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PubMed1999

A phase II study of docetaxel (Taxotere), estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: preliminary results of cancer and leukemia group B Trial 9780.

Combinations of estramustine with other antimitotic agents, such as docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), are synergistic in vitro and show significant clinical activity in hormone-refractory prostate cancer (HRPC). We have studied intravenous docetaxel 70 mg/m2, oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. Of the 47 men who were enrolled, 40 are evaluable for response and/or toxicity. One patient (3%) has had a complete response and eight (20%) have had a partial response, yielding a total objective response rate of 23%. Of 39 patients with elevated pretreatment prostate-specific antigen levels who have had at least one posttreatment prostate-specific antigen measurement, 27 (69%) have had > or =50% decreases and 21 (54%) have had > or =75% decreases in prostate-specific antigen levels. Toxicity is modest but manageable. This therapy is efficacious and well tolerated in HRPC and should be compared in phase III trials with other drugs active in HRPC, such as mitoxantrone and hydrocortisone.

Adenocarcinoma↗
PubMedDate not supplied

Oral estramustine phosphate (NSC-89199) in the treatment of advanced (stage D) carcinoma of the prostate.

Thirty-two patients with stage D carcinoma of the prostate were treated with oral estramustine phosphate at a dose of 15 mg/kg/day from 3 to 15 months. Objective remissions, reduction of greater than 50 percent of measurable lesions such as soft tissue masses, lymph nodes, and prostatic masses, were seen in seven of 32 patients (22 percent response rate). Subjective response, ie, relief of pain, weight gain, sense of well being, snd improved performance status, occurred in all objective responders and in seven other patients with stable disease (15 of 32 patients = 47 percent). No hematologic, hepatic, or renal toxic effects were observed. Transient nausea occurred early in one half of the patients and nausea and vomiting was dose limiting in only two patients. Oral estramustine phosphate is well tolerated and worthy of further clinical use.

Acid Phosphatase↗
PubMedDate not supplied

Clinical results with estramustine phosphate (NSC-89199): a comparison of the intravenous and oral preparations.

The clinical results with estramustine phosphate in far-advanced carcinoma of the prostate refractory to other treatments are presented. Good clinical results have been achieved in about 40 percent of the 90 patients treated and regression of metastases has occurred in about 20 percent. Estramustine phosphate in the primary treatment of far-advanced carcinoma of the prostate shows very good and promising clinical results. A total of 132 patients were treated.

Acid Phosphatase↗
PubMed1992

Combined antimicrotubule activity of estramustine and taxol in human prostatic carcinoma cell lines.

Estramustine (EM) and taxol, two antimicrotubule agents with distinct and apparently opposing mechanisms of action, were found to be effective in combination in the preclinical treatment of EM-resistant and sensitive, wild-type human prostatic carcinoma cell lines. Estramustine combined with 1 nM taxol (concentration 100-fold less than that measured in plasma of patients treated with taxol) produced greater than additive effects on the inhibition of cell survival of both wild-type and EM-resistant cells. When taxol was used with another microtubule-destabilizing drug, vinblastine, no significantly increased cytotoxicity was observed. Other effects on wild-type and EM-resistant cells produced by the combination of EM and taxol included (a) an increased proportion of the cells in the S phase of the cell cycle; (b) no mitotic block; and (c) an increase in the percentage of micronucleated cells from a control value of less than 1% to greater than 20% after drug treatment. Immunofluorescent microscopic analysis of the effect of this drug combination on the mitotic spindle apparatus revealed specific examples of aberrant mitotic figures, including multiple asters, cells with two distinct spindles, and tripolar spindles able to traverse mitosis and complete cytokinesis. These data provide supportive preclinical evidence for the potential development of an EM/taxol combination clinical regimen either for prostate or other cancers.

Alkaloids↗
PubMed2003

[Intermittent oral hormonal chemotherapy using estramustine phosphate and etoposide for the treatment of hormone-refractory prostate cancer].

Seventeen patients were given lower dose and intermittent oral administration of estramustine phosphate (6 mg/kg/day) and etoposide (30 mg/m2/day) for 7 days. Then administration was discontinued for 7 days. This administration cycle was repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. Fifteen of the 17 patients were finally evaluated for PSA response. Overall, the pretreatment PSA levels were lowered at least 50% from baseline in 7 (47%) of the 15 patients. The median survival was 65 weeks. Five of the 17 patients complained of anorexia or nausea during the treatment, but none of them showed over grade 2 anorexia, none requiring transfusion or hospitalization. None of the patients showed edema, deep venous thrombosis, thrombocytopenia, anemia or myocardial infarction. Because of its rare and mild adverse effects, this intermittent administration of oral estramustine and oral etoposide may be a useful and secure regimen for hormone refractory prostate cancer.

