Taxanes remain the only agents to extend survival in castration-resistant metastatic prostate cancer, but their impact on the natural history of this disease is modest. We sought to test the hypothesis that increased delivery of taxane chemotherapy to the tumor through the use of a macromolecular polymer-drug conjugate of paclitaxel modulated by estradiol could extend the utility of this class of drugs. Patients with metastatic adenocarcinoma of the prostate who progressed despite standard hormonal therapy and after docetaxel-containing chemotherapy were treated with transdermal estradiol (0.2 mg/24 h) for 4 weeks followed by the same dose of transdermal estradiol and paclitaxel poliglumex (PPX; 150 mg/m intravenous) every 28 days. The primary objective was to determine the level of activity of the regimen measured using a fraction of patients who experienced a confirmed decline in serum prostate-specific antigen (PSA) of 50% or more. A two-stage phase II study designed to identify a response rate of > or =25% required three responders among 21 patients in the first stage. Twenty-one patients who received a median of two earlier chemotherapy regimens were enrolled in the trial between March 2007 and May 2008. During the estradiol-only treatment phase, no patient had a PSA decline in excess of 50% and lesser PSA declines that ranged from 8.8 to 34.1% were seen in five patients. No patients achieved a > or =50% PSA decline following the addition of PPX and there were no responses in measurable disease. The median time to progression was 4 weeks. In conclusion, this regimen of low-dose transdermal estradiol induction followed by PPX does not have activity in taxane pretreated patients with castration-resistant prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(L-g-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.
[Show abstract][Hide abstract] ABSTRACT: The standard treatment for patients with castration-refractory prostate cancer (CRPC) is the combination docetaxel-prednisone, if the patient can support chemotherapy. Several new treatments have been tested in chemotherapy-naïve or docetaxel-pretreated patients with CRPC. Some of these treatments have shown activity in first-line and second-line treatment. In this review, an update is given of new treatment studies performed in patients with CRPC.
Advances in Therapy 05/2010; 27(5):285-96. DOI:10.1007/s12325-010-0038-1 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Taxanes have received considerable attention owing to their significant activity against a variety of tumors. Nevertheless, many different approaches have been developed to improve their safety profile and water solubility, in terms of both dosing schedules and delivery strategies.
Among the different taxane delivery systems, macromolecule conjugates have been widely explored; this review collects and summarizes such systems from reports after 1990. Natural and synthetic polymers, proteins and polysaccharides have been covalently coupled with taxanes; immunoconjugates have also been developed for targeted delivery. In-depth descriptions, from synthesis to preclinical or clinical data, are given.
The choice of macromolecule, the spacer, the chemistry of the linkage with taxane, as well as other cytotoxic drugs, are key points to obtain effective conjugates with higher activity than that of the free drug, reducing side effects. Critical evaluation of the different approaches may help in comprehending and comparing the results and may elucidate the role of individual components.
Taxane covalently-bound to macromolecules shows advanced properties, and although only one compound is in advanced clinical trials, this area deserves attention and seems a promising route to achieve effective new anticancer compounds.
Expert Opinion on Drug Delivery 01/2011; 8(1):33-55. DOI:10.1517/17425247.2011.541437 · 4.84 Impact Factor
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