Preclinical and clinical perspectives on the use of estramustine as an antimitotic drug

doi:10.1016/0163-7258(92)90023-S

Pharmacology & Therapeutics

Volume 56, Issue 3, 1992, Pages 323-339

https://doi.org/10.1016/0163-7258(92)90023-S Get rights and content

Abstract

A variety of cell biological, pharmacological, crystallographic and clinical approaches have indicated that the antimitotic drug estramustine has interesting and unusual properties. Although designed as an alkylating agent, the marked stability of the carbamate linkage to the steroid carrier molecule prevents the formation of alkylating intermediates. The affinity of the parent molecule for microtubule associated proteins and the concomitant antimicrotube activity have cytotoxic consequences in tumor cells. Both preclinical and clinical studies of estramustine in combination with other antimicrotubule agents have shown that this approach has great potential to achieve therapeutic advantage, especially in disease states such as hormone refractory prostate cancer.

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Cited by (37)

Ablation of the ATP-binding cassette transporter, Abca2 modifies response to estrogen-based therapies
2012, Biomedicine and Pharmacotherapy
Citation Excerpt :
No significant changes were observed in apoptotic indices at this dose of EMP. Other non-life threatening side effects of EMP, including mild hematologic toxicity and flushing are attributable to release of the metabolites, estrone and estradiol [26,27]. While previous reports have linked ABCA2 transport properties with lipids, cholesterol and steroids, it remains unknown whether EMP is a specific substrate for transport.
The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein expressed in oligodendrocytes and Schwann cells, prostate, ovary and macrophages. In cell cultures, ABCA2 over-expression has been linked with resistance to the anticancer agent, estramustine phosphate (EMP; a nor-nitrogen mustard conjugate of estradiol). The present study shows that Abca2 knockout (KO) mice have greater sensitivity to a variety of side effects induced by EMP treatment. Chronic EMP (12 × 100 mg/kg body weight) produced mortality in 36% of KO mice, but only 7% of age-matched wild type (WT). Side effects of the drug were also more prevalent in the KO mouse. For example, during the first week of EMP treatments, 67% of KO males (compared to 6% of WT males) responded with episodic erectile events. In WT mice, ABCA2 protein localized within pene corpuscles, (which rely on modified Schwann cells for amplification of tactile signals) suggesting that the transporter may function in the erectile process. Endothelial nitric oxide synthase (eNOS; a source of nitric oxide during erectile response) levels were similar in WT and KO male penile tissue. Treatment with 100 mg/kg EMP (once daily for four days) elevated serum estradiol and estrone in both WT and KO. However, the circulating levels of these estrogens were higher in KO mice implying a reduced plasma clearance of estrogens as a consequence of ABCA2 ablation. Consistent with the pro-convulsant effects of estrogens, KO mice also displayed an increased incidence of seizures following EMP (14% vs. 0%). Taken together, these data indicate that ABCA2 deficiency renders mice more sensitive to EMP treatment-induced effects implying that the transporter has a role in regulating EMP transport and/or metabolism.
Chemotherapy of hormonorefractory and hormonoresistant metastatic prostate cancer
2008, Progres en Urologie
Depuis 2004 et les premières études montrant des résultats significatifs en terme de survie globale grâce au docétaxel, le traitement de l’adénocarcinome prostatique en échappement hormonal (HRPC) a fait l’objet de nombreux essais de phase II et III. En l’absence d’amélioration de la survie, les manipulations hormonales (retrait d’anti-androgène, diethylstilbesterol, dexaméthasone) sont à réserver aux patients avec rising-PSA sans métastase clinique ni radiologique. En première ligne, le traitement de référence est le docétaxel à la dose de 75 mg/m² toutes les 3 semaines en association avec la prednisone (5 mg × 2/j). Les chimiothérapies de seconde ligne (mitoxantrone, ixabepilone, retraitement par docétaxel, vinorelbine, doxorubicine…) n’ont montré que de modestes résultats sur la survie sans progression sans résultat sur la survie globale. L’interruption prématurée de l’essai de phase III du Satraplatin n’a pas permis de conclure sur l’utilité de ce sel de platine.
Les thérapies ciblées anti-angiogéniques ont montré des résultats encourageants en cas de métastases avérées dans des essais de phase II, mais soulignent la nécessité de mieux définir les patients répondeurs grâce à des marqueurs spécifiques (surexpression mTOR ou EGFR, etc.) et de développer d’autres marqueurs d’efficacité que le PSA. Le bevacizumab fait l’objet d’un essai de phase III en association avec le docétaxel avec un objectif de survie globale. Dans un essai de phase III, le vaccin Provenge a montré un gain de quelques mois de survie globale, tout comme le DN 101 (Calcitriol). L’utilisation d’oligonucléotides antisens fait l’objet d’un essai de phase II de l’EORTC. Enfin, la question du moment de l’introduction de la chimiothérapie reste ouverte : le traitement de l’adénocarcinome prostatique en échappement hormonal commence-t-il avant le stade de l’hormonorésistance ? Telle est la question à laquelle le GETUG 15 tentera de répondre prochainement.
Since 2004 and the first improvement in overall survival in hormone refractory prostate cancer patients (HRPC) brought about by docetaxel, numerous phase II and III studies have been initiated. Considering the lack of efficacy in terms of overall survival, hormonal manipulations such as antiandrogen withdrawal, di-ethylstilbesterol or dexamethason are only indicated in “rising PSA” patients without clinical or radiological evidence of metastases. As first line treatment, the optimal chemotherapy regimen is docetaxel (75mg/m² every 3 weeks) in association with prednisone (5mg twice daily). Second line chemotherapies (mitoxantron, ixabepilon, docetaxel as a re-treatment, vinorelbin, doxorubicin…) provide modest results only in terms of progression-free survival. A phase III study of Straplatin has been prematurely interrupted.
