except for TX sample No.1), and NKCA was non detectable in 4 out of 7 and 5 out of 13 samples (pretreatment with either ETMN or TX< respectively). The use of other concentrations and different preincubation times for these chemotherapeutic agents also produced NKCA inhibition, which was time and dose dependent. Preincubation with lipopolysaccharide (LPS; n = 16, final conc. 50 micrograms/ml), an endotoxin prominently involved in the etiology of septic shock, resulted in a statistically significant enhancement of NKCA [baseline (x +/- SD; expressed as percentage of specific chromium release) of 25.4 +/- 20.4 and LPS treated sample of 36.6 +/- 17.4, respectively; Student's t paired t-test p < 0.005]. At least a 20% increase in NKC lytic function over its own baseline value was recorded for each and everyone of the samples tested with LPS.2+ the pathophysiology associated with septic shock.

Adult↗
PubMed1996

Increase of beta(III)- and beta(IVa)-tubulin isotopes in human prostate carcinoma cells as a result of estramustine resistance.

Estramustine (EM), an antimicrotubule agent, is effective against hormone-refractory prostate cancer when used in combination with vinblastine or paclitaxel. To understand the effect of EM on beta-tubulin, a cellular target for this class of drugs, human prostate carcinoma cells (DU-145) were made resistant to EM, and two cell lines were selected at 12- (EM-12) and 15-microMolar (EM-15) concentrations of the drug. These cell lines exhibited 8- to 9-fold resistance to EM and 2- to 4-fold cross-resistance to paclitaxel. Immunofluorescent staining of the cells with beta-tubulin isotype-specific antibodies showed an approximately 6-fold increase in the beta(III)-tubulin levels and moderate increase in overall beta-tubulin levels in EM-resistant cells when compared to DU-145 cells. This increase of beta(III) isotype was confirmed by Western analysis. A reverse transcriptase-PCR assay was also employed using beta-tubulin isotype-specific primers to quantify beta-tubulin isotype RNA. A 4-fold increase in beta(III) and a 3-fold increase in beta(IV alpha) transcript were seen in both EM-resistant cell lines. These results indicate that overexpression of specific beta-tubulin isotypes may play a role in the cellular defense against EM and other antimicrotubule agents.

Antineoplastic Agents↗
PubMedDate not supplied

Effects of microtubule inhibitors-taxol, vinblastine and estramustine on the growth and p53 gene expression in the hormone independent human prostatic JCA-1 cells.

Treatment of the JCA-1 prostate cells with different concentrations of microtubule inhibitors-taxol (paclitaxel) vinblastine, and estramustine-was accompanied by reduced cell growth and, correspondingly, characteristic morphological changes. The reduction of cellular proliferation was unlikely to be attributable to an inhibitory effect of the antimicrotubule agents on cell cycling, but was correlated with the decreased expression of the p53 gene. These results suggest that antimicrotubule agents may be considered as potentially complementary treatment modalities for patients with hormonally independent prostate cancer.

Antineoplastic Agents↗
PubMed1997

[Effect of estramustine phosphate on hormone refractory prostate cancer].

Clinical effects of estramustine phosphate (EMT) on hormone refractory prostate cancer were studied. Prostate cancer relapsed in 70 of the 259 patients with stage C and D diseases who had initially responded to endocrine therapy. After cancer relapse, endocrine therapy was changed to oral administration of EMT in 21 patients, while initial endocrine therapy was continued in 14 and additional radiation therapy was given in 35. A partial response or no change was observed in 11 of the 21 patients (52%) given EMT therapy, the mean duration of the response being 14.2 months. The 21 patients given EMT therapy survived significantly longer than the 14 patients with continued on endocrine therapy, and those responding to EMT therapy tended to have a better survival than those unresponsive. Side effects of EMT included loss of appetite in 2 patients and edema of the lower limb in 1, but they were not severe enough to require discontinuation of the drug. EMT may be a useful drug for patients with advanced prostate cancer with relapse after endocrine therapy.

Administration, Oral↗
PubMedDate not supplied

Tumor control of locally advanced prostate cancer following combined estramustine, vinblastine, and radiation therapy.

PURPOSE: A prospective phase II study was carried out to determine whether estramustine phosphate (EMP) plus vinblastine (VBL) in combination with radiotherapy (RT) would improve the control of locally advanced prostate cancer. The rationale for combining EMP plus VBL with RT was based on the clinical and radiobiological data that EMP plus VBL acted as an excellent radiation sensitizer in cultured human prostatic carcinoma cells with the property of tissue selectivity. The combined EMP and VBL were well tolerated in the phase II clinical study of patients with advanced prostate cancer. MATERIALS AND METHODS: Between January 1991 and July 1996, 65 patients, stage T2 (B2) through stage T4 (D1), were entered into the study. Gleason pattern scores ranged from 4 to 10. Pretreatment prostate-specific antigen (PSA) was as follows: < 20 in 21 patients (32%), 20 to 50 in 23 patients (35%), and > 50 in 21 patients (32%). The median age was 70 years (55-83). All patients were treated with megavoltage beam radiation with a total tumor dose of 65 to 70 Gy. Oral EMP 450 mg/m2 daily and VBL 3 mg/m2 weekly were given concomitantly in 46 patients during the 7- to 7 1/2-week course of radiotherapy. RESULTS: All patients showed prompt and complete tumor regression on digital rectal examination at 6 weeks following the completion of treatment. Median follow-up time is 43 months (3-65). PSA fell to an undetectable level by 6 weeks in 56 of 65 patients (86%). For the whole group at 5 years clinical control was 81%, but biochemical control (PSA < 4 ng/mL) was 48%. The likelihood of being free of biochemical relapse at 5 years was a function of initial PSA value (PSA < 20 in 64% of the cases, 21-50 in 60%, and > 50 in 0%). The biochemical-relapse-free survival at 5 years for each stage was T2, 49%; T3, 38%; and T4, 17%. In particular, a group of patients with pretreatment PSA levels of 20 to 50 ng/mL responded quite favorably to the present combined regimen in that only 40% of the patients showed a biochemical failure at 5 years, considering the high level of initial PSA. CONCLUSIONS: The present combined approach is effective in achieving a high rate of tumor control with no disproportionately enhanced side effects. The rapid regression of the tumor nodules and sustained freedom from biochemical relapse suggest excellent long-term tumor control, especially in the group of patients with pretreatment PSA levels of 20 to 50 ng/mL.