Administration, Oral↗
PubMed2004

[Combination therapy with estramustine and docetaxel for hormone refractory prostate cancer].

Six patients with hormone refractory prostate cancer were orally administered 560 mg of Estramustine daily in 2 equally divided doses for four or five days. In addition 70 mg/m2 of Docetaxel was infused through intravenous drip from day 1, decreasing to 40-60 mg/m2 if any side effects such as bone marrow depression were observed. One cycle was three weeks in hospital and one month after discharge. Patients were treated until progression or the development of treatment-limiting toxicity. In five of the six patients (83.3%), serum prostate specific antigen (PSA) was decreased by more than 50%. Currently, this therapy is ongoing in four outpatients. A side effect of leucopenia (grade 2 or 3) was observed in all patients. Granulocyte-colony stimulating factor (G-CSF) formulation was given as treatment. One case was withdrawn due to loss of appetite after one cycle. This therapy is considered to be effective against hormone refractory prostate cancer. However, further examination is needed about dosage and dosing regimen of Estramustine and Docetaxel.

Administration, Oral↗
PubMedDate not supplied

High efficacy of docetaxel with and without androgen deprivation and estramustine in preclinical models of advanced prostate cancer.

BACKGROUND: To assess the activity of docetaxel in combination with hormonal therapy in preclinical models of prostate cancer. MATERIALS AND METHODS: Since prostate cancer has a predilection for the bone, we assessed the antitumor activity of docetaxel in in vivo models of both bone metastasis and localized prostate cancer, using MDA PCa 2b and PC3 cells in SCID mice. RESULTS: Dramatic antitumor efficacy was observed regardless of whether the tumor cells were implanted in the prostate or in the bone. Antitumor activity was also evident in both osteolytic and osteoblastic lesions. Reasoning that docetaxel efficacy might be enhanced if it were to be used earlier in the course of the disease, we studied the sequence of docetaxel and androgen ablation (part of standard treatment for early-stage prostate cancer) in the MDA PCa 2b xenograft model. The activity was similar whether docetaxel and androgen ablation were used alone, simultaneously, or in sequence, indicating a lack of synergism or antagonism. Finally, we studied the combination of docetaxel and estramustine on androgen-sensitive and androgen-independent cell lines in vitro and in vivo. Estramustine did not increase the activity of docetaxel in these models. CONCLUSION: These results provide a strong preclinical rationale for the clinical development of docetaxel for the treatment of both locally advanced and disseminated prostate cancer.

Animals↗
PubMed1991

Hormone-resistant metastatic prostate cancer. Comparisons between estramustine phosphate and low-dose epirubicin treatments.

We compared the effect and toxicity of estramustine phosphate and weekly low-dose epirubicin in a prospective randomized trial in 41 patients with metastatic prostate cancer refractory to hormonal manipulation. No significant difference between treatment modalities was seen. Palliation was reached in over 60% of patients. The median survival was 15 months in both groups. Toxicity was mild. Further, we investigated the effect of epirubicin after the failure of preceding estramustine phosphate therapy in additional 20 patients. Pain relief was achieved in 50% of these patients. The median survival was 10 months. Toxicity was acceptable.

Aged↗
PubMedDate not supplied

[Treatment of hormone-refractory prostate cancer with estramustine phosphate].

Twenty-one patients with hormone refractory prostate cancer were treated with oral estramustine phosphate, 600 mg/day, and the response was monitored through serial dosages of prostatic specific antigen (PSA). Patients showed biological response (67%) and clinical response (43%). The duration of the biological response was 6 months in 50% cases and over 12 months in 18%. Survival was higher for responders than non responders. It is concluded that estramustine phosphate is effective in this type of therapy and that PSA allows to measure the type of response and its duration.

Antigens, Neoplasm↗
PubMed1988

[Complete androgen blockade (orchiectomy + flutamide) versus androgen blockade with cytostasis (orchiectomy + estramustine) in the treatment of virginal advanced prostate cancer].

