Pharmacoclinical study of oral estramustine phosphate (Estracyt) in advanced carcinoma of the prostate.
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Acid Phosphatase↗
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Suppression of matrix metalloproteinase-2-mediated cell invasion in U87MG, human glioma cells by anti-microtubule agent: in vitro study.
Because microtubules are important components of cell motility and intracellular transport, it is reasonable to propose that the depolymerizing effect of an antimicrotubule agent, estramustine, on glioma microtubules would modulate cell invasiveness. To determine whether matrix metalloproteinases, key factors in cell invasion, are affected by exposure to estramustine, a cell proliferation assay, a zymogram, a collagenolysis assay and a haptoinvasion assay were used in this study. The zymogram revealed that an activated (62 kDa) form of matrix metalloproteinase-2 diminished with increasing estramustine concentrations. The collagenolysis assay demonstrated approximately 2.5- to 21-fold lower rates of enzymatic activity suppressed by estramustine in a dose-dependent manner at estramustine concentrations of 1, 5, and 10 microM, compared with the control group. On the haptoinvasion assay, no statistically significant difference was seen in the 0.5 microM estramustine group, whereas 1-10 microM estramustine groups revealed significant suppression of invasion from 6 to 24 h in a dose-dependent manner. The results suggest that estramustine suppresses the invasion of U87MG cells in vitro using the decreasing available matrix metalloproteinase-2, an effect caused by the disassembly of microtubules. Suppression of the infiltrative capacity of malignant glioma cells could be of significant value in the treatment of this disease.
Antineoplastic Agents, Alkylating↗
Future directions in the treatment of androgen-independent prostate cancer.
The rationale for evaluating the taxanes in hormone-refractory prostate cancer (HRPC) is strong. Preclinical data demonstrate that docetaxel is a potent inhibitor of bcl-2, an antiapoptotic gene implicated in the progression of HRPC and the development of chemotherapy resistance. The results of early clinical trials with docetaxel suggested that it could improve survival; trials in which docetaxel was combined with estramustine appeared even more promising. The Southwest Oncology Group intergroup trial (SWOG 9916) phase III was developed to compare the combination of docetaxel and estramustine to mitoxantrone-prednisone in men with HRPC. A total of 684 eligible patients were enrolled. Median survival was significantly improved with docetaxel-estramustine (17.5 months vs 15.6 months with mitoxantrone-prednisone, P = .02), and the relative risk of death was reduced by 20%. Progression-free survival was improved from 3.2 months with mitoxantrone-prednisone to 6.3 months with docetaxel-estramustine (P < .001). Significantly more patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50% compared with those treated with mitoxantrone-prednisone (50% vs 27%, P < .001). Toxicity was more common in the docetaxel-estramustine arm, likely due to estramustine. Other docetaxel-based regimens under investigation include combinations with calcitriol, thalidomide, or bevacizumab. With docetaxel/prednisone approved by the US Food and Drug Administration (FDA) as first-line treatment of HRPC, ongoing and future trials will build on its success by evaluating a number of docetaxel-based combinations in various prostate cancer settings. Other novel agents, including the oral platinum analog satraplatin, are being investigated as second-line treatment for HRPC.
Angiogenesis Inhibitors↗
Targeting microtubule-associated proteins in glioblastoma: a new strategy for selective therapy.
BACKGROUND: This report presents a summary of preclinical data concerning the use of estramustine, an antimicrotubule agent against human glioblastoma cells. The strategy for the investigation of estramustine is predicated on the unique affinity of this agent for microtubule-associated proteins (MAPs). METHODS: A series of laboratory investigations were used to demonstrate antiproliferative effects (MTT assay, colony forming assay, thymidine incorporation), cell cycle synchronization (flow cytometry), intracellular localization of binding sites (immunocytochemistry, electron microscopy), and activity in subcutaneous xenografts of human glioblastoma. RESULTS: Estramustine has potent in vitro activity against human glioblastoma cells and can enhance the cytotoxic effects of ionizing radiation. Estramustine-binding protein was abundantly expressed in glioblastoma cells and may contribute to the selective effects of estramustine on neoplastic cells. This agent has activity against subcutaneous xenografts of human glioblastoma. Synthesized novel estrogen carbamates also can inhibit proliferation of glioblastoma cells. CONCLUSIONS: Cytoskeletal elements (MAPs) of glioblastoma cells may provide a useful target for therapy with agents like estramustine because of the potent antimitotic effects of this agent and its affinity to a protein that is expressed in glioma cells. These observations have stimulated a search for other estrone carbamates with antimitotic activity that exceeds more conventional antimicrotubule agents.
