Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Transitional cell carcinoma of the urothelium is a chemosensitive tumor, and combination chemotherapy can provide not only palliation but a modest survival advantage in patients with advanced disease. While the four-drug regimen methotrexate/vinblastine/doxorubicin/cisplatin remains the standard combination therapy, its toxicity can be formidable. The overall response rate in phase III trials with this combination is in the 35% to 45% range, with a median survival duration in treated patients of only 12 months. Although attempts to decrease the toxicity of the regimen with the addition of hematopoietic growth factors have been successful, attempts to increase its efficacy by dose escalation have not. This has prompted a search for new active agents that can be incorporated into alternative combination regimens. Recently, activity has been noted for several drugs (including gallium nitrate, ifosfamide, and gemcitabine). In untreated patients, paclitaxel has demonstrated significant activity and is certainly among the most active single agents in the treatment of advanced bladder cancer. Studies incorporating these new agents into novel combination regimens are ongoing, with the goal of providing a regimen that has superior efficacy in advanced disease and, ultimately, in earlier stages of disease with curative intent.
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PMID:Palliative chemotherapy in advanced bladder cancer. 753 96

Much of bladder cancer in East Africa and the Middle East is attributed to chronic urinary infection with Schistosoma haematobium ('schistosomiasis'). Most schistosomal bladder cancer (SBC) is squamous cell carcinoma (SCC) and occurs in the fifth decade of life. In contrast, nonschistosomal bladder cancer (NSBC) in Western countries usually occurs in the seventh decade of life and is largely transitional cell carcinoma (TCC). To shed light on the mechanisms underlying these different patterns of bladder cancer we looked for mutations in the p53 gene in SBC from 92 patients in Egypt, where schistosomiasis is hyperendemic. Patients' mean age at presentation of bladder cancer was 49.4 +/- 9.9 years and 90% had a clinical history of schistosomiasis and/or histological evidence of schistosomal eggs adjacent to the carcinoma. There were 53 SCC, 23 TCC, 13 adenocarcinomas and three other carcinomas. Thirty patients had tumours with mutations in exons 5-8 of the p53 gene: 17/53 SCC, 8/23 TCC, 4/13 adenocarcinomas and 1/3 other tumours. Of 19 mutations in SCC, 16 were base pair substitutions (BPS), two were deletions and one an insertion. Two tumours each contained two mutations. Of the BPS, nine were transitions at CpG dinucleotides and two were G-->T transversions. All the mutations in TCC were BPS: four were transitions at CpG dinucleotides and three were G-->C transversions. One TCC had two mutations. Of four adenocarcinomas with mutations, two had transitions at CpG dinucleotides. Of the 30 BPS mutations, 16 were transitions at CpG dinucleotides, of which 12 were C-->T. We combined these 33 mutations with six obtained from Egyptian SCC reported by Habuchi et al. (Cancer Res., 53, 3795-3799, 1993) to compile a mutational spectrum. This was compared with a NSBC spectrum assembled from 118 mutations reported in the literature. The proportion of BPS at CpG dinucleotides was significantly higher in SBC than in NSBC (18/34 versus 25/103, P = 0.003). There was also a bias away from mutations in exons 7 and 8 towards mutations in exons 5 and 6. We suggest that the excess of transitions at CpG dinucleotides in SBC results from nitric oxide (NO) produced by the inflammatory response provoked by schistosomal eggs. NO could produce such mutations directly, by deamination of 5-methylcytosine, and indirectly, following conversion to nitrate, bacterial reduction to nitrite and endogenous formation of urinary N-nitroso compounds. These produce O6-alkylguanines in DNA, leading to very high rates of G:C-->A:T transitions, a process possibly augmented by inefficient repair of alkylated bases at CpG dinucleotides.
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PMID:Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours. 776 83

The role of bacteria isolated from patients with urinary tract infection (UTI) was studied with a view to the possibility that such bacteria are an etiological factor in the development of bladder cancer. The bacterial strains of Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Serratia marcescens, Staphylococcus epidermidis and Enterococcus faecalis, isolated from patients with UTI at the Kyushu University Hospital, were tested for their nitrate-reducing activity after 1 hr of incubation with sodium nitrate (3.57 mM) in a growth medium (pH 7.2) at 37 degrees C. Of 35 strains tested, 27 strains (77%) showed the ability to reduce nitrate to nitrite with yields ranging from 2 to 310 microM NO2-/hr/10(7) bacterial cells, but in 8 strains (23%) including all the 7 strains of E. faecalis no elevated activity (0.0-0.3 microM) could be detected. Various kinetic profiles were observed for the nitrate-reducing bacteria, at various rate ranging from rapidly to slowly, during 5 hr of incubation. The effect of nitrate-reducing bacteria on mutagen formation in the human urine was examined. The mutagenic activity of smokers' or non-smokers' urine incubated with or without bacteria for 72 hr at 37 degrees C was assayed by the Ames Salmonella/microsome test (using TA100 or TA98 with S9-mix). The mutagenic activity increased in urine incubated with the nitrate-reducing S. marcescens or P. aeruginosa, compared to controls which were incubated without bacteria. Potent mutagenic activity could be induced when the urine concentrate prepared from smokers' urine with an XAD-2 resin column was incubated with sodium nitrite (40 mM) at pH 3 for 4 hrs. The potent mutagenic activity observed here seems to be due to the class of direct-acting mutagen(s), because no metabolic activation was required. The mutagen formation at an optimal pH 4 proceeded rapidly during 4 hrs of incubation, but decreased thereafter. It was noted that even at a physiological pH 6 of human urine, a lower but significant level of mutagenic activity could still be detected. The mutagenic activity of individual urine concentrate from 14 male smokers and from 6 male non-smokers was assayed after 30 min of incubation with or without sodium nitrite (40 mM) at pH 6. Mutagenic activity increased in most of these urine concentrates incubated with sodium nitrite. The levels were variable between individuals with a 1.3- to 53-fold increase compared with the controls incubated without sodium nitrite.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Experimental study on the role of bacteria from urinary tract infections on the bladder carcinogenesis]. 799 11

