Prostate cancer remains a medical dilemma and a major cause of morbidity and mortality in many western countries. It represents the most common cancer in US men, with an estimated 192 280 new cases diagnosed in 2009. The median survival for men with metastatic castrate-resistant prostate cancer is 1-2 years, with improvements in survival seen primarily with docetaxel-based therapies. The purpose of this article is to discuss developments of novel agents in the field of metastatic castration-resistant prostate cancer (CRPC), including new cytotoxic agents, immune-based therapies, circulating tumor markers and targeting agents.
During this past year, several promising approaches yielded disappointing results in the phase III setting (GVAX); nonetheless, expectations for other agents (Abiraterone, MDV3100, Zibotentan, immunotherapy agents) still remain high.
Systemic therapy options are limited in CRPC and survival benefit remains to be seen with the new therapies. Circulating tumor cells continue to provide important prognostic information and will likely become an important aspect of future clinical decision-making.
"This therapy includes surgical or chemical castration, achieved by: administration of gonadotropin-releasing hormone (GnRH) analogs; blocking of the binding of androgens to their receptor by antiandrogens; inhibition of steroidogenic enzymes. Unfortunately, despite an excellent initial response, in approximately 2 to 3 years, most prostate cancers will progress to castration-resistant prostate cancer (CRPC) stage with increased proliferation and malignancy , . For CRPC patients, taxane-based chemotherapy represents the treatment of choice , . "
[Show abstract][Hide abstract] ABSTRACT: Gonadotropin-releasing hormone (GnRH) receptors are expressed in prostate cancer, specifically in the most aggressive stage of the tumor (castration-resistant prostate cancer, CRPC) for which the standard treatment, docetaxel-based chemotherapy, can only improve the median survival time by few months. We previously showed that GnRH agonists exert an antitumor activity in CRPC cells; however, a link between GnRH receptors and the apoptotic machinery remains to be defined. Aim of this study was to evaluate whether, in CRPC cells, GnRH agonists might affect the expression/activity of apoptosis-related proteins and might sensitize, or resensitize, cancer cells to chemotherapeutics. We demonstrated that, in p53-positive DU145 cells, GnRH agonists: a) increase the expression of the proapoptotic protein Bax; this effect is mediated by the phosphorylation (activation) of p53, triggered by the p38 MAPK; b) potentiate the antiproliferative/proapoptotic activity of docetaxel; c) resensitize docetaxel-resistant cells to the antitumor activity of the cytotoxic drug. These data indicate that GnRH agonists sensitize and, more importantly, resensitize DU145 CRPC cells to chemotherapy in a p53-dependent manner. To confirm the crucial role of p53 in the activity of GnRH agonists, experiments were performed in p53-null PC3 cells. We found that GnRH agonists fail to increase Bax expression and do not potentiate the cytotoxic activity of docetaxel. These results may provide a rationale for novel combination treatment strategies, especially for docetaxel-resistant CRPC patients expressing a functional p53 protein.
PLoS ONE 04/2014; 9(4):e93713. DOI:10.1371/journal.pone.0093713 · 3.23 Impact Factor
"Although the effects of several anticancer drugs for prostate cancer have been evaluated in vitro and in animal experiments in vivo, most have little or no impact on the survival of patients with CRPC or metastatic prostate cancer.4,5 Docetaxel (DTX), a semisynthetic toxoid produced from the needles of the European yew tree, is the first chemotherapy agent to improve survival in CRPC, and the US Food and Drug Administration has recommended a 3-week DTX-prednisone regimen as a first-line treatment option for CRPC patients.6–8 "
[Show abstract][Hide abstract] ABSTRACT: Docetaxel (DTX) is one of the most important anticancer drugs; however, the severity of its adverse effects detracts from its practical use in the clinic. Magnetic nanoparticles of Fe3O4 (MgNPs-Fe3O4) can enhance the delivery and efficacy of anticancer drugs. We investigated the effects of MgNPs-Fe3O4 or DTX alone, and in combination with prostate cancer cell growth in vitro, as well as with the mechanism underlying the cytotoxic effects. MgNPs-Fe3O4 caused dose-dependent increases in reactive oxygen species levels in DU145, PC-3, and LNCaP cells; 8-hydroxydeoxyguanosine levels were also elevated. MgNPs-Fe3O4 alone reduced the viability of LNCaP and PC-3 cells; however, MgNPs-Fe3O4 enhanced the cytotoxic effect of a low dose of DTX in all three cell lines. MgNPs-Fe3O4 also augmented the percentage of DU145 cells undergoing apoptosis following treatment with low dose DTX. Expression of nuclear transcription factor κB in DU145 was not affected by MgNPs-Fe3O4 or DTX alone; however, combined treatment suppressed nuclear transcription factor κB expression. These findings offer the possibility that MgNPs-Fe3O4-low dose DTX combination therapy may be effective in treating prostate cancer with limited adverse effects.
International Journal of Nanomedicine 08/2013; 8:3151-60. DOI:10.2147/IJN.S40766 · 4.38 Impact Factor
"Moreover, whereas the synthesis of paclitaxel relies on 10-deacetylbaccatin III which is available from the needles of various Taxus species (Cragg et al., 2009), total synthesis of patupilone B has been accomplished (Su et al., 1997). The progress of epothilones in the PC setting has been extensively reviewed (Lee & Kelly, 2009, Lassi & Dawson, 2010, Cheng et al., 2008, Bystricky & Chau, 2011). Patupilone inhibits the proliferation of DU145 and TSU-Pr1 PC cells in the low nanomolar range causing mitotic arrest (Sepp-Lorenzino et al., 1999). "
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