Effect Of Estramustine Phosphate Research Articles

Estramustine Phosphate Monotherapy in Castration-Resistant Prostate Cancer Patients Who Cannot Receive Cytotoxic Chemotherapy

Purpose To investigate whether estramustine phosphate (EMP) monotherapy is applicable to castration-resistant prostate cancer (CRPC) patients who cannot receive cytotoxic chemotherapy. Materials and Methods This retrospective single-arm study was conducted in CRPC patients who had not experienced cytotoxic chemotherapy and received EMP monotherapy (560 mg/day) at 2 institutions from 2008 to 2017. We analyzed prostate-specific antigen (PSA) responses, overall survival, and adverse effects of EMP treatment. Results A total of 28 patients were analyzed. A reduction in serum PSA was observed in 11 patients (39.3%). Seven cases (25.9%) achieved more than 25% reduction of PSA, and 5 of them (18.5%) experienced more than 50% reduction. Median overall survival was 23 months (interquartile range, 10–60 months). Multivariable analyses demonstrated that low level of PSA at diagnosis of CRPC and long duration of prior androgen deprivation therapy were independent favorable factors predicting long-term overall survival. Adverse effects were edema (n=2; grade 2), nausea/vomiting (n=1; grade 2), gynecomastia (n=1; grade 2), and dyspnea (n=1; grade 1). Neither throm-boembolic event nor grade 3–5 toxicity was observed. There was no discontinuation caused by side effects of EMP. Conclusions EMP monotherapy could be considered as a safe treatment option with some effectiveness for CRPC patients who did not undergo cytotoxic chemotherapy. EMP is not generally recommended anticancer drug in the current guidelines for CRPC, but EMP monotherapy is thought to have an alternative role when a standard treat-ment cannot be selected due to patient's age, health condition, or comorbidity. Key Words: Castration-resistant prostatic neoplasm; Estramustine.

Hypoxia in Du-145 Prostate Cancer Xenografts After Estramustine Phosphate and Radiotherapy

Purpose: Practically all solid malignant tumours have central hypoxia, which makes them less vulnerable to most forms of both radiotherapy and chemotherapy. Estramustine phosphate (EMP) is known to sensitise cancer cells and tumours to irradiation and to increase blood flow in malignant tumours. This study was designed to assess the effect of EMP and radiotherapy on the oxygenation status of the tumours. Methods and Materials: Nude mice with DU 145 human prostate cancer cell tumours were divided into four groups: group ER was treated with EMP 0.2 mg/d and external irradiation 3 × 6 Gy; group E received EMP, group R irradiation only; and group O no treatment. The degree of hypoxia in the tumours before and after treatment was measured using 18F-labelled fluoromisonidazole ([18F]FMISO) as a marker. The testis served as a control organ. Histological samples were studied for necrosis and proliferation (DAPI-stain for mitoses and Ki-67). Results: The tumours showed more [18F]FMISO uptake, indicating more hypoxia, than the testes in all four groups. EMP did not improve tumour oxygenation but enhanced the ability of radiotherapy to cause tumour necrosis. Conclusions: The angiogenic effect of EMP, if present, is not crucial in the mechanism of radiosensitation. Keywords: Estramustine, radiotherapy, fluoromisonidazole, hypoxia, DU-145, Prostate Cancer Xenografts, Estramustine Phosphate, malignant tumours, central hypoxia, chemotherapy, human prostate cancer, necrosis, DAPI-stain for mitoses and Ki-67, tumour necrosis, radiosensitation, central necrosis, angiogenesis, DNA, deoxyribonucleic acid, hormone-independent prostate cancer, carcinomas, neurological malignancies, prostate carcinoma model, Dunning R 3327, vascular endothelial growth factor, Nitroimidazoles, fluorine-18 labelled fluoromisonidazole, hypoxia-specific factor, positron emission tomography (PET) technology, polymethylmethacrylate, Monoclonal antibody PP-67, fluorescein isothiocyanate (FITC)-coupled goat, analysis of variance (ANOVA), Dunnett's method, SAS/STAT® software, Immunohistochemistry, G2/M-phase, neovascularisation, R3327, BT4C, Rat glioma model

Hypoxia in DU-145 Prostate Cancer Xenografts after Estramustine Phosphate and Radiotherapy

