Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function of p21 is related to cell apoptosis, progression and malignancies. It is thought that p21 is related to cancer formation but is not related to tumor grade. We aimed to investigative the polymorphism of p21 codon 31 as a candidate for the genetic marker of bladder cancer and its progression. The distribution was analyzed in 53 bladder cancer patients, 119 healthy controls in Taiwanese patients. Polymerase chain reaction based restriction analysis was used for the study of the association of p21 codon 31 polymorphism with bladder cancer. There was a significant difference in p21 codon 31 polymorphism between the control and the cancer patients (p < 0.01). The arginine form was prominent in the cancer patient (per copy of the A allele, odds ratio = 2.03, 95% confidence interval = 1.23-3.37). Furthermore, the distribution of this polymorphism was significantly different from non-invasive to invasive bladder cancer (p < 0.05). Serine heterozygote was more prominent in the invasive group with 25 to 1% respectively when compared with the non-invasive group. The polymorphism of p21 codon 31 is associated with bladder cancer. An individual possessing one allele of arginine form in p21 codon 31 has a higher risk of developing bladder cancer than the serine form. Although the mechanism is unclear, our results show p21 gene is associated with tumor grade.
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PMID:p21 gene codon 31 polymorphism is associated with bladder cancer. 1247 24

Carcinoma in situ (CIS) of the bladder has recently been proposed to be a heterogeneous group of diseases with varied histogenesis and biological behavior. In this study, we describe the sequential steps of CIS development and progression in a transgenic mouse model expressing low levels of the SV40 large T antigen. We found that CIS in transgenic mice arose from urothelial dysplasia, that CIS could persist for an extended period of time without invasion, and that the majority of CIS eventually evolved into high-grade, superficial, papillary tumors before a small fraction of them advanced to invasion/metastasis. A genome-wide search of chromosomal imbalances by comparative genomic hybridization revealed that 9 of 11 (82%) of CIS had losses on chromosome 11. Southern blotting demonstrated the allelic loss of the p53 gene, which resides on mouse chromosome 11, in four comparative genomic hybridization-tested tumors and 10 of 11 (91%) additional CIS examined. Consistent with the reduced p53 gene dosage because of the allelic loss and the functional inactivation of p53 protein of the remaining allele by SV40T antigen, there was a dramatic decrease in CIS of Mdm-2, a major p53 target. In contrast, the level of p21, another p53 target, was largely unaltered, suggesting that p21 expression can be regulated by p53-independent mechanisms. These results delineate the early stages of bladder tumorigenesis and suggest that the loss of a p53-bearing chromosome is an early event in bladder tumorigenesis and is crucial for the genesis and the maintenance, but not the progression, of bladder CIS. On the basis of our current and previous transgenic studies, we have proposed an integrated pathway progression model of bladder cancer.
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PMID:Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder. 1251 96

Bladder cancer is one of the malignancies for which considerable information is available regarding molecular pathogenesis and genetic predictors of natural history, as well as response to treatment. Loss of heterozygosity of chromosome 9 appears to be essential to the genesis of superficial bladder cancer, and mutation of the p53 suppressor gene frequently is associated with progression to invasive and metastatic disease. Many oncogenes, gene products, and suppressor gene mutations, including those of Ras, Myc, p53, Rb, p16, p21, thrombospondin-1, glutathione, and factors controlling expression and function of the epidermal growth factor receptor, have been shown to be involved in the biology of this disease. Retrospective studies have demonstrated that some of these factors have important roles as independent prognostic determinants or predictors of response to chemotherapy, and clinical trials have now been established to validate the utility of molecular prognostication in bladder cancer. Paradigms developed from the treatment of colorectal malignancy, in which the metabolism of cytotoxic agents is affected by genetic and racial factors, now are being applied to the management of bladder cancer. This review summarizes current knowledge in these evolving domains.
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PMID:Molecular targeting and pharmacogenomics in the management of advanced bladder cancer. 1267

Annonaceous acetogenins are a group of potential anti-neoplastic agents isolated from Annonaceae plants. In this study, we purified annonacin, a cytotoxic mono-tetrahydrofuran acetogenin, from the seeds of Annona reticulata and analyzed its biological effects. Herein, we have shown that annonacin caused significant cell death in various cancer cell lines. T24 bladder cancer cells at the S phase were more vulnerable to the cytotoxicity of annonacin. Furthermore, annonacin activated p21 in a p53-independent manner and arrested T24 cells at the G1 phase. It also induced Bax expression, enhanced caspase-3 activity, and caused apoptotic cell death in T24 cells. In summary, these results suggest that annonacin is potentially a promising anti-cancer compound.
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PMID:Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway. 1269 68