Animals↗
Adjuvant therapy for clinical localized prostate cancer treated with surgery or irradiation.
OBJECTIVE: Because of efficacy demonstrated with chemotherapy in patients with metastatic disease, the National Prostate Cancer Project in 1978 initiated two protocols evaluating adjuvant therapy following surgery (Protocol 900) and irradiation (Protocol 1000) for patients with localized disease at high risk for relapse. METHODS: All patients underwent staging pelvic lymph node dissection. Following definitive treatment, patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years, estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only. Accession closed in 1985 and included 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable). RESULTS: Nodal involvement was identified in 198 patients (49% of total): 29% in Protocol 900 and 63% in protocol 1000. Median progression-free survival (PFS) and survival have been greater for patients in Protocol 900 regardless of adjuvant, reflecting their lower pathologic stage. Median PFS is significantly greater for patients in Protocol 1000 receiving estramustine (52.2 months) compared to cyclophosphamide (35.0 months). Median PFS for patients with nodal involvement in Protocol 1000 receiving estramustine is increased (43.5 months) compared to no treatment (21.5 months). Patients with limited nodal involvement in Protocol 1000 have a longer median PFS (45.6 months) compared to patients with extensive disease (23.6 months). But in the latter group patients receiving estramustine experienced a significantly longer median PFS (43.5 months) compared to cyclophosphamide (29.1 months) or no adjuvant (13.5 months). Increased PFS with estramustine adjuvant was also noted in stage C patients (only Protocol 900) and in those with high-grade (grade 3) tumors (both protocols). CONCLUSIONS: With now over 10 years mean follow-up for this series of patients, we conclude that adjuvant estramustine is beneficial for prostate cancer patients receiving definitive irradiation. This benefit is particularly noted in those patients with extensive nodal involvement (N+, D-1).
Adenocarcinoma↗
New steroidal alkylating agents in advanced stage D carcinoma of the prostate.
In a previous study, 50 patients with prostatic carcinoma were given continuous oral estramustine phosphate at a dose of 15 mg/kg/day. All patients had progressed on prior standard treatment. The objective and subjective response rates were 19% and 36% respectively. Seven of the 50 patients are still receiving treatment after 1-3 years. One patient who was given estramustine phosphate therapy for 1 year achieved a complete response, which included disappearance of osteoblastic metastasis. He still continues in unmaintained remission despite the fact that estramustine phosphate therapy was stopped because of gastrointestinal toxicity. No serious side effects related to the drug have been seen. Estramustine phosphate may be given safely for a prolonged period and has a place in the treatment of advanced prostatic cancer refractory to hormonal therapy. Twenty-one patients with stage D prostatic adenocarcinoma who failed hormonal therapy were treated with a combination of estramustine phosphate (600 mg/m2/day) plus prednimustine (Leo-1031) (15 mg/m2/day) in daily oral doses. Fifteen patients have been treated with prednimustine alone. The preliminary results of the combination therapy (after 2-9 months) are as follows: five patients (24%) had an objective response and nine patients (44%) had subjective improvement. Only five (24%) did not benefit from the drug and seven (33%) are stable. Of the 16 patients treated with prednimustine alone, one patient has had an unequivocal objective response and one experienced a considerable objective improvement. These preliminary results indicate the possible advantage of adding an alkylating agent (prednimustine) to estramustine phosphate in advanced prostatic carcinoma.
Aged↗
Docetaxel (Taxotere) in hormone-refractory prostate cancer.