Purpose: Practically all solid malignant tumours have central hypoxia, which makes them less vulnerable to most forms of both radiotherapy and chemotherapy. Estramustine phosphate (EMP) is known to sensitise cancer cells and tumours to irradiation and to increase blood flow in malignant tumours. This study was designed to assess the effect of EMP and radiotherapy on the oxygenation status of the tumours. Methods and Materials: Nude mice with DU 145 human prostate cancer cell tumours were divided into four groups: The group ER was treated with EMP 0.2 mg/d and external irradiation 3 x 6 Gy; group E received EMP, group R irradiation only; and group O no treatment. The degree of hypoxia in the tumours before and after treatment was measured using 18F-labelled fluoromisonidazole ([18F]FMISO) as a marker. The testis served as a control organ. Histological samples were studied for necrosis and proliferation (DAPI-stain for mitoses and Ki-67). Results: The tumours showed more [18F]FMISO uptake, indicating more hypoxia, than the testes in all four groups. EMP did not improve tumour oxygenation but enhanced the ability of radiotherapy to cause tumour necrosis. Conclusions: The angiogenic effect of EMP, if present, is not crucial in the mechanism of radiosensitation. Keywords: Estramustine, radiotherapy, fluoromisonidazole, hypoxia, DU-145

Estramustine Phosphate Sodium

Abstract Estramustine phosphate sodium (estramustine phosphate) [Emcyt®] acts as a microtubule inhibitor through its metabolites, estramustine and estromustine, and has demonstrated cytotoxic activity in vitro. It showed activity in hormone-refractory prostate cancer (HRPC) when administered concurrently with agents with synergistic mechanisms of action (intravenous taxanes, vinca alkaloids, oral etoposide) in three comparative (n = 127–193) and numerous small noncomparative trials. The prostate-specific antigen (PSA) response rates for estramustine phosphate-based regimens with docetaxel (67% and 63%), paclitaxel (48%) or vinblastine (25%) were greater than those for comparators, mitoxantrone, paclitaxel or vinblastine, respectively. Median times to PSA progression were also longer with estramustine phosphate plus docetaxel or vinblastine, compared with mitoxantrone or vinblastine. Survival durations (beyond the 9–12 months observed with historical controls) in comparative and noncomparative studies demonstrate a trend in favor of estramustine phosphate-based regimens; there was a significant survival advantage with cyclic administration of estramustine phosphate (840 mg/day for 5 days per 21-day cycle) plus docetaxel (70 mg/m2 given in one or two doses per cycle) over mitoxantrone (secondary endpoint, p = 0.002) and a trend for a survival advantage for estramustine phosphate with vinblastine over vinblastine alone (primary endpoint, p = 0.051). Adverse effects of estramustine phosphate are mainly estrogenic, and those of combination treatment largely reflect the profile of the individual agents. Estramustine phosphate combination therapy was associated with nausea, vomiting, and edema in comparative trials, and cardiovascular events were reported in 6–14% of patients; concurrent anticoagulant therapy may be beneficial. Intermittent therapy with lower-dose estramustine phosphate has improved the tolerability of the drug. Estramustine phosphate lacks the myelosuppression, neurotoxicity and alopecia associated with some other cytotoxic agents. Moreover, in comparative trials, neutropenia, and granulocytopenia occurred less often with estramustine phosphate combinations than with the concomitant agents administered alone. Conclusion: Oral estramustine phosphate, administered concurrently with other cytotoxic agents (taxanes, vinca alkaloids or etoposide), has shown activity in comparative and noncomparative trials in patients with HRPC. Of note are the better PSA response rates and the improved survival duration for some estramustine phosphate-based regimens versus comparators. The apparent survival advantage with estramustine phosphate plus docetaxel compared with mitoxantrone plus prednisone may be confirmed in a large, ongoing, randomized, phase III trial. Current efficacy data, the manageable tolerability profile, and the convenient oral route of administration of estramustine phosphate suggest potential for estramustine phosphate-based treatment regimens in patients with HRPC.

Estramustine phosphate enhances the effects of hyperthermia and induces the small heat shock protein HSP27 in the human prostate carcinoma cell line PC-3.