An international consultation on the diagnosis of non-invasive urothelial neoplasms was held in Ancona, Italy in May 2001. Besides histology and problems of classification, one group of experts (Committee no. 3) discussed the molecular pathology and cytometry of non-invasive urothelial carcinomas. In the following first part, special immunohistochemical and molecular markers for stratifications in bladder cancer were discussed including different cytokeratins (clone 34betaE12, CK 20), cell proliferation markers (Ki67/MIB-1, PCNA, AgNOR, DNA-cytometry), tumor suppressor genes and oncogenes (p53, p21, erb-B2, bcl-2), different receptor expressions of epidermal growth factor and vascular endothelial growth factor and others. These molecular markers were analyzed in diagnosis of urothelial carcinomas, recurrences, progression and response to treatment.
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PMID:Molecular pathology of non-invasive urothelial carcinomas (part I). 1271 66

To identify gene expression changes along progression of bladder cancer, we compared the expression profiles of early-stage and advanced bladder tumors using cDNA microarrays containing 17,842 known genes and expressed sequence tags. The application of bootstrapping techniques to hierarchical clustering segregated early-stage and invasive transitional carcinomas into two main clusters. Multidimensional analysis confirmed these clusters and more importantly, it separated carcinoma in situ from papillary superficial lesions and subgroups within early-stage and invasive tumors displaying different overall survival. Additionally, it recognized early-stage tumors showing gene profiles similar to invasive disease. Different techniques including standard t-test, single-gene logistic regression, and support vector machine algorithms were applied to identify relevant genes involved in bladder cancer progression. Cytokeratin 20, neuropilin-2, p21, and p33ING1 were selected among the top ranked molecular targets differentially expressed and validated by immunohistochemistry using tissue microarrays (n = 173). Their expression patterns were significantly associated with pathological stage, tumor grade, and altered retinoblastoma (RB) expression. Moreover, p33ING1 expression levels were significantly associated with overall survival. Analysis of the annotation of the most significant genes revealed the relevance of critical genes and pathways during bladder cancer progression, including the overexpression of oncogenic genes such as DEK in superficial tumors or immune response genes such as Cd86 antigen in invasive disease. Gene profiling successfully classified bladder tumors based on their progression and clinical outcome. The present study has identified molecular biomarkers of potential clinical significance and critical molecular targets associated with bladder cancer progression.
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PMID:Gene discovery in bladder cancer progression using cDNA microarrays. 1287 71

By using a mouse NIH3T3 derivate designed 7-4 harboring the inducible Ha-ras oncogene, we demonstrated the close relationship between Ha-ras expression level and sensitization of 5-flurouracil (5-FU)-treated cells. Further studies revealed that the cells susceptible to 5-FU treatment died of apoptosis, which was demonstrated by caspase-3 activation, loss of mitochondria membrane potential (MMP), and DNA fragmentation. The 7-4 cells coexpressing dominant negative Ras (Ras(Asn17)), dominant negative Raf-1 (Raf-1(CB4)), Bcl-2, or active form of phosphatidylinositol 3-kinase (PI3K) became resistant to 5-FU, and apoptosis was prevented. In contrast, the cells coexpressing dominant negative Rac 1 (Rac1(Asn17)) or dominant negative Rho A (RhoA(Asn19)) showed no change of sensitivity to 5-FU. These results indicate that Ras, Bcl-2, as well as Raf-1 and PI3K pathways play pivotal roles in 5-FU-induced apoptosis under Ha-ras-overexpressed condition. Aberrant levels of cyclin E and p21(Cip/WAF-1) expression as well as Cdc 2 phosphorylation at Tyrosine 15 suggest that perturbation of G1/S and G2/M transitions in cell cycle might be responsible for 5-FU triggered apoptosis. Sensitization of Ha-ras-related cells to 5-FU was also demonstrated in human bladder cancer cells. Through understanding the mechanism of 5-FU induced apoptosis in tumor cells, a new direction toward the treatment of Ha-ras oncogene-related cancers with 5-FU at more optimal dosages is possible and combinational therapy with other drugs that suppress PI3K and Bcl-2 activities can also be considered.
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PMID:Ha-ras overexpression mediated cell apoptosis in the presence of 5-fluorouracil. 1291 31

