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    ABSTRACT: Chondrosarcomas are malignant cartilage tumours. They are poorly responsive to chemotherapy and radiotherapy. Treatment is usually limited to surgical resection; however, survival of patients with high-grade chondrosarcoma is poor, even with wide surgical resection. Induction of apoptosis in chondrosarcoma cells, either directly or by enhancement of the response to chemotherapeutic drugs and radiation, may be a route by which outcome can be improved. In this article, we review potential molecular targets that regulate chondrocyte apoptosis and discuss the experimental evidence for their utility.
    Full-text · Article · Oct 2010 · International Journal of Experimental Pathology
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    ABSTRACT: Prostate cancer cells can exist in a hypoxic microenvironment, causing radioresistance. Nitric oxide (NO) is a radiosensitiser of mammalian cells. NO-NSAIDs are a potential means of delivering NO to prostate cancer cells. This study aimed to determine the effect and mechanism of action of NO-sulindac and radiation, on prostate cancer cells and stroma, under normoxia (21% oxygen) and chronic hypoxia (0.2% oxygen). Using clonogenic assays, at a surviving fraction of 10% the sensitisation enhancement ratios of radiation plus NO-sulindac over radiation alone on PC-3 cells were 1.22 and 1.42 under normoxia and hypoxia, respectively. 3D culture of PC-3 cells revealed significantly reduced sphere diameter in irradiated spheres treated with NO-sulindac. Neither NO-sulindac nor sulindac radiosensitised prostate stromal cells under normoxia or hypoxia. HIF-1α protein levels were reduced by NO-sulindac exposure and radiation at 21 and 0.2% oxygen. Alkaline Comet assay analysis suggested an increased rate of single strand DNA breaks and slower repair of these lesions in PC-3 cells treated with NO-sulindac prior to irradiation. There was a higher level of γ-H2AX production and hence double strand DNA breaks following irradiation of NO-sulindac treated PC-3 cells. At all radiation doses and oxygen levels tested, treatment of 2D and 3D cultures of PC-3 cells with NO-sulindac prior to irradiation radiosensitised PC-3, with minimal effect on stromal cells. Hypoxia response inhibition and increased DNA double strand breaks are potential mechanisms of action. Neoadjuvent and concurrent use of NO-NSAIDs have the potential to improve radiotherapy treatment of prostate cancer under normoxia and hypoxia.
    Full-text · Article · Sep 2010 · Biochemical pharmacology
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    ABSTRACT: ContextMedical therapies derived from natural sources have been used for centuries. Many are as effective as synthetic medications. The use of plant-derived medications for benign prostatic hyperplasia (BPH) is no exception. In particular, extracts of Serenoa repens (SrE), the fruit of the American dwarf palm, are widely available, and their use is rising throughout the world.ObjectiveThe underlying basis for SrE popularity stems from its safety and tolerability profile. However, despite its extensive use, its mechanism of action has not been definitely clarified. In this paper, we analyse the scientific basis for SrE efficacy in the treatment of BPH and explore the mechanisms by which its effects are induced.Evidence acquisitionThis literature review focuses on the actions of the lipidosterolic SrE on a host of targets. Several cellular and molecular techniques have been used to characterise the biologic pathways that may mediate these actions. Morphologic studies have been carried out to identify the changes of prostate ultrastructure and to determine modifications that may shed light on the mechanisms underlying SrE efficacy.Evidence synthesisSelectivity of the action of SrE for the prostate has been demonstrated. There are several morphologic changes, and these are accompanied by an increase in the apoptotic index of the gland, along with inhibition of the activity of the 5α-reductase isoenzymes. The drug also acts on a number of other biologic systems and shows a capacity to moderate the androgenic, apoptotic, and inflammatory pathways of the cell. These pathways have been implicated in the hyperplastic process.ConclusionsThe interaction between prostate cells and SrE is manifest at several levels of the gland's biological spectrum and results in antiandrogenic, anti-inflammatory, and proapoptotic effects. These effects may account for the beneficial response triggered in some patients with BPH treated with SrE.
    Full-text · Article · Dec 2009 · European Urology Supplements
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