The antimicrotubule drug estramustine phosphate (EMP) has been shown to sensitize prostate carcinoma cells to radiation via synchronization at the G2/M phase of the cell cycle. This synchronization may also render cells more sensitive to hyperthermia, providing a rationale for multimodal treatment approaches. We have investigated the effects of EMP and hyperthermia, as well as the regulation of heat shock proteins (HSP) in the PC-3 prostatic carcinoma cell line. Cells were incubated with four doses of EMP for 48 h followed by a 1-h hyperthermia treatment ranging from 41 degrees C to 44 degrees C. Cell cycle distribution at the end of the EMP incubation was investigated by flow cytometry. Cytotoxicity was assessed by colony formation assays. HSP accumulation was investigated by Western immunoblotting. Doses of 1, 5, 10 and 15 microM EMP synchronized 27, 28, 46, and 68% of PC-3 cells at G2/M. With 5, 10 and 15 microM, a sensitizing effect of EMP was assessed at hyperthermic temperatures of 42, 43 and 44 degrees C. EMP did not alter the expression of HSP72, but substantially induced the synthesis of HSP27 in PC-3 cells. Our data show that EMP sensitizes PC-3 cells to hyperthermia induced cytotoxicity. This observation supports the rationale for multimodal treatment approaches in locally advanced prostate cancer.

Drug-induced apoptosis by anti-microtubule agent, estramustine phosphate on human malignant glioma cell line, U87MG; in vitro study.

The drug effect of estramustine phosphate (EMP), an anti-microtubule agent on human glioma cells has been studied with the focus being mainly its cytotoxity or its targeting of organelles. However, the pharmacological knowledge of estramustine with respect to its cytotoxity and mechanism is limited. To acquire such knowledge, the present study investigates the ability of EMP to induce apoptosis in a human malignant glioma cell line. Transmission electron microscope (TEM) images were examined to monitor periodic changes. Agarose gel electrophoresis was also examined. Cellular DNA fragmentation ELISA was performed to investigate the DNA fragmentation rates and an MTT assay was studied to evaluate the ID50. A TEM study revealed condensing and fragmentation of the chromatin. Laddering of the bands was observed in all EMP exposure groups in agarose gel electrophoresis. DNA fragmentation in all EMP groups began at 0.5 h following an exposure with EMP and increased in a dose- and time-dependent manner as revealed by DNA ELISA fragmentation. ID50 at 24 h was 5.0 microM according to the MTT assay, a value close to 4.8 microM of ID50 was revealed by the DNA fragmentation assay. None of the above mentioned changes was observed in the control group. These results indicated that EMP caused a drug-induced apoptosis in the human malignant glioma cell line, U87MG.

Combined hormono/chemotherapy as primary treatment for metastatic prostate cancer: A randomized, multicenter study of orchiectomy alone versus orchiectomy plus estramustine phosphate

Objectives Based on the theory that hormone-resistant cells are present in all metastatic patients, early administration of chemotherapy appears to be logical and its use is supported by experimental studies. Therefore, trials with combined hormonal and cytotoxic treatment as primary therapy should be conducted. In the present trial, the efficacy and tolerance of estramustine phosphate (EMP) as a chemotherapeutic agent in addition to hormonal treatment (orchiectomy) was studied in patients with metastatic and nonmetastatic prostate cancer not previously treated. EMP was chosen because it produces few serious adverse reactions and no cumulative toxicity. Methods Four hundred nineteen patients were included in a 1.5-year period starting in January 1989. Patients with locally advanced prostate cancer or with bone metastases were randomized to orchiectomy (O) or orchiectomy followed by EMP (O+E), given until progression. Results Analysis of the total group showed no significant difference in time to progression between the treatment groups. Because the course of the disease is different in patients with either T4 tumor only or with lymph node m'etastases only (MO) as compared with patients with bone metastases (M1) and because the number of progressions in the MO patients was low, corresponding analyses were performed for these subgroups as well. In the M1 patients, there was a tendency for a longer time to progression in the O+E group than in the O group, but there was no indication of a difference between the groups with regard to survival. In the MO patients, there was no indication of any difference in results between the treatments. Multivariate analysis of prognostic factors showed pain, alkaline phosphatase, metastasis status, and tumor stage to be significant factors. There was a relation between age and drug treatment in that a significant beneficial effect of EMP in terms of prolonged progression-free interval as well as survival was evident in younger patients (aged less than 73 years) with metastatic disease. Tumor stage was also of importance for the drug effect; T0 to T3 patients who received EMP survived longer than those who were treated with orchiectomy only. The most common adverse reaction was nausea in the O+E group, which led to discontinuation of the drug in 7 patients. Cardiovascular problems are not uncommon in this age group, and there was a higher incidence of cardiovascular events, predominantly cardiac failure, in the O+E group, leading to treatment interruption in 16 patients. Conclusions Our results indicate that future studies of hormono/chemotherapy should focus on younger patients with bone metastases.

