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Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy., (Copyright © 2011 S. Karger AG, Basel.)

Caffeine has been widely described as a chemo/radiosensitizing agent, presumably by inhibiting DNA repair, and affecting preferentially cells with an altered p53 status. We evaluated the effects of caffeine using isogenic and isophenotypic K1 cells derived from a papillary thyroid carcinoma and displaying either a wild type or a mutated p53 status. Apoptosis and clonogenic survival were examined after exposure of the cells to cisplatin or UVc irradiation. We find that at the most currently used concentration, 2mM, caffeine hinders cisplatin or UVc induced apoptosis in K1 cells. In addition, at this already barely achievable concentration in vivo, caffeine does not decrease their clonogenic survival. Hence in our cellular model, caffeine does not behave as a chemo- or a radiosensitizer. Although surprising, these results (1) are in agreement with the delayed G2/M block caused by caffeine that we previously observed in normal human fibroblasts and K1 cells and (2) allow us to elucidate some discrepancies concerning this molecule throughout the literature such as increase or decrease of apoptosis and clonogenic survival, activation or deactivation of molecules involved in DNA damage repair and proliferation inhibition but accelerated G2/M traverse.

Aim: p53 is the most frequently altered gene in human cancer. It was expected to be the principle marker for chemo/radiosensitivity, resistance, tumor recurrence and ultimate survival, but is no longer considered a universal prognostic factor. Different alterations in the p53 gene have led to conflicting results depending on cell/tissue specificities and on radiation and drug specificities., Methods: We evaluated the properties of isogenic and isophenotypic cell lines from the K1 papillary thyroid carcinoma in which p53 function was disrupted either by mutation (expression of dominant-negative p53, 143(ala)) or by inactivation (expression of human papilloma virus protein HPV16 E6). Their proliferation, their propensity to trigger apoptosis and their survival were analyzed after treatment with cisplatin (CDDP)., Results: Only K1 lines with wild-type p53 had significantly accumulated apoptotic bodies 72 h after treatment. Despite their incapacity to trigger apoptosis in response to CDDP treatment, the survival of K1 cell lines in which p53 expression was altered was not significantly different from the survival of K1 cell lines expressing wild-type p53. In addition, the order of magnitude of resistance of K1 cells in which p53 was mutated was similar to that in which p53 was totally inactivated, although the pathways involved may be different., Conclusions: These results show that the means by which p53 expression is disrupted and the consequence on downstream pathways regulated by p53 deserve to be considered in order to elucidate some apparently conflicting responses of this gene.

p53 mutations are found in about 70% of human cancers. In order to evaluate the role of these mutations in response to chemotherapeutic agents, it is important to distinguish between p53 response to DNA-damaging agents in normal and in tumour cells. Here, using normal human fibroblasts (NHFs), we show that cisplatin and UV radiation induce G2/M arrest which is temporally linked to p53-protein induction. To study the contribution of p53 to this G2/M arrest, we inhibited p53 induction in NHFs using p53 anti-sense oligonucleotides. Following exposure of NHFs to UV radiation, the inhibition of p53-protein induction leads to a greater accumulation of cells in the G2/M phase, but also to a decreased fraction of cells in the G1 phase. We propose that p53 does not induce G2/M arrest directly, and that the extent of this arrest may depend on the fraction of cells that do not stop at the G1 phase following exposure to DNA-damaging agents. Furthermore, inhibition of p53-protein induction leads to increased sensitivity of NHFs to UV radiation. These results suggest that inhibition of p53 protein enhances sensitivity to DNA-damaging agents in normal human cells.