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PubMed1987

Carcinoma of the prostate clinically and radiologically simulating malignant lymphoma.

A 65-year-old man presented with supraclavicular, mediastinal, and retroperitoneal lymphadenopathy clinically thought to be due to malignant lymphoma. Biopsy of a supraclavicular lymph node revealed metastatic adenocarcinoma positive for prostatic-specific antigen. This site of the primary tumor was confirmed by needle biopsy of the prostate gland. The tumor regressed dramatically following treatment with estramustine phosphate.

Adenocarcinoma↗

PubMed2002

The flare in alkaline phosphatase activity post-orchidectomy predicts which patient may benefit from early chemotherapy in metastatic prostate cancer.

BACKGROUND: A flare in serum alkaline phosphatase (ALP) activity post-orchidectomy has been shown to be of negative prognostic value for progression-free survival (PFS) in patients with prostate cancer. The aim of this study was to investigate whether a flare in ALP may help identify patients in whom prognosis could be positively influenced by early chemotherapy. METHODS: A retrospective analysis of the database of a Dutch multicenter study was conducted to evaluate the prognostic value of the flare in ALP post-orchidectomy for survival and PFS in 112 patients treated with orchidectomy (previously reported) compared to 121 age- and stage-matched patients additionally treated with estramustine-phosphate (EMP) as first line therapy. RESULTS: There was no overall difference in PFS and survival between the two treatment regimen. Subgroup analysis of patients demonstrating a greater than 50% increase in ALP post-orchidectomy showed, however, a significant increase in PFS in patients additionally treated with EMP. CONCLUSIONS: Our data suggest that the simple measurement of ALP activity within 4 weeks of castration represents a useful adjunct in assessing which patients with prostate cancer undergoing androgen ablation may benefit from additional early chemotherapy.

Aged↗

PubMed2005

In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines.

BACKGROUND: The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145. METHODS: The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram. RESULTS: Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells. CONCLUSIONS: The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.

Antineoplastic Agents↗

PubMed1982

Human prostatic adenocarcinoma: comparative experimental treatment of the tumor line PC 82 in nude mice.

A human prostatic adenocarcinoma, growing as a transplantable line in nude mice, was subjected comparatively to the usual endocrine treatment schedules including orchiectomy, estrogens, estramustine phosphate, and a study with flutamide (SCH 13521) and cyproterone acetate. The regression under treatment in tumor volume and in the histological pattern in demonstrated, and the possibilities and limitations of the nude mouse model are discussed.

Adenocarcinoma↗

PubMed1983

Organ culture studies of human prostatic adenocarcinomas.

The proliferative responses of human prostatic carcinoma have been evaluated in organ culture using [125I]-iododeoxyuridine ([125I]UdR) to monitor DNA synthesis. The morphological preservation was not influenced by the addition of fetal calf serum or insulin (5 mu gm/ml), transferrin (10 mu gm/ml), and thyrotropin releasing hormone (10(-9) M) to the active medium. Testosterone (4 X 10(-7) M) stimulated [125I]UdR uptake, whereas diethylstilboestrol (4 X 10(-6) M) had no direct effect on uptake. Both estramustine phosphate (4 X 10(-6) M) and oestradiol-17 beta (4 X 10(-6) M) inhibited uptake in a similar manner. Thus while explants of human prostatic carcinoma derived from transurethrally resected specimens can be well maintained in organ culture for a few days, proliferative responses are small and difficult to measure for individual patients.

Adenocarcinoma↗

PubMed1984

Treatment of prostatic cancer: the EORTC experience--preliminary results of prostatic carcinoma trials.

Six prospective studies in the field of prostatic carcinoma have been carried out to date by the EORTC Urological Group. In three phase II studies, adriamycin, procarbazine, vindesine, and mitomycin C have been studied. Two of the three protocols have been completed. In three phase III studies, 3 mg of diethylstilbestrol (DES) is compared to cyproterone acetate (CPA), medroxyprogesterone acetate (MPA), and Estramustin phosphate (Estracyt). These two protocols have been closed to entry. The current protocol compares DES, 1 mg, to castration and to cyproterone acetate plus castration. From the phase II studies, no drug has emerged that is recommended for treatment of hormone-resistant prostatic cancer. The endocrine protocols, designed for the primary treatment of T3, T4, and M1 carcinoma of the prostate, have resulted in several important observations. Responses to DES, 3 mg/day, and to Estracyt were very similar and amounted to 25-30%. There was somewhat less objective response in the CPA and significantly less (P = 0.005) in the MPA group. It has become evident that DES at a dosage of 3 mg/day carries a significantly higher risk of overall cardiovascular toxicity than does cyproterone acetate, but severe cardiovascular complications did not differ between treatment groups. Up to now, no differences in survival were observed within the different treatment groups. Grade, local tumor extension, and performance were found to have a significant impact on survival.

Castration↗

PubMed1986

Design of cytotoxic steroids for prostate cancer.

