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PubMed1991

Accumulation of estramustine and estromustine in adipose tissue of rats and humans.

The tissue distribution of estramustine and estromustine, two cytotoxic lipophilic metabolites of estramustine phosphate (Estracyt, EMP) was studied in rats and humans. A single dose of [3H]-estramustine was given i.v. to groups of rats. At 24 h after administration, the concentration of radioactivity in fat was about 20, 12, and 2 times that in muscle, plasma, and liver, respectively. Liquid chromatography verified that the radioactivity represented estramustine and estromustine. The clinical relevance of these results was investigated in pancreas cancer patients treated with a single oral dose of Estracyt at 12-16 h before surgery. As judged by gas chromatography, the concentration of estromustine, which is the main metabolite in man, was about 13 times higher in fat than in plasma and was also higher in adipose tissue than in muscle and liver. After 5 days of Estracyt treatment, the adipose uptake of estromustine was even higher, namely, about 40 times that in plasma and 8 times that in muscle and liver. Thus, our results demonstrate that estramustine and estromustine are stored in adipose tissue after the administration of EMP; this is important for the pharmacokinetics and, consequently for the therapeutic effects of Estracyt.

Adipose Tissue↗

PubMed1985

Interaction of estramustine phosphate with microtubule-associated proteins.

We have reported [(1984) Cancer Res., in press] that estramustine phosphate inhibits microtubule assembly and disassembled preformed microtubules. We now present evidence that estramustine phosphate inhibits microtubule assembly by binding to the microtubule-associated proteins. We have found that: additional microtubule-associated proteins relieved the inhibition of assembly by estramustine phosphate; 3H-labelled estramustine phosphate bound predominantly to the microtubule-associated proteins; and the content of the microtubule-associated proteins was reduced in taxol reversed estramustine phosphate-inhibited microtubules.

Alkaloids↗

PubMed1979

Relationship of prior hormonal therapy to subsequent estramustine phosphate treatment in advanced prostatic cancer.

The relationship of prior hormonal therapy to subsequent response on estramustine phosphate (Estracyt) was examined in 107 patients with advanced prostatic cancer treated in two different Phase II chemotherapy trials. In both trials patients with the longest prior hormonal treatment were the least likely to respond to estramustine phosphate. Patients in the series from the National Prostatic Cancer Project with a response classification to prior hormonal therapy had only a 26 per cent response to subsequent estramustine phosphate therapy, whereas 40 per cent of those with no prior response to hormonal therapy responded to estramustine phosphate. This latter group had the shortest average disease duration from diagnosis. The sample of prostate cancers studied appeared to include groups that were sensitive to both hormones and cytotoxic activity as well as to either of these two alone. These data support the contention that estramustine phosphate may act both as an estrogenic and a cytotoxic agent.

Aged↗

PubMed1986

A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer.

In a randomized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate (280 mg. twice daily for 8 weeks and 140 mg. twice daily thereafter) was compared to diethylstilbestrol (1 mg. 3 times daily) in patients with stages T3 to T4, M0 or M1 prostatic cancer. Of 248 patients entered 227 were evaluable for analysis: 115 received estramustine phosphate and 112 received diethylstilbestrol. The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol. There was no significant difference between treatments for response rate of metastases, interval to local progression, distant progression, over-all survival and death of carcinoma of the prostate. Duration of survival was correlated with the assessment of local response as determined by palpation. The response of distant lesions also was correlated closely with survival. Diethylstilbestrol (1 mg. 3 times daily) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate. This finding was especially obvious in patients who had no history of cardiovascular disease. Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate, including 6 in whom cessation of treatment was necessary. Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate, and to establish the best form of hormonal treatment for prostatic carcinoma.

Aged↗

PubMed1988

Estramustine binds a MAP-1-like protein to inhibit microtubule assembly in vitro and disrupt microtubule organization in DU 145 cells.

The twofold purpose of the study was (a) to determine if a MAP-1-like protein was expressed in human prostatic DU 145 cells and (b) to demonstrate whether a novel antimicrotubule drug, estramustine, binds the MAP-1-like protein to disrupt microtubules. SDS-PAGE and Western blots showed that a 330-kD protein was associated with microtubules isolated in an assembly buffer containing 10 microM taxol and 10 mM adenylylimidodiphosphate. After purification to homogeneity on an A5m agarose column, the 330-kD protein was found to promote 6 S tubulin assembly. Turbidimetric (A350), SDS-PAGE, and electron microscopic studies revealed that micromolar estramustine inhibited assembly promoted by the 330-kD protein. Similarly, estramustine inhibited binding of the 330-kD protein to 6-S microtubules independently stimulated to assemble with taxol. Immunofluorescent studies with beta-tubulin antibody (27B) and MAP-1 antibody (MI-AI) revealed that 60 microM estramustine (a) caused disassembly of MAP-1 microtubules in DU 145 cells and (b) removed MAP-1 from the surfaces of microtubules stabilized with 0.1 microM taxol. Taken together the data suggested that estramustine binds to a 330-kD MAP-1-like protein to disrupt microtubules in tumor cells.