Mutations of the tumor suppressor gene p53 are common in bladder cancer. To determine whether p53 gene transfer would lead to decreased viability of bladder cancer cells, we studied the effect of p53 gene transfer in human bladder cancer cell lines with either mutant or wild-type p53. Bladder cancer cell lines 5637 and J82 (which express only mutant p53) and 253J-BV (which expresses wild-type p53) were transduced with vectors containing the beta-galactosidase gene (Ad5-lacZ), wild-type human p53 gene (Ad5CMV-p53), or no foreign gene (DL312 or Ad5-polyA). X-gal staining of cells exposed to Ad5-lacZ showed that the adenoviral vector was capable of transducing each of the cell lines. Increases in p53, p21(waf1/cip1) and bax protein were demonstrated following exposure to Ad5CMV-p53, and there was a dose-dependent increase in the number of apoptotic cells. Cell viability was decreased in all three cell lines, although J82 was less sensitive than either 5637 or 253J-BV. To determine whether cisplatin increases sensitivity of J82 cells to Ad5CMV-p53, we performed median effect analysis for cisplatin combined with Ad5CMV-p53 or DL312. The combination index for cisplatin plus Ad5CMV-p53 revealed synergy, whereas cisplatin and DL312 were only additive. These results suggest that forced p53 gene expression is cytotoxic to human bladder cancer cells with either p53 mutant or wild-type background, and that combination with cisplatin is a potential method for overcoming resistance.
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PMID:Adenoviral p53 gene transfer in human bladder cancer cell lines: cytotoxicity and synergy with cisplatin. 1469 72

Bortezomib (PS-341, Velcade) is a dipeptidyl boronic acid inhibitor of the 20S proteasome that was developed as a therapeutic agent for cancer. Here, we investigated the effects of bortezomib on the growth of human 253JB-V bladder cancer cells. Although the drug did not stimulate significant increases in levels of apoptosis, it inhibited cell growth in a concentration-dependent fashion and augmented the growth inhibitory effects of gemcitabine in vitro. These effects were associated with accumulation of p53 and p21 and suppression of cyclin-dependent kinase 2 activity. Bortezomib also inhibited secretion of the proangiogenic factors matrix metalloproteinase-9, interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF). In vivo studies with 253JB-V tumors growing in nude mice demonstrated that bortezomib (1 mg/kg) did not inhibit tumor growth when it was delivered as a single agent, although it reduced tumor microvessel density and inhibited expression of VEGF and IL-8. However, combination therapy with bortezomib plus gemcitabine produced synergistic tumor growth inhibition associated with strong suppression of tumor cell proliferation. Together, our results demonstrate that bortezomib has significant antiproliferative activity in aggressive bladder cancer cells, which is best exploited within the context of combination chemotherapy.
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PMID:The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo. 1502 48

Bladder cancer is the fourth and eighth most common cancer in men and women in the USA, respectively. Flavonoid phytochemicals are being studied for both prevention and therapy of various human malignancies including bladder cancer. One such naturally occurring flavonoid is silibinin isolated from milk thistle. Here, we assessed the effect of silibinin on human bladder transitional cell carcinoma (TCC) cell growth, cell cycle modulation and apoptosis induction, and associated molecular alterations, employing two different cell lines representing high-grade invasive tumor (TCC-SUP) and high-grade TCC (T-24) human bladder cancer. Silibinin treatment of these cells resulted in a significant dose- and time-dependent growth inhibition together with a G(1) arrest only at lower doses in TCC-SUP cells but at both lower and higher doses in T-24 cells; higher silibinin dose showed a G(2)/M arrest in TCC-SUP cells. In other studies, silibinin treatment strongly induced the expression of Cip1/p21 and Kip1/p27, but resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins involved in G(1) progression. Silibinin treatment also showed an increased interaction between cyclin-dependent kinase inhibitors (CDKIs)-CDKs and a decreased CDK kinase activity. Further, the G(2)/M arrest by silibinin in TCC-SUP cells was associated with a decrease in pCdc25c (Ser216), Cdc25c, pCdc2 (Tyr15), Cdc2 and cyclin B1 protein levels. In additional studies, silibinin showed a dose- and a time-dependent apoptotic death only in TCC-SUP cells that was associated with cleaved forms of caspase 3 and poly(ADP-ribose) polymerase. Together, these results suggest that silibinin modulates CDKI-CDK-cyclin cascade and activates caspase 3 causing growth inhibition and apoptotic death of human TCC cells, providing a strong rationale for future studies evaluating preventive and/or intervention strategies for silibinin in bladder cancer pre-clinical models.
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PMID:Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. 1511 15


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