Considerations of both molecular biology and data from in vitro studies suggest a potential for the combination of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) with estramustine in the treatment of patients with hormone-refractory prostate cancer. Based on data from two phase I studies, the docetaxel dose recommended for phase II study in combination with estramustine in minimally and extensively pretreated patients is 70 mg/m2 and 60 mg/m2, respectively. The dose-limiting toxicity was neutropenia. In one phase I study, 63% of the 34 patients treated showed at least a 50% decline in prostate-specific antigen. An objective response was seen in 28% of patients with measurable disease, and overall median survival (22.8 months) is highly encouraging. In the second study, 82% of 17 patients showed a greater than 50% decline in prostate-specific antigen and, at the 70 mg/m2 dose level, two of six patients showed prostate-specific antigen normalization. Phase II studies have demonstrated more than 50% declines in 59% to 88% of patients treated at 70 mg/m2. Although reduction of the dose of estramustine appears to result in a somewhat lower response rate, the contribution made by estramustine to the efficacy of the estramustine/docetaxel combination must be established by randomized trials. Dexamethasone, however, does not appear to significantly contribute to the response rate of estramustine and docetaxel. Phase III studies comparing docetaxel plus estramustine with mitoxantrone plus corticosteroids are currently being planned. If the promise of docetaxel hormone-refractory prostate cancer is realized, it may be appropriate to design clinical trials that evaluate docetaxel-based regimens as adjuvant therapy in patients who are at a high risk for relapse after definitive local therapy.
Antineoplastic Agents, Hormonal↗
Docetaxel in prostate cancer.
In contrast to several other tumor types, there has been relatively little experience with docetaxel in hormone-refractory prostate cancer. However, two phase II trials investigated the combination of docetaxel with estramustine, and reported prostate-specific antigen response rates of 69 and 74% and objective responses in 23% and 57% of patients. This activity is comparable with that of other estramustine combinations. However, there is uncertainty about whether estramustine itself should be omitted from therapy because of its emetogenic and thromboembolic potential, and also over the optimal schedule of docetaxel to avoid neutropenia. Preliminary data suggest that weekly docetaxel, with or without limited exposure to estramustine, may provide the right balance between efficacy and tolerability. Phase III studies now in progress are comparing regimens containing docetaxel and estramustine with a recent standard therapy consisting of mitoxantrone plus prednisone. In the future, the efficacy of docetaxel plus estramustine may be enhanced by adding agents to this regimen.
Antineoplastic Agents, Phytogenic↗
Salvage immunotherapy with subcutaneous recombinant interleukin 2 (rIL-2) and alpha-interferon (A-IFN) for stage D3 prostate carcinoma failing second-line hormonal treatment.
Immunotherapy with subcutaneous rIL-2 and alpha IFN was administered to stage D3 prostate cancer patients after failure of secondary treatment with oral estramustine phosphate. Of a total of 15 patients, 2 are in partial response, with estramustine maintained after 44+ and 36+ weeks, respectively. Response to estramustine was observed initially in 7 of 13 patients, with a median duration of 12 weeks (range 8-20). No response to estramustine was observed in the remaining 6 patients. After the failure of estramustine, 13 patients were treated with immunotherapy. After the first cycle, progression of disease no therapy was given to those patients. A reduction of PSA levels was observed during the first cycle in 2 patients (15.3%); levels subsequently increased during the second cycle of treatment. A partial response was observed in 4 patients (30.7%), with a reduction of PSA levels in 3. The duration of response was 28 and 32 weeks in 2 patients who survived after failure for 18 and 21 weeks, respectively. Two patients are still alive, with continued partial response at 62+ and 42+ weeks. Side effects were represented mainly by a flu-like syndrome, associated with fever and nausea in all patients. The serum concentration of IL-10 was measured in 8 patients under study and in 11 matched controls. Levels higher than mean + 2D of controls before, during, or after immunotherapy were correlated with treatment failure, whereas levels below 6 ng/ml were encountered among the patients who showed a clinical response and a reduction of PSA during treatment. Within the limitations of this pilot study, it appears difficult to distinguish between a spontaneously slowly progressing disease and a true response to therapy.