Blotting, Western↗

PubMed1978

Autoradiographic studies of 3H-estramustine in the rat ventral prostate.

The alkylating agent 3H-estramustine was administered to castrated male rats and found to accumulate in the epithelium of the ventral prostate 5 and 20 min. following intravenous administration, as judged from autoradiography. Four hrs. after intravenous injection of this isotope, the radioactivity was recovered in the secretion of the prostatic lobuli. A preferential accumulation of radioactivity in prostatic secretion was also observed 2 hrs. after intramuscular administration of 3H-estramustine to intact or castrated rats. In contrast, 3H-oestradiol and 3H-testosterone, which were also taken up by the ventral prostatic epithelium, were not recovered in prostatic secretion. The present results indicate that 3H-estramustine is secreted from the prostatic cells into the lumina of the prostatic lobuli. It is speculated that a recently detected estramustine-binding protein in rat ventral prostate may be involved in this process and that the present finding may be of relevance in the understanding of the mechanism of action of the chemotherapeutic agent Estracyt (estramustine phosphate) used in the treatment of advanced prostatic carcinoma.

Animals↗

PubMed1989

The effect of estramustine, nor-nitrogen mustard and tauromustine on macromolecular labelling in the human prostatic tumour cell line 1013L.

To further clarify the mode of action of estramustine, the influence on macromolecular synthesis in the human prostatic tumour cell line 1013L was investigated. Cell treatment with estramustine, nor-nitrogen mustard and tauromustine, followed by radioactive nucleotide and leucine incorporations, as a measure of RNA, DNA and protein labelling, were carried out. The initial effect of estramustine clearly differed from that obtained after treatment with nor-nitrogen mustard and tauromustine. No inhibition of DNA synthesis was found whereas an inhibition of overall RNA synthesis was predominant. Adaption of an established RNA separation method was used in an indepth study of RNA labelling after estramustine treatment. An inhibition of 29S, 18S and 4-7S RNA was found after estramustine treatment, indicating disturbances in either RNA processing or RNA transport. The lack of 45S RNA labelling additionally indicates pre-ribosomal inhibition.

Affinity Labels↗

PubMed1991

Evidence that estramustine binds MAP-1A to inhibit type IV collagenase secretion.

Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. Immunofluorescence studies revealed that at 30 microM levels estramustine blocked type IV collagenase secretion by partial disruption of the MAP-1A microtubule networks. Immunoprecipitation studies with polyclonal antibodies provided quantitative evidence that 30-60 microM estramustine blocked secretion of a 105 x 10(3) Mr type IV collagenase. Pulse-labeling experiments confirmed that the effect was not a result of inhibition of either protein synthesis or altered rates of type IV collagenase turnover. Finally, drug uptake studies with [3H]estramustine, scintillation counting and fluorography demonstrated that the principal target of the drug was MAP-1A. For the first time we have shown that the drug blocks secretion by binding MAP-1A and causing incomplete disruption of the microtubule networks.

Cell Line↗

PubMed1990

A study on the effects of estradiol and estramustine on gastrointestinal cell lines.

We have studied the effect of estradiol and the combined estradiol/nitrogen mustard compound estramustine on cell lines derived from human gastric and colorectal cancers. Significant stimulation of the two gastric and two fo the colorectal cell lines occurred at physiological concentrations of estradiol. Estramustine showed an inhibitory effect in all of the cell lines at 10 micrograms/l, and a direct dose-dependent inhibition was seen in two of the cell lines. Each of the cell lines was immunohistologically stained using the estrogen-receptor-related protein ERD5, and all of the cell lines except one were positive for this protein. The inhibitory effect of estramustine was lost with increasing concentrations of estradiol, suggesting that the effects of estramustine may be linked to estrogen receptors. We conclude that reduction of circulating levels of estradiol, or treatment with estramustine may have a beneficial effect in the palliation of gastrointestinal malignancy.

Cell Division↗

PubMed1988

Estramustine-binding protein in rat and human prostate.

