Growth inhibitory effect of p21 and p53 containing adenoviruses on transitional cell carcinoma cell lines in vitro and in vivo
ABSTRACT Altered p53 expression has been demonstrated in the majority of advanced transitional cell carcinoma (TCC) of the bladder tumors. The objective of this investigation was to examine the effect of the introduction of a p53 or p21((WAF1/CIP1)) adenovirus on the proliferation and apoptosis of various human TCC cell lines in vitro and in vivo. Proliferation was measured by 3H-thymidine incorporation. Apoptosis was measured by DNA fragmentation and bax expression. We also examined the effect of ex vivo introduction of the p21((WAF1/CIP1)) or the p53 gene on growth of the T24 TCC cells and UMUC-3 TCC cells introduced subcutaneously into athymic nude mice. We found that although the effect of the p21-adenovirus on the proliferation of various TCC lines varied with each individual cell line, there was a substantial growth inhibition observed (greater than 80% growth inhibition) in seven of the eight TCC cell lines at the highest viral dosage. In contrast, after 24 h, the highest dosage of the p53-adenovirus produced only a heterogeneous decrease in proliferation compared to the highest dose of the p21((WAF1/CIP1))-adenovirus (40-90%). In ex vivo experiments, no tumors were found in nude mice injected subcutaneously with either TCC cell line exposed in vitro to the AdSCMV-p21((WAF1/CIP1)) or AdSCMV-p53 viruses before three weeks. There was a threefold decrease in tumor square area at week 5 in the Ad5CMV-p21((WAF1/CIP1)) or Ad5CMV-p53 TCC cells injected mice (p<0.001, p<0.009) compared to either mock or Ad5CMVLacZ TCC bladder tumor cells. These data suggest that significant portion of the effect of altered p53 on TCC phenotype may be mediated through the p21((WAF1/CIP1)) pathway. Thus, the restoration of p21((WAF1/CIP1)) function in this tumor system may be a beneficial therapeutic strategy.
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- "Prostate cancer is the most common cancer and the third most common cause of cancer related mortality in men in the United States . While early detection has increased with the advent of serum prostate specific antigen (PSA) testing, the disease is often advanced when patients present with symptoms. "
ABSTRACT: The development of therapeutic resistance, after hormone or chemotherapy for example, is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress related proteins, including small heat shock proteins (HSPs). HSPs interact with various client proteins to assist in their folding and enhance the cellular recovery from stress, thus restoring protein homeostasis and promoting cell survival. The vents of cell stress and cell death are linked, as the induction of molecular chaperones appears to function at key regulatory points in the control of apoptosis. On the basis of these observations and on the role of molecular chaperones in the regulation of steroid receptors, kinases, caspases, and other protein remodelling events involved in chromosome replication and changes in cell structure, it is not surprising that molecular chaperones have been implicated in the control of cell growth and in resistance to various anticancer treatments that induce apoptosis. Recently, several molecular chaperones such as Clusterin and HSP27 have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the molecular and cellular events initiated by treatment induced stress, and discuss the potential role of chaperone proteins as targets for prostate cancer treatment.Current Genomics 06/2007; 8(4):252-61. DOI:10.2174/138920207781386951 · 2.34 Impact Factor
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ABSTRACT: Heat shock protein 27 (Hsp27) is a cytoprotective chaperone that is phosphoactivated during cell stress that prevents aggregation and/or regulate activity and degradation of certain client proteins. Recent evidence suggests that Hsp27 may be involved in tumor progression and the development of treatment resistance in various tumors, including bladder cancer. The purpose of this study was to examine, both in vitro and in vivo, the effects of overexpression of Hsp27 and, correspondingly, the down-regulation of Hsp27 using small interfering (si) RNA and OGX-427, a second-generation antisense oligonucleotide targeting Hsp27. Hsp27 overexpression increased UMUC-3 cell growth and resistance to paclitaxel. Both OGX-427 and Hsp27 siRNA decreased Hsp27 protein and mRNA levels by >90% in a dose- and sequence-specific manner in human bladder cancer UMUC-3 cells. OGX-427 or Hsp27 siRNA treatment induced apoptosis and enhanced sensitivity to paclitaxel in UMUC-3 cells. In vivo, OGX-427 significantly inhibited tumor growth in mice, enhanced sensitivity to paclitaxel, and induced significantly higher levels of apoptosis compared with xenografts treated with control oligonucleotides. Collectively, these findings suggest that Hsp27 knockdown with OGX-427 and combined therapy with paclitaxel could be a novel strategy to inhibit the progression of bladder cancer.Molecular Cancer Therapeutics 01/2007; 6(1):299-308. DOI:10.1158/1535-7163.MCT-06-0417 · 5.68 Impact Factor
Article: Gene therapy in bladder cancer[Show abstract] [Hide abstract]
ABSTRACT: Gene therapy remains a promising therapy for controlling cancer. Bladder cancer is a particularly interesting tumor system for consideration of a gene therapy approach based on several factors, including the ability to access the tumor in a relatively noninvasive fashion. Several gene therapy strategies have been studied in the treatment of bladder tumors. In this review, an update of the recent outcomes of viral-based gene therapy for bladder cancer is discussed. Several preclinical in-vitro and in-vivo studies have demonstrated the feasibility of intravesical viral-mediated gene therapy. Recent studies have introduced additional viral systems as useful vectors for transfection of the bladder and associated tumor. Advances in targeting techniques have improved transgene delivery to the bladder. Additionally, a variety of therapeutic strategies, including gene corrective treatment, gene-directed enzyme prodrug therapy, and immunomodulation have been recently investigated with positive findings. Viral-based gene therapy for bladder cancer remains an intriguing potential future therapy for bladder cancer. Additional advances in gene delivery and the establishment of novel vector safety will be required to move this therapeutic option out of the laboratory and into the clinical setting.Current opinion in urology 10/2008; 18(5):519-23. DOI:10.1097/MOU.0b013e32830b86e3 · 2.33 Impact Factor