Aged↗
Adjuvant therapy for localized prostate cancer.
BACKGROUND: In 1978, the National Prostatic Cancer Project launched two protocols evaluating adjuvant therapy after surgery (Protocol 900) or irradiation (Protocol 1000) for clinically localized prostate cancer. All patients underwent staging pelvic lymphadenectomy. METHODS: After definitive treatment, the patients were randomized either to receive cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years or estramustine phosphate 600 mg/m2 orally daily for up to 2 years or to undergo observation only. Patient accession closed in 1985 and includes 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable). RESULTS: Lymph node involvement was identified in 198 patients (49% of total), 29% in Protocol 900 and 63% in Protocol 1000. The median progression-free survival (PFS) and survival were greater for patients in Protocol 900 compared with 1000, regardless of the adjuvant therapy. This reflected the greater proportion of patients with lower pathologic stage disease in the surgically treated group. The median PFS was significantly greater for all patients in Protocol 1000 receiving estramustine phosphate adjuvant (48.2 months) compared with patients randomized to receive cyclophosphamide (35.6 months). The median PFS for patients with nodal involvement in Protocol 1000 who received estramustine phosphate adjuvant was prolonged significantly (37.3 months) compared with no treatment (20.9 months). The median PFS for patients with limited nodal disease in Protocol 1000 was longer (39.9 months), regardless of the adjuvant therapy, compared with those with extensive nodal disease (20.7 months). However, in the latter patient group, those receiving adjuvant estramustine phosphate had a significantly longer median PFS (32.8 months) compared with those receiving adjuvant cyclophosphamide (22.7 months) or no adjuvant therapy (12.9 months). CONCLUSION: Adjuvant estramustine phosphate was beneficial in patients with prostate cancer and pelvic node involvement who received irradiation as definitive treatment.
Chemotherapy, Adjuvant↗
Chemotherapy for prostate cancer.
Androgen deprivation therapy remains the mainstay of therapy for patients with advanced prostate cancer and for selected patients with localized prostate cancer. Androgen deprivation therapy is the model of target-based therapies in this disease. Although it is clear that other target-based therapies need to be developed, cytotoxic chemotherapy is emerging as an effective form of treatment for men with prostate cancer. The early studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic hormone-refractory prostate cancer with minimal toxicity, and significant palliation could be provided. Since then, it has been recognized that estramustine, when combined with a variety of microtubular inhibitors, is very active in hormone-refractory prostate cancer. Doublets combining estramustine plus a taxane seem to be the most active. Although it appears that estramustine may add some activity to taxanes, the mechanism of its activity is uncertain, and its overall value is similarly questioned, particularly in light of its significant toxicity. Regimens that omit estramustine are being explored (ie, either taxane alone or taxane plus biologic agents). In addition, triplet therapy (combining estramustine plus a taxane plus a third drug, such as carboplatin or etoposide) is being explored. Finally, the utility of chemotherapy is beginning to be explored in the context of earlier disease in the neoadjuvant, adjuvant, or serologically relapsing group of patients. Data from these studies are just beginning to be gathered.
Antineoplastic Combined Chemotherapy Protocols↗
Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines.
OBJECTIVE: To evaluate combinations of anti-tumour agents in tissue cultures using three established cell lines derived from patients with prostate cancer to obtain potential candidates for therapeutic testing in patients with prostate cancer. MATERIALS AND METHODS: Seventeen anti-tumour agents were tested for synergism or antagonism in combination studies in DU 145, PC 3 and LnCaP cell lines. After determining the dose required for 50% inhibition of growth in each, combinations were screened using the median-effect plot and combination-index isobolograms. RESULTS: Estramustine (the primary product of dephosphorylation of estramustine phosphate) showed strong synergism in all three cell lines with hydroxyflutamide, the non-immunosuppressive cyclosporin analogue PSC 833, and Liarozole. In the hormone-sensitive cell line LnCaP alone, synergism was also observed with vinblastine, paclitaxel, docetaxel, bicalutamide, ketoconazole and all-trans-retinoic acid. Other synergistic combinations of two agents were: Liarozole plus docetaxel in LnCaP, PSC 833 plus bicalutamide in DU 145 and PC 3, dexamethasone plus docetaxel in LnCaP, and finasteride plus hydroxyflutamide. Synergistic combinations of three agents were: estramustine plus PSC 833 and Liarozole and schedule-dependent combinations of estramustine, PSC 833, and all-trans-retinoic acid. CONCLUSION: Some of the synergistic combinations have shown clinical effects in patients with hormone-refractory prostate cancer. Based on these findings, new combinations, e.g. estramustine with either PSC 833 or Liarozole, need to be clinically evaluated.
