Archivos Espanoles de Urologia Sep 2019Estramustine is an stable estradiol and nitrogenated mustard conjugatewith antymicotic properties. Currently, with the appearance of chemotherapy and new molecules,... (Review)
Estramustine is an stable estradiol and nitrogenated mustard conjugatewith antymicotic properties. Currently, with the appearance of chemotherapy and new molecules, estramustin acetate is not a drug of choice for castration resistant prostate cancer.
We describe two patients with castration resistant prostate cancer under treatment with estramustine acetate and complete biochemical response and stable disease. We review the literature to elucidate if the drug should be stopped and changed for the new molecules that have demonstrated survival increase.
To our knowledge, there are not data in the literature to either solve the questions posed or shed light regarding cumulative toxicity due to prolongued use of estramustine acetate.
We recognize that these clinical cases do not translate that estramustine acetate is a first line treatment for patients with CRPC. Nevertheless, they translate the heterogeneity of CRPC. It would be interesting to investigate the combination of new agents with estramustine acetate as well as the search of biomarkers that enable selection of candidates who could respond to estramustine acetate.
Topics: Antineoplastic Agents, Alkylating; Estramustine; Humans; Male; Prostatic Neoplasms
Estramustine phosphate induces prostate cancer cell line PC3 apoptosis by down-regulating miR-31 levels.European Review For Medical and... Jan 2018Prostate cancer seriously threats to patient's life and health. Estramustine phosphate (EP) is one of the most important drugs in the clinical treatment of prostate...
Prostate cancer seriously threats to patient's life and health. Estramustine phosphate (EP) is one of the most important drugs in the clinical treatment of prostate cancer. This study aims to explore the molecular mechanism of estramustine phosphate in regulating PC3 cell growth and survive through mediating miR-31.
MATERIALS AND METHODS
Estramustine phosphate was used to treat prostate cancer cell line PC3. Flow cytometry was applied to detect PC3 cell growth and apoptosis. RT-PCR was performed to test miR-31 level. Prostate cancer tissue and paracarcinoma tissue were collected to test miR-31 level. PC3 cells were transfected with miR-31 or control microRNA by lipofectamine, and followed treated by estramustine phosphate.
PC3 cell appeared growth restrain and apoptosis after treated by estramustine phosphate. MiR-31 level decreased after estramustine phosphate treatment. Prostate cancer tissue presented higher miR-31 level than paracarcinoma tissue. MiR-31 over-expression inhibited estramustine phosphate induced PC3 cell apoptosis.
Estramustine phosphate induces prostate cancer cell line PC3 apoptosis through reducing miR-31.
Topics: Apoptosis; Caspase 3; Down-Regulation; Estramustine; Humans; Male; MicroRNAs; PC-3 Cells; Prostatic Neoplasms
Chemotherapy with or without estramustine for treatment of castration-resistant prostate cancer: A systematic review and meta-analysis.Medicine Sep 2016Recently, increasing relevant studies researched the efficacy of castration resistant prostate cancer (CRPC) patients using chemotherapy with or without estramustine, in... (Meta-Analysis)
Recently, increasing relevant studies researched the efficacy of castration resistant prostate cancer (CRPC) patients using chemotherapy with or without estramustine, in order to assess the efficacy and toxicity of combining estramustine with chemotherapy for the treatment of CRPC.
Relevant randomized clinical trials were systematically searched from the databases Pubmed, Embase, and Web of science up to April 1, 2016. Data were centrally extracted and analyzed from the previous studies by 2 independent reviewers. The primary endpoint was overall survival (OS) with pooled hazard ratios. Secondary endpoints were prostate-specific antigen (PSA) response and grade 3 or 4 toxicity using pooled odds ratios. Stata version 12.0 software was used for statistical analysis.
Overall, this meta-analysis identified 9 eligible articles, including a total of 956 patients, who had been accrued between January 1, 1993 and December 1, 2010 and randomly divided into chemotherapy with estramustine and without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, epirubicin, and vinblastine. Patients who received chemotherapy with estramustine had a better improvement in PSA response rate, comparing those without estramustine (OR = 1.84, 95% CI = 1.20-2.80). However, OS between the 2 groups indicated no significant differences (HR = 0.90, 95% CI = 0.77-1.05). Besides, these results of meta-analysis showed no obvious differences between these 2 groups in grade 3 or 4 adverse effects, including anemia (OR = 0.78, 95% CI = 0.38-1.57), neutropenia (OR = 0.91, 95% CI = 0.59-1.43), thrombocytopenia (OR = 0.68, 95% CI = 0.19-2.42), nausea (OR = 2.34, 95% CI = 0.81-6.72), vomiting (OR = 2.43, 95% CI = 0.69-8.51), diarrhea (OR = 3.45, 95% CI = 0.93-12.76), fatigue (OR = 0.67, 95% CI = 0.32-1.41), neuropathy (OR = 0.54, 95% CI = 0.21-1.44), allergic reaction (OR = 1.60, 95% CI = 0.37-6.84), thromboembolic event (OR = 2.18, 95% CI = 0.86-5.51), and edema (OR = 1.02, 95% CI = 0.18-5.95).
