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The long-term disease-free survival in patients with metastatic transitional cell carcinoma (TCC) is still considerably low. Novel chemotherapeutic agents are needed to decrease the morbidity and mortality of TCC. In this study, we have evaluated several epigenetic modifiers for their therapeutic application in bladder cancer. Both histone deacetylase inhibitors (FK228, TSA) and DNA hypomethylating agent (5-Azacytidine) were tested using in vitro assays such as cell viability, cell cycle analysis and western blot to determine their mechanisms of action. Drug combination experiments were also designed to study any additive or synergistic effects of these agents. In addition, two bladder cancer xenograft models (one subcutaneous and one orthotopic) were employed to assess the therapeutic efficacy of these agents in vivo. Three agents exhibited various growth inhibitory effects on 5 different TCC cell lines in a dose-and time-dependent manner. In addition to G 2 /M cell cycle arrest, FK228 is more potent in inducting apoptosis than the two other single agents, and combination of both FK228 and 5-Aza further enhances this effect. p21 induction is closely associated with FK228 or TSA but not 5-Aza, which is mediated via p53-independent pathway. Consistent with in vitro results, FK228 exhibited a significant in vivo growth inhibition of TCC tumor in both subcutaneous and orthotopic xenograft models. FK228 is a potent chemotherapeutic agent for TCC in vivo with minimal undesirable side effects. The elevated p21 level mediated via p53 independent pathway is a hallmark of FK228 mechanism of action. ' 2007 Wiley-Liss, Inc.Key words: bladder cancer; chemotherapy; histone acetylation; DNA methylationIn the United States, transitional cell carcinoma (TCC) of the bladder is estimated to affect 63,210 persons in 2005, resulting in 13,180 deaths. 1 In recent times, patients with metastatic TCC have experienced improved prognosis; however, the long-term diseasefree survival is still low. 2 Conventional cytotoxic chemotherapy is currently the main treatment for these patients. 3 Several single agents and combinations have been used, but the MVAC (Methotrexate, Vinblastin, Adriamycin and Cisplatin) regimen has been yielding the best results. 3,4 This regimen, however, is not without serious side effects. Treatment-related deaths can occur in up to 4% of patients. 5,6 Still, with the best regimens available, median survival ranges from 13 to 15 months. 4,[6][7][8] The importance of finding alternatives to MVAC, which are at least as effective but with less side effects, has encouraged several investigators to try other chemotherapeutic combinations, such as gemcitabine plus cisplatin 8 and docetaxel plus cisplatin. 9 However, these agents did not prove to be superior to the traditional MVAC regimen. Novel chemotherapeutic regimens are currently needed to decrease the morbidity and mortality of TCC.Epigenetic mechanisms result in changes in gene expression without altering the DNA sequence per se. 10 These changes involve DNA methyl...

Random coefficient methods provided a more reliable fit of PSA profiles than other models and were superior to other available models for predicting disease-specific survival in patients with androgen-independent prostate carcinoma. The authors concluded that consideration should be given to applying the RCL or RCQ models in future assessments of PSADT as a predictive parameter.

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