Targeted anti-angiogenic therapies have shown encouraging results in patients with metastatic localizations, and underline the need to identify target patients early through cellular markers (mTOR or EGFR overexpression) as well as the uselessness of PSA dosage to monitor efficacy. An ongoing phase III study is evaluating bevacizumab in association with docetaxel to improve overall survival. Both the Provenge vaccine and DN 101 (calcitriol) showed a survival gain of a few months in phase III studies. An ongoing EORTC phase II trial is evaluating antisense oligonucleotids in HRPC. Early introduction of docetaxel raises the issue of when to start chemotherapy as it may be relevant to initiate this treatment before the onset of hormone independence. GETUG 15 trial will try to answer this question.
Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data
2007, Lancet Oncology
Citation Excerpt :
Estramustine phosphate is a nornitrogen mustard-oestradiol conjugate that has been shown to have hormonal and non-hormonal effects in vivo.6 Estramustine mainly inhibits microtubule function by binding to both tubulin7–9 and microtubule-associated proteins.10 In human beings, estramustine has little antitumour activity as a single drug in the treatment of patients with castration-refractory prostate cancer with responses reported in 20% of patients.11
Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer.
We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used.
The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2·8 years (range 0·0–3·4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0·0001), use of chemotherapy plus estramustine (p=0·008), performance status (p=0·002), and serum PSA concentrations (p=0·04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0·77 [95% CI 0·63–0·93], p=0·008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9·5% (SE 4·0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0·53 [0·38–0·72], p<0·0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0·74 [0·58–0·94], p=0·01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275).
In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.
Changing Perspectives of the Role of Chemotherapy in Advanced Prostate Cancer
2006, Urologic Clinics of North America
Citation Excerpt :
Estramustine is a synthetic conjugate of estradiol and a nitrogen mustard that was rigorously studied in the NPCP trials and found to have modest activity [4,27]. Although the drug was designed to target delivery of the mustard conjugate to malignant cells that overexpressed sex hormone receptors, estramustine acts through binding microtubule-associated proteins and inducing microtubule destabilization [27,28]. Preclinical studies suggest that combination of estramustine with other antimicrotubule agents could potentiate a cytotoxic effect in vivo [29,30].
The current role of chemotherapy in metastatic hormone-refractory prostate cancer
2005, Urology
Since the publication of the Southwest Oncology Group (SWOG) 99-16 and TAX 327 studies, which demonstrated a survival benefit for docetaxel-based therapy, clinicians for the first time have a therapy to offer men with metastatic prostate cancer that is not merely palliative in its effects. Phase 2 and phase 3 trials are now building on the findings of SWOG 99-16 and TAX 327 by evaluating the potential of combination taxane-based therapies, such as docetaxel plus high-dose calcitriol, docetaxel-estramustine-bevacizumab, and docetaxel-thalidomide. The optimal timing of docetaxel-based chemotherapy is still unknown, as there are no prospective clinical trial data to indicate whether earlier treatment (eg, at the time of prostate-specific antigen failure) is more or less effective than later treatment (eg, in metastatic and/or symptomatic disease).
Gene expression profiling reveals novel targets of estramustine phosphate in prostate cancer cells
2004, Cancer Letters
Estramustine phosphate (EMP) is a compound widely used for the treatment of hormone-refractory prostate cancer. In order to better understand the precise molecular mechanism(s) by which EMP exerts its effects on hormone-resistant PC3 prostate cancer cells, we have utilized microarray to interrogate 22,215 known genes to determine the gene expression profiles altered by EMP treatment. The purpose of this investigation was to identify gene expression profile first and then in future studies determine the specific role of these genes in EMP-induced apoptosis in prostate cancer cells. We found a total of 726 genes which showed >2 fold change after EMP treatment. Clustering analysis showed 12 different types of expression alteration. These genes were also subjected to cluster analysis according to their biological functions. We found that EMP regulated the expression of genes, which are critically involved in the regulation of cell growth, cell cycle, apoptosis, iron homeostasis, cytoskeleton and cell signaling transduction. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to confirm the results of microarray, and the results of real-time quantitative RT-PCR were consistent with the microarray data. From these results, we conclude that EMP caused changes in the expression of a large number of genes that are related to the control of cell survival and physiological behaviors. The gene expression profiles may provide comprehensive molecular mechanism(s) by which EMP exerts its pleiotropic effects on prostate cancer cells. EMP-induced regulation of these genes may be further exploited for devising therapeutic strategies for prostate cancer.