This meta-analysis indicated chemotherapy with additional estramustine increased the PSA response rate. However, OS and grade 3 or 4 toxicity were not improved for these patients with CRPC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Survival Analysis
Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial.Clinical Genitourinary Cancer Apr 2018This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).
This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).
PATIENTS AND METHODS
We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest.
Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant.
The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.
Topics: Administration, Intravenous; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Treatment Outcome
The efficacy and safety comparison of docetaxel, cabazitaxel, estramustine, and mitoxantrone for castration-resistant prostate cancer: A network meta-analysis.International Journal of Surgery... Aug 2018The aim of this study was to compare the efficacy and safety of docetaxel, cabazitaxel, docetaxel + estramustine, mitoxantrone in the management of... (Comparative Study)
Comparative Study Meta-Analysis
The aim of this study was to compare the efficacy and safety of docetaxel, cabazitaxel, docetaxel + estramustine, mitoxantrone in the management of castration-resistant prostate cancer (CRPC).
Electronic databases including PubMed, Cochrance Library and Embase were searched for studies published from when the databases were established to January 1st, 2018. Randomized controlled trials (RCTs) that compared docetaxel + prednisone (DP), cabazitaxel + prednisone (CP), docetaxel + estramustine + prednisone (DEP), and mitoxantrone + cabazitaxel + prednisone (MP) for CRPC treatment were identified. The network meta-analysis was conducted with software R 3.3.2. We analyzed the main outcomes, including the overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) response, tumor response and severe adverse events (AEs). Ranking of the chemotherapeutic agents was based on probabilities of interventions for each of the outcomes that were performed. The consistency of direct and indirect evidence was assessed by node splitting.
10 RCTs, with 3590 patients, were analyzed. The network meta-analysis results revealed that CP significantly increased OS, PFS, PSA response, tumor response, and severe AEs compared to MP. DP showed similar results with CP except for tumor response, where it showed slight inferiority in effectiveness. DEP was associated with clearly improved outcomes in PFS, PSA response and tumor response compared to those of MP, but this was not the case for OS benefit and severe AEs. No significant difference was detected in DP, CP and DEP except for the outcomes of severe AEs. MP was less effective in survival and clinical benefit, but much safer in safety outcomes than other chemotherapy agents. The probabilities of rank plots showed that CP ranked first in OS and tumor response; DEP ranked first in PFS time and PSA response; MP was the best treatment mode for safety.
DP and CP survival benefit (OS, PFS) and clinical benefit (PSA response and tumor response) were comparable, as well as their associated AEs. DEP was associated with less survival benefit, similar clinical improvement and more AEs than DP or CP. MP had the lowest survival and clinical benefit but excellent safety than other agents. Based on evidences of current results, we recommended CP as the most suitable chemotherapy agent for CRPC patients, followed by DP, MP as third, and DEP as the last choice. However, considering limitations of our network meta-analysis, additional high-quality studies are needed for further evaluation.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Middle Aged; Mitoxantrone; Network Meta-Analysis; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome
Estramustine Phosphate Inhibits TGF--Induced Mouse Macrophage Migration and Urokinase-Type Plasminogen Activator Production.Analytical Cellular Pathology... 2018Transforming growth factor-beta (TGF-) has been demonstrated as a key regulator of immune responses including monocyte/macrophage functions. TGF- regulates macrophage...
Transforming growth factor-beta (TGF-) has been demonstrated as a key regulator of immune responses including monocyte/macrophage functions. TGF- regulates macrophage cell migration and polarization, as well as it is shown to modulate macrophage urokinase-type plasminogen activator (uPA) production, which also contributes to macrophage chemotaxis and migration toward damaged or inflamed tissues. Microtubule (MT) cytoskeleton dynamic plays a key role during the cell motility, and any interference on the MT network profoundly affects cell migration. In this study, by using estramustine phosphate (EP), which modifies MT stability, we analysed whether tubulin cytoskeleton contributes to TGF--induced macrophage cell migration and uPA expression. We found out that, in the murine macrophage cell line RAW 264.7, EP at noncytotoxic concentrations inhibited cell migration and uPA expression induced by TGF-. Moreover, EP greatly reduced the capacity of TGF- to trigger the phosphorylation and activation of its downstream Smad3 effector. Furthermore, Smad3 activation seems to be critical for the increased cell motility. Thus, our data suggest that EP, by interfering with MT dynamics, inhibits TGF--induced RAW 264.7 cell migration paralleled with reduction of uPA induction, in part by disabling Smad3 activation by TGF-.
Topics: Animals; Cell Movement; Estramustine; Fluorescent Antibody Technique; Macrophages; Mice; Microtubules; RAW 264.7 Cells; Smad3 Protein; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator
Hinyokika Kiyo. Acta Urologica Japonica Feb 2017We retrospectively evaluated the efficacy and toxicity of low-dose estramustine phosphate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC)....
