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PubMed1993

Estramustine and estrone analogs rapidly and reversibly inhibit deoxyribonucleic acid synthesis and alter morphology in cultured human glioblastoma cells.

Estramustine is an estradiol-based agent that has been shown to accumulate in human glioma cells, resulting in a concentration-dependent alteration in cell size and shape within minutes and an inhibition of proliferation over 3 to 6 days. We evaluated human glioblastoma cultures with [3H]thymidine incorporation assays to determine estramustine's early effects on deoxyribonucleic acid synthesis in these tumors. Because estramustine shares a common structural motif with other antimicrotubule drugs, we synthesized four A-ring conjugates of estrone that contained a carbamate moiety but lacked nitrogen mustard. These analogs were examined by [3H]thymidine incorporation and compared with vinblastine. Greater than 70% inhibition of [3H]thymidine incorporation occurred within 1 hour of treatment with estramustine at 10(-5) mol/L, which increased to 80% inhibition at 4 hours. Ethyl carbamate JE208 was nearly as effective as estramustine in inhibiting deoxyribonucleic acid synthesis, and both were more effective than vinblastine. The inhibitory effects of estramustine and estrone analogs were reversible; vinblastine was not reversible. Although estramustine and JE208 induced similar antiproliferative and morphological changes in glioblastoma cells that persisted for at least 4 days, there was a modest recovery of morphology and thymidine incorporation with JE208 after prolonged treatment. The common findings with estramustine and JE208 suggest that these agents may have a similar mechanism of action and form the basis for the investigation of new agents that may rapidly and reversibly inhibit glioblastoma.

Brain Neoplasms↗

PubMed1994

Selective antimitotic effects of estramustine correlate with its antimicrotubule properties on glioblastoma and astrocytes.

Estramustine is an estradiol-based agent that accumulates in cells containing estramustine binding protein. Previous studies have shown that this binding site is expressed in human glioblastoma cells and that estramustine accumulates in glioma cells, resulting in a concentration-dependent inhibition of proliferation. We have shown that estramustine treatment results in a rapid inhibition of deoxyribonucleic acid synthesis (within 4 h) in human glioblastoma cells associated with an alteration of cell size and shape, consistent with its known antimicrotubule activity. To extend these findings, we performed an immunohistochemical analysis of microtubules with a monoclonal antibody to beta-tubulin, using a colorimetric assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to measure the antimitotic effects of estramustine on both human glioblastoma and astrocyte cultures. Within 4 hours, estramustine (10 mumol/L) caused a dramatic alteration in the tubulin staining in glioma cells, characterized by a disorganization in microtubules. Cell shape and microtubule staining in astrocytes were relatively preserved. Estramustine had a concentration-dependent cytotoxic effect in tumor cultures, whereas it had no effect on astrocyte viability at any concentration. Differences in the antimitotic effects do not appear to be related to variations in proliferation rates among these different types of cells. These data suggest that although estramustine is a potent inhibitor of proliferation in glioblastoma cells, it has modest antiproliferative effects on astrocytes and its selective activity is closely correlated with its antimicrotubule properties.

Astrocytes↗

PubMed1988

Expression of an estramustine-binding associated protein in human lung cancer cell lines.

Estramustine-binding protein has previously been demonstrated in normal rat prostatic tissue, in normal human prostate epithelium, and in prostatic carcinomas. It binds specifically estramustine and estromustine, the cytotoxic metabolites of estramustine phosphate (Estracyt), a drug which is used in the treatment of prostatic carcinoma. In this study we have examined the presence of an estramustine-binding associated protein in a panel of human cell lines, representing the major histopathological types of lung cancer. A mouse (murine) monoclonal antiserum developed against rat estramustine-binding protein was used for immunohistochemical detection. Fast protein liquid chromatography was used for biochemical characterization. As judged from the immunohistochemical investigation, estramustine-binding protein was present in large amounts in five of six non-small cell carcinoma cell lines, while seven of eight small cell carcinoma cell lines were essentially negative. Fast protein liquid chromatography analyses of lysated cells from the lung cancer cell lines, incubated with [3H]estromustine, concurred with the results from the immunohistochemical stainings. These data strongly indicate a convincing connection between the immunoreactivity and ligand-binding properties of estramustine-binding protein in the cell lines examined. The presence of an estramustine-binding associated protein in human lung cancer cell lines has implications for further investigations into the biological relevance and the potential for eventual therapeutic applications.