The results of orchiectomy + flutamide (n = 28) versus orchiectomy + estramustine (n = 27) in the initial therapy of advanced prostatic cancer were compared in a prospective randomized study. The minimum observation period was one year. In the group orchiectomy + flutamide the incidence of side effects was 25%, the response rate (complete + partial remission) was 28% and the progression rate was 18%. 5 patients (18%) died within the first year. In the group orchiectomy + estramustine the incidence of side effects was 22%, the response rate (complete + partial remission) was 29% and the progression rate was 33%. 2 patients (7%) died within 1 year of treatment. There is no significant difference either in the response rate or the progression rate between the two groups.

Aged↗
PubMed1978

Estramustine phosphate in the treatment of advanced malignant melanoma.

Twenty-six patients (14 men and 12 women) with histologically proven advanced malignant melanoma, who previously had not responded to DTIC, methyl-CCNU, and procarbazine, received estramustine phosphate (estracyt) (15 mg/m2) in daily divided doses. All patients had measurable disease. One patient developed a complete remission and one patient had improvement in liver function without measurable regression in the tumor. In three other patients (11%), the disease remained static for a period of 3--5 months. The mean survival time from the beginning of therapy was 16.8 months for the patients with a response or static disease and 2.18 months for those who had no response. Gastrointestinal toxicity was minimal; no hematologic toxicity was observed. It appears that estramustine phosphate used as a single agent for treating advanced malignant melanoma after patients failed to respond to DTIC and to the combination of methyl-CCNU and procarbazine has a poor response rate.

Adult↗
PubMed1981

Effect of treatment with diethylstilbestrol-polyestradiol phosphate or estramustine phosphate (estracyt) on natural killer cell activity in patients with prostatic cancer.

We evaluated the effect of treatment of patients with prostatic cancer with estramustine phosphate or the combination diethylstilbestrol-polyestradiol phosphate on the natural killer cell activity in peripheral blood. Although estramustine phosphate did not affect natural killer cell activity, diethylstilbestrol-polyestradiol phosphate substantially reduced natural killing after a treatment period of 1 week. The activity was only slightly further lowered after 4 weeks of treatment. Possible clinical implications of the difference in susceptibility of natural killer cells to these agents are discussed.

Aged↗
PubMedDate not supplied

Growth of prostatic cancer cells, DU 145, as multicellular spheroids and effects of estramustine.

The human prostatic carcinoma cell line DU 145 was grown as multicellular spheroids in vitro. The volume doubling time during the early exponential growth phase was about 5 days. The saturation volume, in the plateau phase of the growth curve, was in the order of 1.4 mm3. The spheroids developed a central degenerative region surrounded by a 0.1-0.3 mm layer of viable cells. The DU 145 spheroid system is planned to be used as a model in studies on chemotherapy and targeted radiotherapy of micrometastases of prostatic cancer. Some effects of the drug estramustine, EM, a conjugate of estradiol and nornitrogen mustard, were analysed in this introductory study. Tritium-labelled estramustine, 3H-EM, bound both in the viable cell layers and in the degenerative region of the spheroid already after 1 hour of incubation which indicated good penetration. The viable cells bound only low levels of 3H-EM while the degenerative region bound 3H-EM to a higher extent. The amount of bound 3H-EM increased after incubation for 24 hours. The binding was nonspecific since it could not be inhibited by pretreatment with an excess of non-radioactive EM. Furthermore, 3H-EM bound to a similar extent in glioma and colon carcinoma spheroids used for comparison. Incubation of DU 145 spheroids for 24 hours with EM (20 mg/ml) induced a growth delay of 6-7 days and a transient increase in the volume of the extracellular spaces for a few days following the treatment. The results showed that the binding of EM to prostate DU 145 cells growing as spheroids was not specific and that the toxic action was limited. An interesting result was that EM works as an extracellular space expander. This might be exploited in combination treatments with other agents.

Autoradiography↗
PubMed1998

Apoptotic tumor cell death induced by estramustine in patients with malignant glioma.

Estramustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, is metabolized and exerts specific cytotoxic effects in malignant glioma in vitro and in vivo. In the present study, we have evaluated the cytotoxic effect of EMP in the clinical situation with regard to appearance of DNA damage and its correlation to the uptake of estramustine (EaM) in human malignant astrocytoma tissue. Ten patients were given 280 mg of EMP p.o. 12 h before surgery. Specimens from brain tumor tissue were collected during surgery and used for detection of fragmented DNA, a hallmark of apoptosis, with in situ end labeling (ISEL) and agarose gel techniques. The main metabolite of EMP in glioma tissue, EaM, was analyzed with gas chromatography. It was demonstrated that EMP induced clusters of ISEL-positive tumor cells and fragmentation of DNA on agarose gels in patients treated with EMP. In the same patients, a significant uptake of EaM in tumor tissue was demonstrated. In control patients, who were not treated with EMP, and in two EMP-treated patients with no uptake of EaM, no signs of fragmented DNA and only a few scattered ISEL-positive cells were seen in the tumor tissue. Signs of apoptosis were also seen in two different experimental models, i.e., in vitro cell cultures of rat glioma cells and an in vivo rat glioma model. It is suggested that EaM can induce apoptosis by a direct effect on a subpopulation of glioma cells in human brain tumors in the clinical situation.

Adult↗
PubMed1997

Taxol and estramustine-induced modulation of human prostate cancer cell apoptosis via alteration in bcl-xL and bak expression.

bcl-xL is an antiapoptotic protein that shares sequence homology with bcl-2 and seems to convey chemoresistance in many human tumor cell lines. bcl-xL protein is expressed at a 3-fold higher level in PC-3 cells than it is in LNCaP cells. Taxol causes apoptosis in both these cell lines, as measured by the formation of DNA ladders and by the observation of typical cellular morphological changes (chromatin condensation and nuclear fragmentation) after 4', 6-diamidino-2-phenylindole staining. Overexpression of bcl-2 in LNCaP cells did not prevent Taxol-induced apoptosis. Treatment of LNCaP cells with 10 nm Taxol led, after 24 h, to relatively specific and almost total down-regulation of bcl-xL protein in the absence of alteration of bax, bak, or bcl-2 levels. This change was paralleled by a similar decrease in the level of bcl-xL mRNA, as demonstrated by reverse transcription-PCR. The level of glyceraldehyde-3-phosphate dehydrogenase mRNA was not changed. In PC-3 cells, 48 h were required for both maximal bcl-xL protein down-regulation and cellular apoptosis. In contrast, treatment of LNCaP cells with estramustine induced apoptosis, but this was not associated with any change in the intracellular level of bcl-xL or bax protein. Instead, relatively specific 2-fold up-regulation of the proapoptotic protein bak was observed. In PC-3 cells, cellular apoptosis induced by estramustine was bak independent. These results augment our understanding of the importance of bcl-xL in prostate cancer and suggest that appropriate manipulation of cytotoxic chemotherapeutic agents may favorably alter the balance between pro- and antiapoptotic proteins in this tumor.

Apoptosis↗
PubMed1996

Clinical study on estramustine binding protein (EMBP) in human prostate.

To elucidate the characteristics of estramustine binding protein (EMBP) in human prostate, tissue EMBP concentration was examined in 42 benign prostatic hypertrophy (BPH), 34 untreated prostatic carcinoma (PC), 8 hormone refractory PC (hr-PC), as well as 13 control prostate human tissue samples by RIA using rat-EMBP antibody, and the concentration thus obtained was compared with dihydrotestosterone (DHT), prostatic acid phosphatase (PAP), prostate-specific antigen (PSA), and zinc, indices exhibiting androgen dependency in the prostate. EMBP concentration correlated significantly with DHT and PSA levels in the control prostate and BPH, but not in untreated PC. In BPH, EMBP concentration increased significantly after administration of fluoxymesterone (4 mg/day for 2 weeks), whereas it decreased significantly after estramustine phosphate (280 mg/day for 2 weeks). The EMBP/DHT ratio in moderately and poorly differentiated, and the hr-PC was significantly higher than in controls, BPH, and well-differentiated PC. In addition, untreated PC with an EMBP/DHT ratio of more than 40 showed significantly lower progression-free probability as compared with PC with an EMBP/DHT of less than 40. These results suggest that (1) EMBP in BPH and well-differentiated PC preserves androgen dependency, but not in moderately and poorly differentiated, nor in hr-PCs, indicating that EMBP is a protein different from PAP and PSA, and (2) that the tissue EMBP/DHT ratio might be useful as a marker for predicting disease progression.

Acid Phosphatase↗
PubMed1997

Immunohistochemical analysis of estramustine binding protein with particular reference to proliferative activity in human prostatic carcinoma.