We retrospectively evaluated the efficacy and toxicity of low-dose estramustine phosphate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC). We administered EMP at 140 or 280 mg/day to 89 patients between January 2003 and December 2012. None of the patients were receiving concomitant dexamethasone and none had ever been treated with docetaxel. Fifty-three patients (59.6%) experienced a decline in prostate-specific antigen (PSA) levels, including 20 (22.5%) with a decline of more than 50%. The median time to PSA progression was 90 days. PSA-progression-free survival was significantly longer in patients treated with EMP 140 mg compared with patients treated with EMP 280 mg, and there was no significant difference in the incidence of adverse events between the two groups. The most frequent toxicities were nausea and anorexia. Two patients had grade 3 adverse events of pulmonary embolism and liver dysfunction. EMP treatment was discontinued in nine patients (10.1%) because of side effects (nausea and anorexia in 7, liver dysfunction and lacunar infarction in 1). Low-dose EMP monotherapy is well tolerated and can effectively reduce PSA levels.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Disease Progression; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
Cellular Physiology and Biochemistry :... 2013The nitrogen mustard derivative of estradiol-17β-phosphate estramustine is used for the treatment of prostate cancer. Estramustine may trigger suicidal death of cancer...
The nitrogen mustard derivative of estradiol-17β-phosphate estramustine is used for the treatment of prostate cancer. Estramustine may trigger suicidal death of cancer cells. Side effects of estramustine include anemia. At least in theory, estramustine could cause anemia by stimulation of eryptosis, the suicidal death of erythrocytes. Hallmarks of eryptosis include cell shrinkage, increased cytosolic Ca2+ activity ([Ca2+]), ceramide formation and phosphatidylserine translocation to the outer leaflet of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is stimulated by increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored whether estramustine triggers eryptosis.
[Ca2+]i was estimated from Fluo3 fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin V binding, and hemolysis from hemoglobin release.
A 24 h exposure to estramustine (≤ 100 μM) significantly increased [Ca2+]i, increased annexin V binding and increased hemoglobin release. The effect of estramustine on annexin V binding was significantly blunted by removal of extracellular Ca2+.
Estramustine stimulates both, eryptosis and hemolysis. The estramustine induced translocation of phosphatidylserine to the cell surface is at least partially due to increase of cytosolic Ca2+ activity.
Topics: Annexin A5; Antineoplastic Agents, Hormonal; Calcium; Cell Death; Cell Size; Ceramides; Cytosol; Erythrocytes; Estramustine; Humans; Phosphatidylserines
Both radical prostatectomy following treatment with neoadjuvant LHRH agonist and estramustine and radiotherapy following treatment with neoadjuvant hormonal therapy...World Journal of Surgical Oncology Apr 2014To date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical...
Both radical prostatectomy following treatment with neoadjuvant LHRH agonist and estramustine and radiotherapy following treatment with neoadjuvant hormonal therapy achieved favorable oncological outcome in high-risk prostate cancer: a propensity-score matching analysis.
To date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical trial. We used propensity-score matching analysis to compare the oncological outcomes of high-risk prostate cancer between patients treated with radical prostatectomy (RP) and those treated with radiation therapy (RT).
We studied 216 patients who received neoadjuvant therapy followed by RP (RP cohort) and 81 patients who received neoadjuvant androgen-deprivation therapy (ADT) followed by RT (RT cohort). The RP cohort received a luteinizing hormone-releasing hormone agonist and estramustine phosphate (280 mg/day) for 6 months prior to RP. The RT cohort received ADT for at least 6 months prior to RT using a 3-dimensional conformal radiotherapy technique. The total radiation dose was 70 to 76 Gy administered at 2 Gy/fraction.
Propensity-score matching identified 78 matched pairs of patients. The 3-year overall survival rates were 98.3% and 92.1% in the RP and RT groups, respectively (P=0.156). The 3-year biochemical recurrence-free survival rates were 86.4% and 89.4% in the RP and RT groups, respectively (P=0.878).
Our study findings may suggest almost identical cancer control of RP and RT with appropriate neoadjuvant therapy in high-risk Pca. Therefore, issues of health-related quality of life may have an important impact on decision making in treatment of high-risk Pca.
Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Estramustine; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Male; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Propensity Score; Prostatectomy; Prostatic Neoplasms; Quality of Life; Radiotherapy Dosage; Retrospective Studies; Survival Rate
Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs.Bioorganic & Medicinal Chemistry Letters Jan 2011Shp2 protein tyrosine phosphate (PTP) is a novel target for anticancer drug discovery. We identified estramustine phosphate as a Shp2 PTP inhibitor from the National...
Shp2 protein tyrosine phosphate (PTP) is a novel target for anticancer drug discovery. We identified estramustine phosphate as a Shp2 PTP inhibitor from the National Cancer Institute Approved Oncology Drug set. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triterpenoids, enoxolone, and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors.
Topics: Antineoplastic Agents, Hormonal; Estramustine; Humans; Models, Molecular; Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Structure-Activity Relationship; Triterpenes