Radiosensitizing effect of estramustine in malignant glioma in vitro and in vivo.

Estramustine-phosphate (EMP), a combination of nornitrogen mustard and 17 beta-estradiol, has been demonstrated to exert specific antiproliferative effects on human glioma cells in vitro. The cytotoxic effect is, at least partially, mediated by inhibiting microtubule function. In this study the combined effect of EMP and radiation was evaluated in the human glioma cell-lines, 251-MG and 105-MG, in vitro, and in the rat glioma BT4C in vitro and in vivo. In all cell-lines an additive effect of EMP and radiation was obtained in vitro. Assuming equal effect of EMP is obtained in subsequent radiation fractions, the cell kill will be increased from 2-3 to 5-10 logs if delivering 30 fractions of 2 Gy combined with EMP. In the BT4C rat model the combined effect was found to be synergistic. Flow cytometry demonstrated an arrest in G2/M phase in all cell-lines after EMP treatment. This block in G2/M phase in addition to the previously demonstrated induction of free oxygen radicals, and the increase of blood flow with an assumed subsequent increase of oxygenation, might provide an explanation for the observed radiosensitizing effect of estramustine.

Expression of estramustine-binding protein in ependymomas and in human and developing rat ependymal cells.

The mainstays of primary treatment of ependymoma are aggressive surgery followed by radiotherapy. Although spreading occasionally occurs in the cerebrospinal pathways, chemotherapy is still not established and no ultimate drug has so far been found. Estramustine-phosphate (EMP), with a demonstrated effect on astrocytoma in vitro, has been shown to penetrate the blood-tumor barrier and to accumulate in human brain tumor tissue including ependymoma. It has been proposed that the cytotoxic effect of EMP depends on the presence of a binding protein, estramustine-binding protein (EMBP). In the present paper we have, for the first time, immunohistochemically demonstrated an EMBP-like protein in a series of ependymomas. Immunoreactivity was found within the cytoplasm of the tumor cells with a tendency to increase with increasing malignancy of the tumor. In addition, the occurrence of EMBP-like protein was demonstrated in human ependymal cells. In the rat brain, a weak immunoreactivity was detected in early fetal neuroepithelial cells while the staining intensity was increased in mature ependymal cells in late fetal, neonatal, and adult rat. Thus; immunoreactivity for an EMBP-like protein was demonstrated in ependymoma tissue, normal human ependyma and in the developing rat ependymal cells.

Inhibition of Prostate Cancer Growth by Estramustineand Etoposide: Evidence For Interaction at the Nuclear Matrix

Metastatic prostate cancer which is refractory to hormone therapy remains an incurable disease for which there is no effective therapy. We have begun to investigate the nuclear matrix, the RNA-protein network of the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. It was postulated that estramustine phosphate (EMP), an estradiol-nitrogen mustard conjugate that binds to the nuclear matrix, might enhance the cytotoxicity of etoposide (VP-16), a topoisomerase II inhibitor that acts at the level of the nuclear matrix. In a nascent DNA synthesis assay, EMP and etoposide interact to selectively inhibit new DNA synthesis on the nuclear matrix. In vitro, EMP and etoposide appeared to act synergistically to inhibit the growth of the metastatic Dunning rat prostate adenocarcinoma cell line Mat-LyLu as well as the metastatic human prostate adenocarcinoma cell line PC-3. In vivo, EMP and etoposide inhibited prostate adenocarcinoma growth in the Dunning Copenhagen rat model. These data have formed the basis of a Phase I/II clinical trial to examine the effect of EMP and etoposide in patients with stage D hormone-refractory prostate cancer. Accepted for publication December 21, 1992.

Early morphological detection of estramustine cytotoxicity measured as alteration in cell size and shape by a new technique of microperifusion

The present study describes a new microscopic perifusion technique for detecting momentary alterations in cell volume and shape. The method has been applied for evaluating early signs of cytotoxicity following chemotherapeutic treatments. The effects of estramustine phosphate (EMP) have been evaluated. EMP is a complex between oestradiol-17β and the alkylating agent nor-nitrogen mustard and has recently demonstrated a marked cytotoxicity against malignant glioma cells. The results showed a concentration-dependent increase in cell size and a concomitant decrease in shape factor following EMP-treatment of glioma cells. These changes correlated with cytotoxicity evaluated as cell proliferation and cell membrane alterations shown by 86Rb fluxes and ultrastructural visible membrane damage. The colon cancer line HT-29 displayed no reactions at all following EMP treatment. It is suggested that acute alterations in cell morphology and shape display a strong correlation to the cytotoxicity of EMP encountered by traditional cell culture systems. The findings are discussed with respect to cell membrane disturbances caused by EMP and its potential role as an early test of cytoxicity.

