Drug resistance is a significant challenge of daily oncology practice. Docetaxel and gossypol both have antitumoral activity in hormone-refractory prostate cancer (HRPC). Our results revealed that docetaxel and gossypol were synergistically cytotoxic and apoptotic in PC-3 cells in a dose- and time-dependent manner. We further investigated the expression profiles of genes involved in drug resistance and metabolism with a Human Cancer Drug Resistance and Metabolism PCR Array (SuperArray). Six of the 84 genes that are known to regulate drug resistance, metabolism, cell cycle, DNA repair and oncogenesis were downregulated >or=3-fold change by the combination treatment. These results may be important in devising mechanism-based and targeted therapeutic strategies for prostate cancer, especially in devising combination therapy for drug resistant prostate cancers.
Docetaxel, a semi-synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti-tumoral effects on prostate cancer cells. We have explored the possible additive/ synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC-3 and DU-145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC-3 and DU-145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl-2 in PC-3 and DU-145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer. Ó
In the present study, we aimed to evaluate temporal changes in heart-type fatty acid-binding protein (h-FABP) and myocardial performance index (Tei index) following administration of 5-fluorouracil (5-FU), a chemotherapeutic agent associated with myocardial ischemia induced by coronary vasospasm. Thirty-two patients with cancer receiving their first 5-FU-based chemotherapy were included in the study. Prior to chemotherapy and 24 hours after the initiation of chemotherapy, all patients underwent a comprehensive echocardiographic examination. Blood samples were taken for h-FABP and troponin I (TnI) measurements at different time points during the first 24 hours of 5-FU administration. Postinfusion echocardiography revealed worsening in Tei index (0.37 ± 0.08 vs 0.43 ± 0.07, P < .001). Clinically overt cardiotoxicity was evident in 4 (12.5%) of our patient population. Heart-type fatty acid binding protein and TnI levels were within normal ranges at all time points. Our results suggest that ischemia coronary vasospasm due to 5-FU cardiotoxicity should be reviewed. Furthermore, Tei index might be a sensitive indicator of occult 5-FU cardiotoxicity.
caspase 3/7 activity were measured. We also investigated the effect of combined docetaxel and octreotide on growth factors secreted from prostate cancer cells using a human growth factor antibody array.
RESULTSThe combination of docetaxel and octreotide resulted in significant synergistic cytotoxic activity and apoptosis, which was dose-and time-dependent. The combined treatment also resulted in significantly less secretion of stem cell factor and platelet-derived growth factor-AB in PC-3 cells, and transforming growth factor-β and basic fibroblast growth factor in DU-145 cells, than in untreated controls.
CONCLUSIONOctreotide, a somatostatin analogue, combined with docetaxel might provide a rationale treatment option for hormonerefractory prostate cancer cells, not only by direct inhibition of cell proliferation but also by inhibiting the secretion of growth factors.
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