Estramustine phosphate, a nor-nitrogen mustard carbamate derivative of oestradiol-17 beta-phosphate, labelled with tritium in the oestradiol moiety, caused a higher concentration of radioactivity in rat prostate than did tritiated oestradiol-17 beta-phosphate or oestradiol-17 beta. Further studies in rat prostate demonstrated a protein that binds etramustine, the dephosphorylated metabolite of estramustine phosphate. The physical and chemical properties of this protein have been investigated, as has its presence in different organs of the rat and other species, including man. The finding of estramustine- binding protein in the human prostate gave rise to speculations concerning possible significance of estramustine phosphate's mechanism of action. The initial studies on estramustine-binding protein in rat and human prostate are briefly presented.

Animals↗

PubMedDate not supplied

Immunofluorescent studies of the anti-microtubule effects of the anti-cancer drug estramustine.

Immunofluorescent studies in human prostatic carcinoma cells (DU 145) and cultured squirrel fish epithelial cells (a non-cancer cell) revealed that estramustine, a conjugate of estradiol and nor-nitrogen mustard, possessed microtubule disassembly properties. Sixty microM estramustine produced disassembly at both the proximal and distal ends of microtubules, producing short pieces of less than 2 microM which were "wavy" and oriented in a random manner. With increased time of drug exposure these short microtubules disappeared, to be accompanied by a gradual disassembly of a small population of longer microtubules (greater than 7-8 microM). In dividing DU 145 cells it was possible to show a different degree of sensitivity of specific microtubule-containing cellular structures. In mitotic figures the asters were most sensitive and disappeared completely following exposure to estramustine. These were followed by the "pole-to-pole" and "chromosomal" fibers. In cytokinesis, the intercellular fibers between daughter cells were comparatively resistant to the drug. Estramustine did not induce disassembly of the vimentin filaments in non-dividing or dividing cells but did cause their collapse around the nucleus or the mitotic apparatus. These data suggest that specific microtubules have differing sensitivity to estramustine.

Cells, Cultured↗

PubMed1979

Binding characteristics of a major protein in rat ventral prostate cytosol that interacts with estramustine, a nitrogen mustard derivative of 17 beta-estradiol.

The tissue distribution of [3H]estramustine, the dephosphorylated metabolite of estramustine phosphate (Estracyt), in the male rat was compared to that of [3H]estradiol 30 min and 2 hr following i.p. administration. In contrast to estradiol, estramustine was found to be efficiently concentrated in the ventral prostate gland by a soluble protein. The binding characteristics of this protein were studied in vitro using cytosol preparations of the gland. With a dextran-coated charcoal technique, the protein was found to bind estramustine with a broad pH optimum between pH 7 and pH 8.5, with an apparent Kd of 10 to 30 nM, and with a binding capacity of about 5 nmol/mg cytosol protein. The estramustine/protein complex was not retained by DNA-cellulose. None of the natural steroids tested inhibited the binding of 10 nM [3H]estramustine by more than 35% (progesterone), even when added in 4500-fold excess. The presence of a nitrogen mustard moiety at position 3 of the steroid was necessary for high-affinity binding to the protein. The protein was calculated to constitute about 20% of the total cytosol protein content.

Animals↗

PubMed1987

Hormonal regulation of an estramustine-binding protein in the submaxillary gland of the rat.

An estramustine binding protein, in many aspects similar to the prostatic secretion protein (PSP), has partly been characterized in the submaxillary gland of the male rat. The [3H]estramustine-macromolecule complex is found in the void volume of a Sephadex G 200 column, indicating a Stokes radius larger than 52 A. The estramustine binding protein is bound to Concanavalin-A, indicating a glycoprotein structure. Like PSP, the macromolecule complex that is bound to Concanavalin-A inhibits the binding of the androgen-receptor complex to DNA-cellulose. The concentration of the protein is decreased following testectomy or estrogen treatment but can be restored to normal values following testosterone administration. These results strongly indicate that the estramustine binding macromolecule in the submaxillary gland belongs to the same group of proteins as PSP. We have earlier proposed a role for PSP as an intracellular regulator of androgen activity. Based on these new results it is tempting to speculate that androgen sensitive glycoproteins may act in the same way in all androgen sensitive tissues.

Animals↗

PubMed1979

The use of estramustine and prednimustine versus prednimustine alone in advanced metastatic prostatic cancer patients who have received prior irradiation.