Antibodies, Monoclonal↗

PubMed1986

Relationship of glutathione depletion and inhibition of glutathione-S-transferase activity to the antimitotic properties of estramustine.

A depletion of intracellular glutathione (GSH) is accompanied by a subsequent inhibition of GSH-S-transferase activity in a DU145 human prostatic carcinoma cell line treated with cytotoxic concentrations of estramustine. When GSH depletion reached approximately 50% of normal (approximately 2 hours after 10 microM estramustine), the mitotic index of logarithmically dividing cultures began to increase. A linear increase from 3.14% to 22.5% occurred during the period of 2-24 hours following 10 microM estramustine. Morphological studies showed that mitotic figures accumulated in metaphase and had abnormalities consistent with spindle malformation. Nocodazole and cytochalasin B also possess anticytoskeletal properties, but had little effect upon the intracellular levels of GSH or its associated transferase enzymes. The constituent moieties of estramustine, estradiol, and nor-mechlorethamine had effects on thiol metabolism which were dissimilar from estramustine, confirming previous findings that the unmetabolized parent drug is responsible for pharmacological activity. Estramustine had no effect upon GSH reductase activity, suggesting that drug toxicity was not a general thiol phenomenon. Buthionine sulfoximine decreased intracellular GSH in DU145 cells and enhanced the cytotoxic potential of estramustine in this cell line. The anticytoskeletal and antimitotic properties of estramustine may be enhanced by the drug-induced GSH imbalance and subsequent effects on GSH-S-transferase enzymes.

Buthionine Sulfoximine↗

PubMed1984

[Estracyt (estradiol-nitrogen mustard complex)--estramustine binding protein and its specificity].

Estracyt (estramustine phosphate) is a nitrogen mustard derivative of estradiol-17 beta which is rapidly dephosphorylated to yield estramustine. Estramustine is metabolized to estromustine mainly in the liver. Both estramustine and estromustine are retained in rat prostate with a high degree of specificity. This retention is due to the binding of estramustine and/or estromustine to a protein called EMBP (estramustine binding protein). When estimated by HPLC, the molecular weights of these estramustine binding components in rat prostate are 45,000-50,000 and 25,000-30,000, respectively. HPLC and glycerol density gradient analysis clearly demonstrated the occurrence of EMBP in a cytosol preparation from human prostatic cancer tissue. When estimated by HPLC, the molecular weights of estramustine binding components are 45,000 and 25,000 daltons, respectively. In addition, results of effectiveness of Estracyt studied under a cooperative research group in Japan, are reported in this paper. Effectiveness was evaluated at 3 months of the treatment on 121 patients with untreated prostatic cancer (Study I) and 95 patients with reactivated cancer (Study II), at 12 months of the treatment on 68 patients in Study I and 85 patients in Study II, and at 24 months on 37 patients in Study I and 23 patients in Study II. At 3 months of the treatment, Estracyt was effective in 89% of untreated prostatic cancers, and 38% of reactivated prostatic cancers. At 24 months of the treatment, this drug was effective in 65% of untreated prostatic cancers and 30% of reactivated ones. Estracyt is especially recommended as a first-choice drug for both the untreated patients with poorly differentiated adenocarcinoma and reactivated cancer.

Animals↗

PubMed1997

Estramustine phosphate versus placebo as second line treatment after orchiectomy in patients with metastatic prostate cancer: DAPROCA study 9002. Danish Prostatic Cancer Group.