Our object was to determine if the aromatic nucleus of estramustine (I) is optimal for binding affinity to prostate cytosolic proteins, and if C3 is the preferred position for the N-mustard carbamate moiety. To this end we have submitted 34 steroids for in vitro assay of binding affinity to total prostate cytosolic proteins. Our structures included aromatic and hydroaromatic steroids containing N-mustard carbamate and other substituents at C3, C6, C11, C16, C17, C20, and C21. Our results show that binding affinity to prostate proteins is optimally present in C3-nitrogen mustard carbamates attached directly to a totally planar aromatic ring as in (IV). Partial deviation from total planarity as in enol-carbamates (V) leads to some loss of binding affinity, which largely disappears in hydroaromatic structures (VI). Thus, our data lead to the Ring A aromatic structure (X) as a basis for the design of steroidal N-mustard carbamates with prostate selectivity. Preliminary in vivo studies using the Dunning R3327AT prostatic adenocarcinoma implanted in the Copenhagen rat generally support our in vitro data.

Adenocarcinoma↗

PubMed1985

Comparison between continuous and intermittent administration of Estracyt in the treatment of carcinoma of the prostate.

Ninety-five patients with prostatic carcinoma, stages A-D and of all histological grades were randomized between a continuous and an intermittent treatment regimen of Estracyt (estramustine phosphate). 77 patients were evaluated (46 with continuous and 31 with intermittent therapy). Remissions were seen in 13 (28%) and (13%), respectively. Stable disease was recorded in 30 (65%) and 24 (77%), respectively. Progression experienced 3 (6%) and 3 (10%) respectively. 19% were unable to continue therapy due to intolerable gastrointestinal side effects (7 patients receiving continuous and 8 patients receiving intermittent therapy).

Aged↗

PubMed1986

Activity of phagocytic granulocytes in patients with prostatic cancer.

Chemilumenescence (CL) occurs due to the phagocytosis of bacteria and of tumor cells by polymorphonuclear neutrophils (PMN). Levels of CL were measured in patients with prostatic cancer and from normal subjects. Patients with advanced disease (stage C, D) showed no elevated CL levels as compared to healthy individuals or patients with minimal disease (stage A, B). Following external radiation therapy in patients with stage A-C prostatic carcinoma high levels of CL were recorded. Estrogen medication also resulted in increased CL levels, while estramustine did not affect phagocytic activity. Intradermal BCG vaccination caused increased PMN activity. Progressive prostatic cancer in hormone treated patients was associated with increased CL as compared to patients with stable or regressive disease.

Antineoplastic Agents↗

PubMed1999

The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review.

PURPOSE: Microtubules are important cytoskeletal components involved in many cellular events. Antimicrotubule agents including polymerizing agents (paclitaxel and docetaxel) and depolymerizing drugs (vincristine, vinorelbine, and estramustine phosphate) are widely used either alone or in combination with other anticancer drugs. These antimicrotubule agents are promoters of apoptosis in cancer cells. In this review, we discuss the role of bcl-2 family genes in the regulation of apoptosis, and summarize effects of microtubule targeting agents on apoptotic signal transduction pathways. CONCLUSION: Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.

Animals↗

PubMed2003

Chemotherapy of prostate cancer: present and future.

The role of chemotherapy in prostate cancer continues to evolve. In men with symptomatic androgen-independent prostate cancer, significant reduction in pain and analgesic requirements are achievable with mitoxantrone and glucocorticoid combinations compared with glucocorticoids alone. However, survival rates are not improved. Taxane-based combinations with estramustine phosphate or other new agents show promise. Prostate-specific antigen response rates with these combinations appear to be 1.5 to 2 times more frequent than with mitoxantrone-based combinations. Randomized trials of taxane versus mitoxantrone-based therapies are underway. New agents and applications of current agents in adjuvant settings should be explored if survival in men with prostate cancer is to be improved.

Antineoplastic Agents↗

PubMed1988

Changes in blood coagulation and fibrinolysis in patients on different treatment regimens for prostatic cancer. Predictors for cardiovascular complications?

An analysis of haemostatic variables was done in 31 prostate cancer patients treated with oestrogens (13 pts), estramustine phosphate (7 pts) or orchidectomy (11 pts) before, at about 7 weeks and 6 months of treatment. Six patients treated with either of the drugs developed venous thromboembolism or ischemic vascular disease. Already before treatment there were changes indicating some activation of blood coagulation, fibrinolysis and kallikrein systems. The drug treated group showed significant changes in several variables: i.e. increase in factor VII, plasminogen and prekallikrein but also a decrease in antithrombin and in inhibitors to the fibrinolytic and kallikrein system. Significant difference between the drug treated groups was found in circulating platelet aggregates and in kallikrein inhibiting activity. Tissue plasminogen activator capacity was significantly lower in the drug treated patients with complications than in those without. The study also showed that in addition to the assay of the tissue plasminogen activator capacity during the first weeks of therapy it might be helpful in predicting cardiovascular complications to investigate platelet aggregates, prothrombin complex, factor X, von Willebrand factor antigen, fibrinogen, antithrombin, fibrino-peptide A, and the inhibitors of fibrinolysis as well as C1-esterase inhibitor.