Estramustine binding protein and anti-proliferative effect of estramustine in human glioma cell lines.

Four human cell lines derived from malignant gliomas were immunohistochemically examined for their content of estramustine-binding protein (EMBP). EMBP was detected in a large amount in all glioma cells during the entire cell cycle. EMBP has previously been demonstrated to be the major receptor protein in prostatic cancers for the cytostatic drug estramustine-phosphate (EMP). EMP caused a dose-dependent inhibition of exponentially growing cells by increasing the number of cells in G2/M stage of the cell cycle as monitored by flow cytofluorometry. The effect may be coupled to arrest of the glioma cells at metaphase. The presence of EMBP may suggest a selective binding and effect of EMP in glioma cells.

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

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

Relative affinities of estramustine phosphate metabolites to the cytosol oestrogen receptor of rat testis.

A competitive binding assay was used for analysis of the affinities of ethinyl oestradiol, diethylstilboestrol and metabolites of estramustine phosphate to the oestrogen receptor of rat testis. The affinities were ranked as follows: ethinyl oestradiol greater than oestradiol-17 beta greater than diethylstilboestrol much greater than estramustine. Estromustine did not reveal any oestrogen receptor affinity. The results support the concept that estramustine and estromustine do not mediate the oestrogenic effects of estramustine phosphate. The oestrogenicity of estramustine phosphate is suggested to be mainly due to the metabolite oestradiol-17 beta.

Effects of Diethylstilbestrol and Estramustine Phosphate (Estracyt) on Natural Killer Cell Activity and Tumor Susceptibility in Male Mice

The effects of estramustine phosphate (EMP) and diethylstilbestrol (DES) on natural killer (NK) cell activity, tumor growth, and artificial metastases were investigated in male C57BL/6 mice. Kinetic analysis and studies at the single-cell level indicated that EMP did not influence the number of NK cells but interfered with their lytic activity thereby reducing the actual killer capacity. NK cells from EMP-exposed animals responded normally to the interferon inducer Poly I:C which restored NK activity to control levels. Spleen cells from DES-treated animals had lytic activity comparable to that of control animals. However, more detailed analysis showed that DES reduced the number of lymphocytes able to recognize target cells, while the individual NK cell had an increased lytic activity and recycling capacity. Moreover, NK cells from DES-treated animals were refractory to poly-I:C stimulation, suggesting that they were prestimulated in vivo. The pertubations of the NK cell system induced by both EMP and DES were reversible and normalization of NK activity was reached within a week. The incidence of tumor takes after subcutaneous inoculation of the syngeneic Lewis lung carcinoma was increased in EMP as well as DES-treated animals. Artificial lung metastasis produced by intravenous injection of the same tumor was increased in EMP but not in DES-exposed animals.

Estramustine phosphate-reduced proliferation of murine and human cell lines and murine transplantable tumors.

The effect of estramustine phosphate (Estracyt) on the growth of murine aplastic mammary carcinoma, Ehrlich carcinoma, melanoma B-16, and five cell lines: L929 (mouse fibroblasts), BHK (baby hamster kidney), HeLa (human cervical carcinoma), HEp-2 (human laryngeal carcinoma), and K562 (human granulocytic leukemia) was investigated. In vivo, estramustine phosphate inhibits the growth of aplastic mammary carcinoma and Ehrlich carcinoma, but has no effect on melanoma B-16. In cultured aplastic mammary carcinoma, estramustine phosphate decreased the incorporation of 3H-thymidine into DNA. This drug inhibits the population growth of L929, BHK, HEp-2, and K562 cultures, but stimulates the growth of HeLa cells. We conclude that estramustine phosphate retards the growth of various cells, and that studies of other potential fields of application of the drug (aside from prostatic carcinoma) is justified.

Effects of diethylstilbestrol and estramustine phosphate (estracyt) on natural killer cell activity and tumor susceptibility in male mice.