PURPOSE: We compared the effect of 560 mg. estramustine phosphate daily to placebo as a supplement to standard palliative therapy in patients with progressive disease after bilateral orchiectomy as first line therapy for metastatic prostate cancer. MATERIALS AND METHODS: In a double-blind multicenter study 131 patients with progressing metastatic hormone refractory prostate cancer were randomized to receive 280 mg. estramustine phosphate 2 times daily versus placebo. End points were clinical progression and death. Adverse events, decrease in prostate specific antigen (PSA) and subjective response were also assessed. RESULTS: Adverse events were common in both groups but breast tenderness/gynecomastia and diarrhea were more frequent among patients in the estramustine phosphate group. Subjective responses were few (9 of 50 estramustine phosphate and 4 of 57 placebo cases, p = 0.15). Median observation time for survival was 43 months and 124 patients died. Median time to subjective progression and median overall survival did not differ significantly between the 2 groups at 4.6 and 9.4 months in the estramustine phosphate group versus 5.0 and 6.1 months in the placebo group. Of 61 patients in the estramustine phosphate group 29 achieved a reduction in PSA of more than 25% at 1 month of followup compared to only 3 of 68 receiving placebo. A decrease in PSA after 1 month correlated significantly with survival. CONCLUSIONS: Although this study did not prove estramustine phosphate to be superior to placebo in terms of protocol end points, it generates the hypothesis that prolonged survival may be achieved with estramustine phosphate treatment in a subgroup of patients and that this may be predicted by a decrease in PSA after 1 month of therapy.

Aged↗

PubMed2000

Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: an experimental study.

BACKGROUND: Estramustine in combination with other chemotherapeutic agents has demonstrated synergy in hormone-refractory prostate cancer. Docetaxel has demonstrated antineoplastic activity in a variety of chemotherapeutic-unresponsive tumors. We evaluated the effects of estramustine and docetaxel in preclinical models of prostate cancer. METHODS: Cell viability of PC-3 and MAT-LyLu (MLL) cells were assessed 48 hr after drug treatment. For in vivo studies, each flank of five animals in six groups was injected with 1 x 10(6) MLL cells: control, estramustine, docetaxel (low- and high-dose), and low- and high-dose docetaxel with estramustine. Animals were treated on days 4 and 11, and sacrificed on day 14. RESULTS: The IC(50) value for docetaxel was 2 nM in the PC-3 cells and 40 nM in the MLL cells. The addition of 100 nM of estramustine did not alter the IC(50) value for PC-3 cells. In the MLL cells, however, the IC(50) value was lowered to 15 nM. In vivo, low-dose docetaxel with estramustine demonstrated antineoplastic activity similar to that of high-dose docetaxel alone, suggesting additive activity between the drugs. CONCLUSIONS: These results demonstrate that when used in combination, docetaxel and estramustine can be more effective at lower dosages than when the individual drugs are used alone.

Animals↗

PubMed2004

Simultaneous determination of estramustine phosphate and its four metabolites in human plasma by liquid chromatography-ionspray mass spectrometry.

A sensitive and selective method, using liquid chromatography-ionspray mass spectrometry, was developed and validated for the simultaneous determination of Estracyt (estramustine phosphate) and its four metabolites, estramustine, estromustine, estrone and estradiol, in human plasma. Deuterated internal standards were available for all analytes. The five compounds were extracted from plasma by protein precipitation with acetonitrile. The chromatographic separation was performed using a Zorbax SB C18, (150 x 4.6 mm i.d., 5 microm) reversed-phase column under gradient conditions with a mobile phase containing 2 mm ammonium acetate buffer (pH 6.8) and acetonitrile. MS detection was by electrospray ionization with multiple reaction monitoring in the positive ion mode for estramustine phosphate, estromustine and estramustine, and in the negative ion mode for estrone and estradiol. The limit of quantitation was 10 ng/mL for estramustine phosphate, 3 ng/mL for estromustine, estramustine and estrone and 30 ng/mL for estradiol. Linearity was verified from these LLOQs up to about 4000 ng/mL for the parent drug and 2000 ng/mL for the metabolites. Inter-day precision and accuracy values were all less than 15%. This assay was applied successfully to the routine analysis of human plasma samples collected in cancer patients administered estramustine phosphate intravenously.

Antineoplastic Agents, Alkylating↗

PubMed2006

Results from a pilot Phase I trial of gefitinib combined with docetaxel and estramustine in patients with hormone-refractory prostate cancer.