Aged↗
PubMed1995

Production of monoclonal antibody against the C1 component of rat estramustine-binding protein: immunohistochemical study of rat prostate.

The monoclonal antibody against estramustine-binding protein (EMBP) was produced by immunizing a mouse with EMBP antigen purified from rat ventral prostate. On western blotting analysis this antibody recognized the EMBP C1 component, and in an absorption test it recognized the EMBP antigen. Immunohistochemically, this antibody revealed positive staining for the ventral and dorsolateral prostate. In the epithelium of the ventral prostate, intense immunostaining was observed in the intraluminal secretory product; however, in the epithelium of the dorsolateral prostate, the staining was intense in the cytoplasm of the epithelial cells. These findings suggested differences of EMBP localization in the ventral and the dorsolateral prostate. Since the intensity of immunostaining for EMBP was decreased in the prostate of castrated rats, we considered that this antibody reflected the androgen dependency of EMBP.

Animals↗
PubMed2003

Phase 3 randomized trial evaluating second-line hormonal therapy versus docetaxel-estramustine combination chemotherapy on progression-free survival in asymptomatic patients with a rising prostate-specific antigen level after hormonal therapy for prostate cancer: an Eastern Cooperative Oncology Group (E1899), Intergroup/Clinical Trials Support Unit study.

Despite improvements in early detection of prostate cancer when it is clinically localized--and therefore most amenable to curative local therapies-- approximately 33% of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen (PSA) during follow-up. The early use of androgen suppression in this group of men has changed the clinical picture of androgen-independent disease. Now, there are men on androgen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time. There is no standard approach to this group of men, who have a rising PSA on androgen deprivation, because there are little or no data about strategies that may improve survival, delay time to progression, or improve quality of life. Therefore, current management of this population remains controversial. In an effort to determine which of these 2 approaches--second-line hormone therapy or chemotherapy--is optimal in delaying the time to progression, the Eastern Cooperative Oncology Group (ECOG) developed protocol E1899. Although both approaches offer the potential for response (reduction in PSA and prolonging the time to clinical progression), they have very different toxicity profiles, making impact on quality of life another important end point. This randomized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on androgen ablation for prostate cancer is the subject of this article.

Adenocarcinoma↗
PubMed1994

Estramustine binding protein in primary tumours and metastases of malignant melanoma.

The presence of estramustine binding protein (EMBP), a 54 kD cytosolic glycoprotein, which is distinct from the estrogen receptor, was investigated in a pilot study of primary malignant melanomas and their metastases. In 11 primary melanomas EMBP was demonstrated by immunohistochemistry. The percentage of positive melanoma cells ranged between 11-91% with a mean of 57%. Radioimmunoassay on metastatic tissue revealed significant amounts of EMBP, with values ranging between 0.6-4.2 with a mean of 1.6 ng/mg protein. A high number of cells with a positive stain for EMBP in the primary tumours was significantly correlated to a short interval between diagnosis and the occurrence of metastases. Presence of EMBP in malignant melanoma may have prognostic significance and the role of hormone-linked cytostatic drugs in the treatment of this disease needs further investigation.

Adult↗
PubMedDate not supplied

Relationship of thyroid to estramustine binding protein (EMBP) concentration in rat prostate.

Alternations of estramustine binding protein (EMBP) concentration in rat prostate in relation to androgen status under hypo- and hyperthyroid conditions was estimated by means of radioimmunoassay (RIA). In hyperthyroid rats, EMBP concentration in dorsal as well as in lateral prostate was not significantly changed, but significantly reduced in ventral prostate (P less than 0.01). Ventral tissue concentration of testosterone(T) + dihydrotestosterone (DHT), DHT and T, and the ventral tissue ratio of DHT to T + DHT were not significantly changed in hypo- and hyper-thyroid conditions compared with that of the control. In hyperthyroid rats, serum T level and EMBP concentration in ventral prostate were significantly reduced in comparison to ones of the control (P less than 0.05 and P less than 0.01, respectively), however, the ratio of ventral tissue (T + DHT) to serum T was significantly increased (P less than 0.05). Moreover, in contrast to the control, EMBP concentration expressed as microgram/microgram ventral DNA was significantly reduced in hyperthyroid rats (P less than 0.05). On the other hand, in hypothyroid rats, change of EMBP concentration in ventral prostate in relation to androgen status was not significant in comparison to the control. The results here obtained revealed that EMBP concentration in ventral prostate under hyperthyroid condition would be affected by (a) a modulation of endogenous androgen-dependency in EMBP synthesis or by (b) a reduction of cell numbers responsible for EMBP synthesis.

Animals↗