Blood Coagulation↗

PubMed1977

Inhibitory effects of Estracyt on R-3327 rat prostatic carcinoma.

Estracyt (estramustine phosphate) injected intraperitoneally, 100 mg, per Kg. three days a week for four weeks, retarded growth of the R-3327 tumor in intact rats and in orchiectomized rats given androgen. The growth inhibition was accomplished by reduction of tumor deoxyribonucleic acid concentration and of the activities of acid phosphatase, leucine aminopeptidase, and other hydrolases. Histologic examination revealed cellular necrosis particularly prominent in the orchiectomized, androgen-treated rats. Estracyt did not affect the uptake of 65-Zn in the tumors but markedly reduced the high uptake in the dorsolateral prostate. There was no accumulation of 3H or 14C in the tumors after intravenous administration of 3H, 14C-labeled Estracyt, but the isotope concentrations decreased much in the same way as they decreased in the dorsolateral prostate. The isotopes were retained in the ventral prostate, where their concentrations were approximately twenty times higher than those in the muscle four hours after injection. The results demonstrate the value of the R-3327 tumor in the evaluation of drugs of potential clinical use for the treatment of prostatic cancer. The results also show that Estracyt has an antitumor effect which is not dependent on the antigonadotropic action of the drug.

Acid Phosphatase↗

PubMed1986

Results of another trial of chemotherapy with and without hormones in patients with newly diagnosed metastatic prostate cancer.

From July, 1980, to June, 1983, 319 patients with newly diagnosed metastatic prostatic cancer were randomized to one of three treatment protocols: diethylstilbestrol (DES) or bilateral orchiectomy, cyclophosphamide plus 5-fluorouracil plus DES, and estramustine phosphate (Emcyt). Ninety-three per cent of 296 patients were eligible for evaluation. This report shows no difference in survival, disease-free progression time, or status regarding pain at entry. Other prognostic factors failed to reveal any difference within any of the treatment protocols.

Blood Platelets↗

PubMed1988

Comparison of flutamide and Emcyt in hormone-refractory metastatic prostatic cancer.

A prospective randomized trial for metastatic prostatic cancer in 220 patients who were refractory to hormone therapy was conducted by the National Prostatic Cancer Project from 1984 to 1985. As of July, 1986, the evaluation of these patients reflected no difference in response to either estramustine phosphate (Emcyt) or flutamide. Toxicities were minimal, and the observed survival and progression-free survival intervals were noteworthy in view of the overall prospects for such patients. Future studies dealing with specific quality of life issues seem to be indicated by our results.

Anilides↗

PubMed1989

Progression and complications after external beam radiation therapy for carcinoma of prostate.

Sixty patients with prostatic carcinoma localized to the pelvis have been treated by external beam radiation therapy: 2 patients (2%) were Stage A, 12 (20%) Stage B, 14 (23%) Stage C, and 32 (53%) Stage D1. Twenty-two patients received adjuvant therapy (11 estramustine phosphate [Estracyt] and 11 cyclophosphamide [Cytoxan]) after radiation. Progression occurred in 22 patients (37%): 6 (10%) had local recurrence while 16 (27%) failed distally. The incidence of late major complications was 12 percent.

Adenocarcinoma↗

PubMed1989

Remarkable effect of endocrine therapy on brain metastasis from prostatic carcinoma.

The brain metastasis of prostatic carcinoma is rare and is distinguished by its poor prognosis in cases which are not surgically resectable. Herein we report on a case of brain metastasis of prostatic carcinoma which showed a dramatic regression through bilateral orchiectomy and doses of diethylstilbestrol diphosphate and estramustine phosphate. Neurologic and psychiatric symptoms diminished within three months, and the patient is alive and well without any subjective symptoms after twelve months.

Adenocarcinoma↗

PubMed1990

Quality of life and treatment of hormone resistant metastatic prostatic cancer. The EORTC Genito-Urinary Group.

72 patients with hormone resistant, progressing prostatic cancer completed a self-administered questionnaire to assess subjective morbidity and quality of life before they were entered into a phase III trial of estramustine (34) vs. mitomycin (38). At least one post-treatment assessment was available in 43 patients. This considerable degree of non-compliance is explained by practical problems related to completion and collection of the questionnaires in these rapidly deteriorating patients. Doctors underestimated subjective morbidity (pain, decreased performance status, nausea) in 30-50% of the cases. Decreased functional status, fatigue and pain were identified as the most frequent major morbidities before study entry. In most patients, treatment did not reduce this morbidity. The routine application of self-administered quality of life questionnaires has considerable practical problems but yields clinically worthwhile information about subjective morbidity. Simple but relevant monitoring of subjective morbidity by the patient should be mandatory in cancer trials where palliation is a major endpoint.

Attitude of Health Personnel↗