BACKGROUND: Gefitinib, which is an orally active epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated activity against hormone-refractory prostate cancer (HRPC) in preclinical studies. In this pilot Phase I trial, the authors evaluated the tolerability, efficacy, and pharmacokinetics of gefitinib combined with estramustine and docetaxel in patients with HRPC. METHODS: Patients received gefitinib (at a dose of 250 mg/day or 500 mg/day) on each day of a 21-day treatment cycle. Docetaxel (at a dose of 60 mg/m(2)) was administered on Day 1, and estramustine (at a dose of 280 mg) was administered 3 times daily on Days 1 through 5. RESULTS: Fifteen patients were recruited at each gefitinib dose level. The most common adverse events observed were consistent with the known profiles of gefitinib, docetaxel, and estramustine. No dose-limiting toxicity was observed. Adverse events considered to be gefitinib related included diarrhea (n = 23 patients), rash (n = 8 patients), nausea (n = 7 patients), dry skin (n = 6 patients), and emesis (n = 6 patients). Overall, 9 of 22 evaluable patients (40.9%) experienced a pain response. and 9 of 30 patients (30%) had a prostate-specific antigen response. A partial objective tumor response was demonstrated in 1 of 13 evaluable patients (7.7%) in each dose group; the median time to progression for both doses combined was 185 days (range, 28-233 days). Data comparisons within individual patients suggested that docetaxel and estramustine had no effect on gefitinib steady-state levels. Gefitinib had no effect on docetaxel exposure at the 250-mg dose but decreased exposure at the 500-mg dose. However, gefitinib may increase exposure to estramustine, particularly at the 500 mg/day dose. CONCLUSIONS: The results of the current study demonstrated that gefitinib combined with estramustine and docetaxel had acceptable and predictable tolerability. However, it is unclear whether gefitinib provides an additional clinical benefit over docetaxel and estramustine alone.

Adult↗

PubMed1987

Effect of estramustine phosphate on the assembly of trypsin-treated microtubules and microtubules reconstituted from purified tubulin with either tau, MAP2, or the tubulin-binding fragment of MAP2.

Estramustine phosphate, an estradiol nitrogen-mustard derivative is a microtubule-associated protein (MAP)-binding microtubule inhibitor, used in the therapy of prostatic carcinoma. It was found to inhibit assembly and to induce disassembly of microtubules reconstituted from phosphocellulose-purified tubulin with either tau, microtubule-associated protein 2, or chymotrypsin-digested microtubule-associated protein 2. Estramustine phosphate also inhibited assembly of trypsin-treated microtubules, completely depleted of high-molecular-weight microtubule-associated proteins, but with their microtubule-binding fragment present. In all cases estramustine phosphate induced disassembly to about 50%, at a concentration of approximately 100 microM, at similar protein concentrations. However, estramustine phosphate did not affect dimethyl sulfoxide-induced assembly of phosphocellulose-purified tubulin. Estramustine phosphate is a reversible inhibitor, as the nonionic detergent Triton X-100 was found to counteract the inhibition in a concentration-dependent manner. The reversibility was nondisruptive, as Triton X-100 itself did not affect microtubule assembly, microtubule protein composition, or morphology. This new reversible MAPs-dependent inhibitor estramustine phosphate affects the tubulin assembly, induced by tau, as well as by the small tubulin-binding part of MAP2 with the same concentration dependency. This indicates that tau and the tubulin-binding part of MAP2, in addition to their assembly promoting functions also have binding site(s) for estramustine phosphate in common.

Binding Sites↗

PubMed1983

A comparative study of estramustine and pregnenolone binding to prostatic binding protein: evidence for subunit cooperativity.

The binding of estramustine, a nitrogen mustard derivative of oestradiol to purified rat prostatic binding protein was studied as a test for a possible identity between this protein and the very similar estramustine-binding protein, described by Forsgren et al. In accordance with this hypothesis estramustine binds to purified prostatic binding protein with a high affinity (2.5 X 10(7)M-1). This affinity markedly exceeds the affinity of pregnenolone for this protein (0.9 X 10(6)M-1) or for a complex of prostatic binding protein, with prostatic proline-rich polypeptide, (4.7 X 10(6)M-1). In competition experiments estramustine completely suppresses the binding of [3H]pregnenolone, whereas the binding of [3H]estramustine is only partially suppressed by pregnenolone, even at high concentrations. Prostatic binding protein was separated in its F- and S-subunit by DEAE-Sepharose chromatography performed in the presence of 8 M urea. Only the S-subunit, most probably in its dimer form, displays marked estramustine and pregnenolone binding, with affinities of respectively 3.7 and 1.2 X 10(6)M-1. Recombination of both subunits results in a strong increase of estramustine binding, but not of pregnenolone binding.