Estramustine has been shown previously to be an effective drug in the treatment of metastatic prostatic cancer, demonstrating significant objective and subjective responses in long-term non-randomized trials and in other randomized trials. In this study prednimustine alone has shown a minimal over-all objective response rate of 12.9% of the cases, although with marked subjective improvement of pain relief and patient performance status. The combination of prednimustine with estramustine did not result in improvement of objective or subjective response parameters. The effects in terms of responses or in terms of toxicity for either agent were not additive when they were given in combination. Cross-over for those patients whose disease progressed on prednimustine therapy to estramustine had some benefit in over-all survival. Prednimustine alone or in combination with estramustine may be used safely and could improve markedly the quality of life for irradiated patients with advanced prostatic cancer who failed on hormonal treatment and have too poor a bone marrow reserve to be treated by other currently available myelosuppressive agents.

Chlorambucil↗

PubMed1978

Clinical experimental randomized study of 2.6-cis-diphenylhexamethylcyclotetrasiloxane and estramustine-17-phosphate in the treatment of prostatic carcinoma.

Patients with poorly differentiated prostatic carcinoma and skeletal metastases were randomized to treatment with 2.6-cis-diphenylhexamethylcyclotetrasiloxane (2.6-cis) and estramustine-17-phosphate (estramustine). Parallel with the clinical study a group of non-randomized patients were treated with 2.6-cis. Cytological regression of the tumor could be registered in half of the estramustine group but not in the 2.6-cis group. There were no drug-related changes in blood chemistry, kidney function tests, hematology or liver enzymes. There was in increase in acid and alkaline phosphatase in both groups but more pronounced in the 2.6-cis group. In both groups follicle-stimulating and luteinizing hormone values were depressed. Testicular and penis atrophy was observed in the 2.6-cis group. Relief of pain and marked improvement of conditions occurred in the majority of the cases in both groups. In general, no tumor regression was observed during administration of 300 mg. 2.6-cis daily for at least 3 months. Some tumor regression was noted during 600 mg. estramustine therapy daily.

Aged↗

PubMed1977

Hormone changes in patients with prostatic carcinoma during treatment with estramustine phosphate.

Hormone analyses of plasma were done on 9 patients with prostatic carcinoma before, during and after treatment with estramustine phosphate. In previously untreated men estramustine phosphate suppressed the plasma testosterone levels. Furthermore, suppression of increased gonadotropins was obtained in irradiated or orchiectomized patients. These hormone changes were caused by high plasma levels of estradiol and/or total estrogens during treatment, with estramustine phosphate, which were still present 2 to 3 months after discontinuation of the drug. We conclude that estramustine phosphate acts, at least partially, as an estrogen and may cause estrogen-dependent side effects.

Castration↗

PubMed1977

Estramustine phosphate: a specific chemotherapeutic agent?.

Estramustine phosphate is a nitrogen mustard derivative of estradiol that has been advocated for the treatment of prostatic cancer. The compound was designed with the hope that the estrogen moiety would direct the alkylating moiety to estrogen-dependent malignancies, where the alkylating moiety would be released specifically. Preclinical and clinical data are reviewed to determine to what extent that challenging concept is fulfilled. In addition, we have examined critically the efficacy of this drug for the treatment of prostatic cancer. From available data it appears that there is no evidence that the alkylating moiety of estramustine phosphate is specifically freed in estrogen-dependent tissues. Estramustine phosphate appears to be an active compound with acceptable toxicity in prostatic cancer. However, further clinical trials must be undertaken to clarify the future role of estramustine phosphate in the treatment of prostatic cancer.

Administration, Oral↗

PubMed1979

Purification and distribution of a major protein in rat prostate that binds estramustine, a nitrogen mustard derivative of estradiol-17 beta.

A protein in rat ventral prostate cytosol that binds estramustine [estradiol 3-bis(2-chloroethyl)carbamate) was purified to homogeneity by using chromatography on DEAE-cellulose, Sephadex G-100 (superfine), octyl-Sepharose (CL-4B, and polyacrylamide gel electrophoresis. The estramustine-binding protein was found to have a Mr of 46,000 as estimated by gel filtration. After analysis by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate, the protein was found to consist of two subunits with Mr of about 20,000 and 18,000. After reduction of disulfide bridges, the protein was decomposed into three components with Mr of about 12,000, 11,000, and 8000. Amino acid analysis indicated that the protein is a glycoprotein. Antibodies against the protein were raised in rabbits and a radioimmunoassay was developed for it. The estramustine-binding protein constituted about 18% of the total protein in rat ventral prostate cytosol, was present in the dorsal and lateral lobes of the prostate, and was also detected in the pituitary gland, cerebral cortex, submaxillary gland, thyroid gland, adrenal gland, seminal vesicle, coagulating gland, epididymis, and preputial gland of the male rat. In female rats the protein was detected in cerebral cortex. Because the estramustine-binding protein is predominantly found in the accessory sexual glands of the male rat, it may be of importance for maintaining male fertility.

Amino Acids↗