Antineoplastic Agents, Hormonal↗
Docetaxel (Taxotere)-based chemotherapy for hormone-refractory and locally advanced prostate cancer.
Treatment of hormone-refractory prostate cancer (HRPC) historically has shown limited efficacy. However, taxane-based chemotherapy regimens recently have demonstrated more promising results. Several groups have reported significant efficacy and minimal toxicity in patients with hormone-refractory disease receiving estramustine plus docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA). Others have demonstrated single-agent activity of platinum compounds in HRPC. Therefore, the combination of estramustine, docetaxel, and carboplatin is currently being tested in two separate trials of HRPC. The first is a Dana-Farber/Partners Cancer Care phase I study of estramustine, carboplatin, and escalating doses of weekly docetaxel. The second study is a Cancer and Leukemia Group B multicenter phase II study evaluating the combination of estramustine, docetaxel, carboplatin, and granulocyte colony-stimulating factor. The promise of taxane-based regimens in the treatment of hormone-refractory disease has led to consideration of treating patients at high risk for developing metastatic disease earlier in their clinical course. At Dana-Farber/ Partners Cancer Care, we are evaluating neoadjuvant weekly docetaxel alone followed by surgery in patients with high-risk localized prostate cancer using pathologic response as the primary end point. Adding carboplatin to the active combination of estramustine and docetaxel may improve the response rate in HRPC. Furthermore, the use of promising chemotherapy agents earlier in high-risk localized disease may improve clinical outcomes in these patients by decreasing their risk for systemic relapse.
Antineoplastic Combined Chemotherapy Protocols↗
[Pharmacology and metabolism of a new therapeutic drug for prostatic cancer "Estracyt"].
Estracyt is a new drug for treatment of prostatic cancer, which is a molecule combining estradiol and nornitrogen mustard by a carbamate link. Estracyt is completely dephosphorylated prior to reaching the peripheral circulation after oral administration of the drug to men. Estramustine, i. e. dephosphorylated Estracyt, appears to be metabolized in liver as follows: Estramustine leads to estromustine leads to nitrogen mustard + estrone. There is a large amount of estramustine binding protein (EMBP) in the cytosol 3.5 S fraction of human prostatic cancer tissue, which is involved with the selective uptake and long term retention of both estramustine and estromustine in prostate. The anticancer action of Estracyt appears to be the sum of the direct prostatic action of estramustine and estromustine and the indirect prostatic action of free estradiol-17 beta and estrone via the inhibition of hypothalamo-pituitary axis. Estracyt Research Group in Japan concluded that Estracyt was effective in 38% of reactivated prostatic cancer patients (15% (I-C, I-B), 23% (I-A, O-B, O-C]. Side effects of this drug at the time of 3 months treatment is as follows: gastrointestinal disturbance in 36%, edema in 15%, and hepatic disorder in 7%.
Animals↗
The presence in rat and human prostate of proteins that bind steroid-cytostatic complexes.
During studies on the uptake and distribution of estramustine phosphate (Estracyt) in the rat, a major protein in the rat ventral prostate was found that binds estramustine, estromustine, and several other steroid nitrogen mustard complexes. This protein, called estramustine-binding protein, shares many physicochemical characteristics with alpha-protein, prostatic-binding protein, and prostatein, each reported to constitute a major steroid-binding protein in the rat ventral prostate. There is every indication that these four names designate one and the same protein, the binding properties of which favor the binding of lipophilic compounds, and which has shown an affinity for estramustine and closely structure-related compounds that is 100- to 1000-fold higher than for the natural steroids. Also, the human prostate has been shown to take up and bind estramustine and estromustine. However, the binding entity (or entities) is still under intense investigation.