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Preclinical and clinical perspectives on the use of estramustine as an antimitotic drug

Abstract

J. biol. Chem.

Arch. Biochem. Biophys.

Urology

Mutat. Res.

Biochem. Pharmac.

Pharmac. Ther.

Mutat. Res.

J. Urol.

Urology

Fed. Eur. Biochem. Soc. Lett.

Preliminary results of Phase II trial of estramustine and vinblastine for patients with progressive hormone refractory prostate carcinoma

Estramustine phosphate therapy in carcinoma of the prostate

Structure-activity studies with chiral isomers and with segments of the antimitotic marine peptide dolastatin 10

Biochem. Pharmac.

Estramustine phosphate compared with diethylstilbestrol

Am. J. clin. Oncol.

The Origin of Malignant Tumors

P-glycoprotein expression in multidrug-resistant human ovarian carcinoma cell lines

Cancer Res.

Cold labile and cold stable microtubules in the mitotic spindle of mammalian cells

Ann. NY Acad. Sci.

A phase I trial of taxol given by a 6-hour intravenous infusion

J. clin. Oncol.

Vinblastine and microtubules. I. Induction and isolation of crystals from sea urchin oocytes

Exp. Cell Res.

Mechanisms by which mammalian cells acquire resistance to drugs that affect microtubule assembly

FASEB J.

Molecular Cell Biology, Part III

Microtubule-associated protein (MAP) 1A: a phosphoprotein associated with spindle fibers and microtubule organizing centers

Continuous infusion of vinblastine for advanced hormone-refractory prostate cancer

Cancer Treat. Rep.

Phosphorylation of microtubule proteins in rat brain at different developmental stages: comparison with that found in neuronal cultures

J. Neurochem.

A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma

J. clin. Oncol.

Evidence for an nonestrogenic cytostatic effect of estramustine on human prostatic carcinoma cells in in vivo

Prostate

Certain steroid N-bis-(halo-ethyl)-carbamates

Pharmacokinetics of estramustine phosphate (Estracyt) in prostatic cancer patients

Eur. J. clin. Pharmac.

Impairment of estramustine phosphate absorption by concurrent milk and food

Eur. J. clin. Pharmac.

Cross-resistance of nocodazole-resistant mutants of CHO cells toward other microtubule inhibitors: similar mode of action of benzimidazole carbamate derivatives and NSC 181928 and TN-16

Molec. Pharmac.

Estramustine-induced mitotic arrest in two human prostatic carcinoma cell lines DÚ145 and PC-13

Prostate

Nuclear protein matrix as a target for estramustine-induced cell death

Prostate

Cytotoxicity and metabolism of prednimustine, chlorambucil and prednisolone in a Chinese hamster cell line

Cancer Chemother. Pharmac.

Multipolar mitotic cells in the human cell line NH1K 3025 following treatment with the mitotic inhibitor NY 4137

Invest. New Drugs

Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone refractory prostate cancer

J. clin. Oncol.

Cell division and the mitotic spindle

J. Cell Biol.

Mechanism of inhibition of cell proliferation by vinca alkaloids

Cancer Res.