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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Estramustine (EstracytTM), also known as EMP in the phosphate form, is a chemical conjugate of an estrogen (i.e., 17-β-estradiol) and a nitrogen mustard (i.e., nor-mechlorethamine) linked through a carbamate moiety (Figure 5.23). It was first synthesized in the early 1960s and patented in 1967, although not introduced into clinical practice until 1976. Estramustine, which is administered orally, is approved by the FDA for the palliative treatment of metastatic and/or progressive prostate cancer. Structures of estramustine (EstracytTM) and the related naturally occurring steroid hormones estradiol and estrone.
Prostate cancer: metastatic
Published in J Kellogg Parsons, E James Wright, The Brady Urology Manual, 2019
Estramustine: A conjugate of estradiol and nitrogen mustardDisrupts microtubule function.
Complications of Chemotherapy for Urologic Cancer
Published in Kevin R. Loughlin, Complications of Urologic Surgery and Practice, 2007
Elisabeth M. Battinelli, Marc B. Garnick
These chemotherapeutic agents however, are also associated with numerous toxicities. Docetaxel is derived from the needles of the European yew tree. Its mechanism of action is ignition of microtubules by enhanced tubulin polymerization leading to inhibition of micro-tubules. It is metabolized by the P450 system in the liver. Docetaxel is associated with a number of toxicities including gastrointestinal disturbance (40%), myelosuppression, alopecia (80%), fluid retention (50%), mucositis, and peripheral neuropathy. Treatment-related deaths have been estimated at 0.3% to 2.4% (59,60). The main risk appears to be due to the vascular complications that were elucidated above. Studies have been carried out to try to decrease the overall risk of thromboembolic events, thereby decreasing the risk of potential death of the patient by anticoagulation. Use of aspirin or low-dose anticoagulation has been suggested for prophylaxis while on an estramustine regimen, however, this has not been tested in a randomized clinical trial to date (60).
Issues and promises of bevacizumab in prostate cancer treatment
Published in Expert Opinion on Biological Therapy, 2018
Vittore Cereda, Vincenzo Formica, Mario Roselli
A larger phase II clinical trial (CALGB 90006) evaluated the efficacy of a triplet combination, including 15 mg/kg of bevacizumab and 70 mg/m2 of docetaxel both every 3 weeks plus 840 mg daily of estramustine (a non-nitrogen mustard linked to estradiol) on day 1 through day 5. Seventy-seven chemotherapy-naive mCRPC patients were enrolled [35]. Estramustine was previously shown to synergistically enhance the microtubule stabilization effects of docetaxel in prostate cancer cells [36]. In this trial, median age of patients was 69 years, 80% of them had bone metastases and 19% had visceral disease. The study reported 75% of major PSA declines, 59% of partial responses, and a median OS of 24 months, which compared favorably with the results observed in major docetaxel-based first-line trials (e.g. 19.2 months in the TAX 327 trial) [37,38]. Median PFS was 8 months and did not meet the specified study end point of 11 months. Grade 3 neutropenia was observed in 69% of patients, and was two- to threefold higher than that reported in the pivotal phase III studies with docetaxel in mCRPC [37,38].
Neoadjuvant and adjuvant treatment in high-risk prostate cancer
Published in Expert Review of Clinical Pharmacology, 2018
Marco Bandini, Nicola Fossati, Giorgio Gandaglia, Felix Preisser, Paolo Dell’Oglio, Emanuele Zaffuto, Armando Stabile, Andrea Gallina, Nazareno Suardi, Shahrokh F. Shariat, Francesco Montorsi, Pierre I. Karakiewicz, Alberto Briganti
Similar to ADT, also neoadjuvant CHT was tested in HRPCa before RT. Here, only one phase III study (GETUG-12) reported its results [49,50]. Fizazi et al. [49,50] enrolled 413 patients with newly diagnosed PCa, who were previously staged with pelvic lymph node dissection and exhibited at least one clinical risk factor between cT3–T4 stages, GS ≥8, PSA >20 ng/mL, or pN1 disease. Overall, patients were randomly assigned (1:1) to ADT (goserelin 10.8 mg for 3 years) plus docetaxel 70 mg/m2 and estramustine 10 mg/kg vs. ADT alone. ADT plus docetaxel and estramustine patients exhibited higher 8-year BCR-free survival (62 vs. 50%) than patients treated with ADT alone (p = 0.017). Thirty-one (15%) patients in the ADT plus docetaxel and estramustine group developed metastases compared with 41 (20%) in the ADT only group. Forty-two (20%) patients in the ADT plus docetaxel and estramustine group died vs. 49 (24%) patients in the ADT only group. The 8-year OS was 83% for both groups. The docetaxel and estramustine regimen was generally well tolerated, as well as no treatment-related deaths were recorded. The investigators did not report differences on treatment-related toxicity and second cancer development between the two groups. They concluded that adding docetaxel and estramustine to neoadjuvant ADT significantly improved recurrence-free survival compared to ADT alone in patients with HRPCa (stage T3–T4 disease, GS ≥8, PSA >20 ng/mL, or pN1 disease), with no apparent long-term toxicity related to CHT.
Promising immunotherapy for prostate cancer
Published in Expert Opinion on Biological Therapy, 2018
John C. Henegan, Guru Sonpavde
Personalized peptide vaccines are typically designed by testing for peptide-specific immunoglobulin G (IgG) to multiple vaccine candidate peptides [41]. After an early trial demonstrated both immune and biochemical activity of a personalized peptide vaccine in prostate cancer [17], a phase I study was conducted in men with mCRPC with radiographic or PSA progression. In this study, men were treated with daily estramustine along with six weekly, personalized vaccinations of the four peptides with the strongest antibody responses. At the maximum tolerated dose, four of six patients had an increased IgG response to at least one peptide, all six patients had an increased cytotoxic T lymphocyte response, and one patient had a PSA complete response. A subsequent phase II study of 100 men with progressive mCRPC involved administration of a personalized peptide vaccine using 2–4 peptides selected from 31 candidate peptides [42]. In all, 49% of patients exhibited some decrease in PSA from baseline, with 22% having a ≥50% PSA decline at any one time. A ≥50% PSA decline or a doubling of the PSA doubling time was each associated with significantly longer survival [43]. Total IgG responses to the vaccinated peptide and cytotoxic T cell responses were augmented in 43% of patients by the final vaccination. In a multivariate analysis, positive IgG response was a significantly associated with an improvement in OS.