BACKGROUND: The estramustine binding protein (EMBP) specifically binds to estramustine and was first discovered in the rat ventral prostate. However, the physiological property of EMBP in the human prostate still remains to be elucidated. To elucidate whether EMBP is interrelated with cellular proliferation in human prostatic carcinoma (PC), the change in EMBP immunostaining during luteinizing hormone-releasing hormone (LH-RH) analog administration or during Cis-platinum-based chemotherapy, and the difference in EMBP immunostaining between hormone refractory (hr-PC) and untreated PC were analyzed. METHODS: Forty-six patients with histologically proven untreated PCs (34 were treated with LH-RH analog and 12 were treated with chemotherapy as an initial therapy) and 14 with hr-PC were used in this study. PC tissues were obtained before and 3 months after the initial therapy. The changes in immunostainings for EMBP, proliferating cell nuclear antigen (PCNA), and nm23 protein were compared with the change in serum prostate-specific antigen (PSA) level and the histological response during the treatment. RESULTS: The increased EMBP expression was observed in tumors with high histological grade and high clinical stage as well as in hr-PC. In untreated PC, EMBP expression weakly correlated with PCNA or nm23 protein immunoreactivity. In PC receiving LH-RH analog, EMBP expression was significantly reduced after treatment, however, no significant changes were observed in PCNA or nm23 protein immunoreactivity. In addition, EMBP expression before the treatment significantly correlated with the serum PSA change, while PCNA expression and nm23 protein immunoreactivity did not. On the other hand, no significant relationship was observed between histological changes induced by the LH-RH analog and immunostainings for EMBP, PCNA, and nm23 protein before treatment. In PC patients receiving chemotherapy, immunostainings for EMBP, PCNA, and nm23 protein were not significantly changed during the treatment. EMBP immunoreactivity was significantly higher in hr-PC than in untreated PC with paralleled change of PCNA expression and nm23 protein immunoreactivity. CONCLUSIONS: These observations indicate that EMBP is androgen regulated in some PCs. However, EMBP expression is demonstrated even in hr-PC and is interrelated with cellular proliferation especially in hr-PC.

Aged↗
PubMed1996

Estramustine-binding protein to dihydrotestosterone ratio in human prostatic carcinoma: a new marker for predicting disease progression.

OBJECTIVE: To elucidate the clinical significance of estramustine-binding protein (EMBP) in human prostatic carcinoma (PC) as an indicator for predicting disease progression. PATIENTS AND METHODS: EMBP concentrations in prostate tissue samples taken from 35 patients with benign prostatic hyperplasia (BPH), 33 patients with prostatic carcinoma (PC) taken before treatment, and from nine patients with hormone-refractory PC (hr-PC) were measured by radioimmunoassay using an antibody raised against rat EMBP. The dihydrotestosterone (DHT), prostatic acid phosphatase (PAP), prostate-specific antigen (PSA) and zinc levels in the tissue were also measured. RESULTS: The EMBP concentration in well differentiated PC (W-PC) samples was no higher than in samples of BPH tissue, whereas concentrations in moderately differentiated PC (M-PC) and poorly differentiated PC (P-PC) were significantly higher (P < 0.01 and P < 0.005, respectively); the highest levels were those in tissue from hr-PC (P < 0.001). Levels of PAP, PSA and zinc were significantly lower in tissue from PC than from BPH, while the differences in levels between W-PC, M-PC and P-PC were not significant. The EMBP to DHT ratio in the tissue increased significantly from W-PC through M-PC to P-PC and was greatest in hr-PC tissue. Conversely, the PAP:DHT, PSA:DHT and zinc:DHT ratios did not correlate with the progress of histological grade. In addition, the pre-treatment EMBP:DHT and zinc:DHT ratios in 14 patients who developed hr-PC within 3 years after the administration of estramustine phosphate were significantly higher when compared with the remaining 19 patients (P < 0.001 and P = 0.0184, respectively), whereas the PAP:DHT and PSA:DHT ratios showed no significant difference between the groups. Moreover, patients with a high EMBP:DHT ratio (> or = 82) had a low progression-free probability compared to those with a lower ratio. CONCLUSION: The androgen-dependent property of EMBP tends to decline with the transformation of prostatic tissue into biologically more malignant disease. The tissue EMBP:DHT ratio before treatment may be a good indicator of the individual malignant potential of PCs.

Aged↗