Androgen-Binding Protein↗

PubMed1992

Estramustine-phosphate binds to a tubulin binding domain on microtubule-associated proteins MAP-2 and tau.

Estramustine-phosphate (EMP), a phosphorylated conjugate of estradiol and nor-nitrogen mustard binds to microtubule-associated proteins MAP-2 and tau. It was shown that this estramustine derivative inhibits the binding of the C-terminal tubulin peptide beta-(422-434) to both MAP-2 and tau. This tubulin segment constitutes a main binding domain for these microtubule-associated proteins. Interestingly, estramustine-phosphate interacted with the synthetic tau peptides V187-G204 and V218-G235, representing two major repeats within the conserved microtubule-binding domain on tau and also on MAP-2. This observation was corroborated by the inhibitory effects of estramustine-phosphate on the tau peptide-induced tubulin assembly into microtubules. On the other hand, the nonphosphorylated drug estramustine failed to block the MAP peptide-induced assembly, indicating that the negatively charged phosphate moiety of estramustine-phosphate is of importance for its inhibitory effect. These findings suggest that the molecular sites for the action of estramustine-phosphate are located within the microtubule binding domains on tau and MAP-2.

Amino Acid Sequence↗

PubMed1981

Comparison of estramustine phosphate and vincristine alone or in combination for patients with advanced, hormone refractory, previously irradiated carcinoma of the prostate.

There were 121 men with hormonally refractory metastatic cancer of the prostate who were randomized to receive estramustine phosphate or vincristine, or the combination of these 2 agents. All patients had received prior radiation therapy (greater than 2,000 rad). There were 90 patients who could be compared for response. The objective response rates (partial regression or stabilization of disease) for the 3 treatment groups were 26 per cent for estramustine phosphate, 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine. Subjective parameters varied little among the 3 regimens. The median duration of response for those responding to estramustine phosphate was similar (20 weeks) to that for vincristine (22 weeks) and greater than that for the combination (13 weeks). The probability of survival did not differ significantly for patients randomized to each of the 3 regimens. The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate. Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate.

Drug Therapy, Combination↗

PubMed2001

Diverging effects of 5-HT3 receptor antagonists ondansetron and granisetron on estramustine-inhibited cellular potassium transport.

We used 86Rb+ (K+ analogue) to study potassium influx during the interaction of highly specific 5-HT3-receptor antagonists, ondansetron and granisetron, with the effects of the anticancer drug, estramustine phosphate, on P31 mesothelioma cells. Estramustine phosphate (80 mg/l, 142 micromol/l) for 120 min. reduced 86Rb+ influx by 18.7%. The reduction was inhibited by ondansetron (0.1 micromol/l), but augmented by granisetron (0.1 micromol/l). Serotonin (1.0 micromol/l) antagonized ondansetron inhibition and restored granisetron-augmented reduction of estramustine phosphate-induced 86Rb+ influx to the level of the drug itself. Estramustine phosphate inhibited cellular Na+, K+, 2Cl- -cotransport activity whereas Na+, K+, ATPase activity was unaffected. Ondansetron blockade of estramustine phosphate-induced reduction of 86Rb+ influx was due to increased Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport whereas augmentation of estramustine phosphate-induced reduction of 86Rb+ influx by granisetron, or combination of 5-HT3 receptor antagonists with serotonin was due mainly to inhibition of cellular Na+, K+, ATPase activity Thus, ondansetron possesses a distinct ability to reverse K+ influx of tumour cells exposed to estramustine phosphate whereas granisetron does not, due to different effect on cellular Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport activity. Highly 5-HT3 receptor-specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs.

Antiemetics↗

PubMed2004

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.

BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer. METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

Adenocarcinoma↗

PubMed1997

Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: a possible mechanistic basis for its antitumor action.