Animals↗
The secretion of urokinase-like plasminogen activator is inhibited by microtubule-interacting drugs.
The secretion of proteinases into the extracellular matrix is one of the main features of tumour cells, as related to their invasive behaviour. Considering the role of the microtubule cytoskeleton, and particularly the action of microtubule-associated protein (MAPs) in mediating protein secretion, the effects of the anti-microtubule drugs estramustine and taxol, on the secretion of urokinase-type plasminogen activator (u-PA) and the 72 kDa gelatinase were investigated. Treatment of 5637 bladder carcinoma cells with estramustine and taxol inhibited u-PA secretion into the conditioned medium in a drug concentration-dependent fashion. This inhibition was confirmed by determinations of u-PA enzymatic activities and by measurements of the levels of immunoreactive activator. Studies using gelatin zymograms also showed an inhibition of another tumoural proteinase namely the 72 kDa gelatinase. Time-course uptake experiments showed that estramustine was incorporated into the cells, a process which depended on temperature. On the other hand, immunofluorescence studies indicated that the microtubule network was affected by taxol with the formation of bundles of microtubules at different cell domains. Minor effects were visualized after treatment of the cells with estramustine-phosphate, a drug that blocks primarily the action of microtubule-associated proteins. The studies provide a way to analyse the relationships between u-PA secretion and the integrity of the cytoskeletal network.
Estramustine↗
Influence of prostatic secretion protein on uptake of androgen-receptor complex in prostatic cell nuclei.
Prostatic secretion protein (PSP) is a major component of rat prostatic cytosol, and this protein is also found in the prostatic fluid. Purified PSP was found to inhibit the nuclear uptake of the [3H]methyltrienolone-receptor complex in vitro. Furthermore, purified PSP inhibited the binding of this androgen-receptor complex to DNA-cellulose. It is suggested that these effects of PSP may represent an intracellular control system regulating the concentration of PSP. Administration of estramustine, the dephosphorylated metabolite of the anti-cancer drug estramustine phosphate (Estracyt), to rats was found to decrease the weight of the prostate gland but to maintain the concentration of PSP, calculated as mg PSP/mg protein, at a constant level. In contrast, castration or administration of estradiol-17 beta valerate decreased the weight of the prostate gland as well as the concentration of PSP. These findings indicate that the mechanism of action of estramustine is at least partially different from that of estradiol-17 beta. Furthermore, it is suggested that estramustine may exert part of its action through its effects on the concentration of PSP.
Animals↗
Cooperative clinical trials of the National Prostatic Cancer Project: Protocol 900.
In May 1978, the National Prostatic Cancer Project Treatment Subgroup activated its first clinical trial evaluating adjuvant chemotherapy (Protocol 900). This protocol is a comparison of long-term adjuvant chemotherapy with cyclophosphamide, estramustine phosphate, or no additional treatment in patients with definitive surgical therapy for adenocarcinoma of the prostate. To date, 128 patients have been entered with an entry rate of approximately 2.2 patients per month. One hundred five patients form the basis of this report, with 96 patients still on active therapy. Estramustine phosphate has been administered at a dose of 600 mg/m2 orally daily in three divided doses. The cyclophosphamide is administered 1 g/m2 intravenously every 3 weeks. Results are still preliminary; only two evaluable patients have died. Approximately two-thirds of patients entered have had negative lymph nodes. Recurrent disease has been documented in 15 patients, including eight receiving cyclophosphamide, three receiving estramustine phosphate, and four on the no-treatment arm. The recurrence rate has been disproportionately high (50%) in patients receiving cryosurgery rather than radical prostatectomy (12%). Maximum survival has reached 241 weeks. Side effects have consisted of leukopenia in patients receiving cyclophosphamide (56%), and nausea and vomiting with cyclophosphamide (85%), and estramustine phosphate (36%). This study continues with patient entries now over one-half of the number anticipated in the original study design.
Adenocarcinoma↗