The effects of estramustine phosphate (EMP) and diethylstilbestrol (DES) on natural killer (NK) cell activity, tumor growth, and artificial metastases were investigated in male C57BL/6 mice. Kinetic analysis and studies at the single-cell level indicated that EMP did not influence the number of NK cells but interfered with their lytic activity thereby reducing the actual killer capacity. NK cells from EMP-exposed animals responded normally to the interferon inducer Poly I:C which restored NK activity to control levels. Spleen cells from DES-treated animals had lytic activity comparable to that of control animals. However, more detailed analysis showed that DES reduced the number of lymphocytes able to recognize target cells, while the individual NK cell had an increased lytic activity and recycling capacity. Moreover, NK cells from DES-treated animals were refractory to poly-I:C stimulation, suggesting that they were prestimulated in vivo. The pertubations of the NK cell system induced by both EMP and DES were reversible and normalization of NK activity was reached within a week. The incidence of tumor takes after subcutaneous inoculation of the syngeneic Lewis lung carcinoma was increased in EMP as well as DES-treated animals. Artificial lung metastasis produced by intravenous injection of the same tumor was increased in EMP but not in DES-exposed animals.

Suppression of antibody response of male mice exposed to diethylstilbestrol or estramustine phosphate (estracytR)

The effects of treatment of male mice with diethylstilbestrol (DES) or estramustine phosphate (EMP) on the primary antibody response to sheep red blood cells (SRBC) and lipopolysaccharide (LPS) were investigated using a hemolytic plaque assay for enumeration of antibody-producing cells. DES treatment at a daily dose of 1.4 or 5.6 mg/kg from 2 days prior to and up to 3 days after immunization significantly reduced the number of anti-SRBC as well as anti-LPS-producing cells per 10(6) spleen cells. The 100 mg/kg EMP given as daily intraperitoneal injections significantly diminished the antibody response to both SRBC and LPS. No alteration in the number of anti-SRBC-producing cells per 10(6) spleen cells was detected in spleens from mice receiving 30 mg/kg/day EMP, while the number of anti-LPS-producing cells was reduced. The immunoregulatory effects of EMP are apparently not a pure estrogen effect, since treatment with doses of estradiol-17 beta equivalent to the amounts of estradiol linked to the cytotoxic moiety in 100 mg/kg/day of EMP were without effect. EMP-induced functional impairment in the T-cell population is inferred from the reduced ability of adoptively transferred T cells from EMP-exposed animals to support an antibody response to SRBC in syngeneic nude mice.

Effects of Diethylstilbestrol and Estramustine Phosphate (Estracyt) on Lymphoid Cell Populations and Mitogen Responsiveness in Male Mice

Concentrations of diethylstilbestrol phosphate (DES-P) and estramustine phosphate (EMP) above 10-5 M in cultures of spleen lymphocytes from adult male mice resulted in a dose related inhibition of both Con A and LPS induced lymphocyte proliferation. Male mice injected with 5.6mg./kg. DES daily for 7 days had a significantly reduced responsiveness to both Con A and LPS compared to mice injected with olive oil only. Spleen lymphocytes from male mice treated with 100mg./kg. EMP showed a reduction of Con A induced mitogenesis whereas they exhibited a significantly enhanced response to LPS. The effects of DES and EMP on Con A and LPS induced blastogenesis were abolished within 2 weeks after cessation of treatment.DES treatment resulted in preferential depletion of splenic and lymph node T lymphocytes and a disproportionate T lymphocyte subpopulation with respect to Ly subclasses. Exposure to 30 or 100mg./kg. EMP resulted in a dose related loss of mononuclear cells both in spleen and lymph nodes.T lymphocytes predominantly of the Ly 1 phenotype were most sensitive to EMP. Co-cultures of spleen lymphocytes from normal mice and Mitomycin C blocked spleen cells from either normal or treated mice (DES or EMP) gave no convincing evidence of suppressor cell activity in the population of spleen mononuclear cells.

Effects of estramustine and megestrol on ultrastructure of rat ventral prostate

The effects of estramustine phosphate on the ultrastructure of the rat ventral prostate closely resemble postcastration events, i.e., a decrease in cell size and secretory activities. The fibromuscular stroma, especially collagen fibers, appear to lose their adherence to adjoining muscle cells and fibroblasts. An infiltration of lymphocytes was noted in dilated regions of the fibromuscular stroma. There was an increase in cellular activity in the ventral prostate of rats treated with megestrol acetate with varying degrees of cellular atrophy and cytoplasmic disorganization. Squamous metaplasia was evident in one experimental group of MA-treated animals. Particles resembling mature C-type viruses were observed in several prostates from control and experimental animals.