The cellular targets for estramustine, an antitumor drug used in the treatment of hormone-refractory prostate cancer, are believed to be the spindle microtubules responsible for chromosome separation at mitosis. Estramustine only weakly inhibits polymerization of purified tubulin into microtubules by binding to tubulin (Kd, approximately 30 microM) at a site distinct from the colchicine or the vinblastine binding sites. However, by video microscopy, we find that estramustine strongly stabilizes growing and shortening dynamics at plus ends of bovine brain microtubules devoid of microtubule-associated proteins at concentrations substantially below those required to inhibit polymerization of the microtubules. Estramustine strongly reduced the rate and extent both of shortening and growing, increased the percentage of time the microtubules spent in an attenuated state, neither growing nor shortening detectably, and reduced the overall dynamicity of the microtubules. Significantly, the combined suppressive effects of vinblastine and estramustine on the rate and extent of shortening and dynamicity were additive. Thus, like the antimitotic mechanisms of action of the antitumor drugs vinblastine and taxol, the antimitotic mechanism of action of estramustine may be due to kinetic stabilization of spindle microtubule dynamics. The results may explain the mechanistic basis for the benefit derived from combined use of estramustine with vinblastine or taxol, two other drugs that target microtubules, in the treatment of hormone-refractory prostate cancer.

Animals↗

PubMed2004

Chemohormonal therapy as primary treatment for metastatic prostate cancer: a randomized study of estramustine phosphate plus luteinizing hormone-releasing hormone agonist versus flutamide plus luteinizing hormone-releasing hormone agonist.

BACKGROUND: The present study was undertaken mainly to investigate whether chemohormonal therapy with estramustine phosphate plus luteinizing hormone-releasing hormone (LHRH) agonist has a more beneficial effect than the hormonal therapy with flutamide plus LHRH agonist for newly diagnosed patients with metastatic prostate cancer. METHODS: A total of 57 patients with metastatic prostate cancer aged 59-80 years (median 74 years) were entered in the study and were randomized to the treatment of estramustine phosphate (560 mg/day) plus LHRH agonist (estramustine group) or flutamide (375 mg/day) plus LHRH agonist (flutamide group) with stratification for the degree of performance status, histological differentiation and bone metastasis. RESULTS: Both of the treatment regimens were well tolerated with similar incidences of adverse drug reactions. The overall response rates (complete response plus partial response) at 12 weeks after treatment in the estramustine and flutamide groups were 76 and 55%, respectively. The median time to objective progression for the estramustine group (25.4 months) was longer than that of the flutamide group (14.6 months). The serum levels of follicle stimulating hormone and testosterone were significantly lower in the estramustine group. CONCLUSIONS: Chemohormonal therapy with estramustine phosphate plus LHRH agonist showed longer clinical progression-free survival than the hormonal therapy with flutamide plus LHRH agonist (P = 0.03), although there was no significant difference in the overall survival. A larger-scaled trial with more statistical power is required to clarify that the former regimen is more beneficial than the latter for newly diagnosed patients with advanced prostate cancer.

Aged↗

PubMed1998

Acetaminophen protection against estramustine-induced cytotoxicity on cultured fibroblasts.

Two commonly used analgesics, ibuprofen and acetaminophen (paracetamol) were investigated for possible influence on Chinese hamster fibroblast (V-79) cytotoxicity (measured by cells cloning ability and 86Rb accumulation) of the anti-neoplastic drugs estramustine and bleomycin in vitro. Fibroblast exposure to estramustine (80 mg/l) or bleomycin (50 mg/l), for 1 or 24 hr, reduced the number of surviving clones to approximately 35% and 50% respectively. Acetaminophen (10 or 100 mg/l), but not ibuprofen, significantly increased the number of surviving clones with estramustine. The analgesics had no effect on bleomycin cytotoxicity. The uptake of 86Rb+ (K+ analogue) by V-79 cells was reduced after incubation with 80 mg/l estramustine phosphate. Acetaminophen (30 mg/l) but not 10 mg/l acetaminophen or ibuprofen (30 or 100 mg/l), significantly protected against estramustine reduction of 86Rb accumulation. Acetaminophen inhibition of estramustine cytotoxicity is suggested to be due to reversal of estramustine-induced inhibition of cellular potassium channel ion transport.

Acetaminophen↗