The present study presents, for the first time, the amounts of nitrate, nitrite and volatile N-nitroso compounds in saliva and urine samples of Schistosoma haematobium and Schistosoma mansoni infected patients. Mid-morning saliva and 24 h urine samples were collected from male patients infected with S.haematobium (n = 129 saliva and 79 urine samples) and S.mansoni (n = 64 saliva and 65 urine samples) and in a comparative control group of healthy individuals (n = 27) from the Nile Delta region of Egypt. Saliva samples were analyzed for the presence of nitrate and nitrite; while urine samples were analyzed for the presence of nitrate, nitrite and volatile N-nitroso compounds. In the control group, N-nitroso-dimethylamine (NDMA) was detected at concentrations (mean +/- SD) of 0.27 +/- 0.47 microgram/day. N-Nitrosopiperidine (NPIP; 0.6 microgram/day) and N-nitrosopyrrolidine (NPYR; 0.4 microgram/day) were also present in one sample. S.mansoni infected subjects showed significantly (P < 0.001) higher levels of 2.9 +/- 2.9 micrograms/day NDMA and a higher frequency of NPIP (in 40/65 samples; 0.4 +/- 0.3 microgram/day) and NPYR occurrence (in 59/65 samples; 0.9 +/- 0.9 microgram/day). Significant further increases in the excretion of volatile N-nitroso compounds were found in S.haematobium-infected patients with mean daily excretion of 19.2 +/- 21 micrograms/day NDMA (in all samples; P < 0.001), 1.6 +/- 2.3 micrograms/day NPIP (in 56/79 samples; P < 0.001) and 1.3 +/- 1.9 micrograms/day NPYR (in 58/79 samples; P < 0.1). The differences either in salivary nitrite/nitrate or in urinary nitrite between the three distinct groups were not significant. However, the urinary excretion of nitrate was elevated from 139 +/- 82 mg/day in the control group to 249 +/- 126 mg/day in S.mansoni infected patients (P < 0.001) and to 174 +/- 176 mg/day in S.haematobium infected subjects (P < 0.005 in comparison to S.mansoni infected group). These results suggest a possible role of N-nitroso compounds in the etiology of schistosome-associated bladder cancer and imply a partial participation of S.mansoni in the multistage process of urinary schistosomiasis-associated bladder carcinogenesis.
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PMID:Nitrate, nitrite and volatile N-nitroso compounds in the urine of Schistosoma haematobium and Schistosoma mansoni infected patients. 814 71

Agents that interfere with cellular iron (Fe) incorporation inhibit tumor cell proliferation, including metals that bind to transferrin (Tf) such as gallium (Ga) or indium (In) and Fe chelators such as desferrioxamine (DFO). Ga nitrate is effective in the treatment of metastatic bladder cancer and these patients exhibit evidence for interference with Fe metabolism. We show here that bladder cancer cell proliferation in vitro is dependent on Tf-Fe. Concentrations of DFO that can be readily achieved in vivo inhibit cellular proliferation even in the presence of physiologic concentrations of Tf-Fe. Inhibition of proliferation by Tf-Ga is associated with decreased cellular Fe incorporation. However, when a physiologic concentration of Tf-Fe is added to an equimolar concentration of Tf-Ga, significant Fe incorporation is evident despite inhibition of proliferation. Thus, besides interference with Fe incorporation, Ga may also interfere with intracellular Fe distribution and/or directly inhibit an Fe- (or non-Fe-) requiring process necessary for cellular proliferation. DFO followed sequentially by Tf-Ga results in marked potentiation of inhibition of proliferation. The effects of this combination appear to be related to both interference with Fe metabolism and increased Ga uptake. This sequential combination may be useful in the treatment of bladder cancer.
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PMID:Effects of agents that inhibit cellular iron incorporation on bladder cancer cell proliferation. 836 9

Although chemotherapy for advanced bladder cancer has historically been based on cisplatin-based combination regimens, the limitations of these regimens both in terms of efficacy and toxicity are now widely appreciated. In response to these limitations, other single agents have been studied, and a number have demonstrated significant activity, including ifosfamide. Older single-agent phase II trials of ifosfamide in previously untreated patients suggested a response rate as high as 40%, including objective responses in nontransitional histologies. More recently, the Eastern Cooperative Oncology Group has defined the response rate for ifosfamide in patients with one prior chemotherapy regimen to be 20%, with central nervous system toxicity, nephrotoxicity, and myelosuppression as the dose-limiting toxicities. Phase II trials of ifosfamide in combination with vinblastine and gallium nitrate have been completed, while others, including trials with paclitaxel alone or paclitaxel plus cisplatin, are ongoing. The precise role of ifosfamide in the therapy of advanced bladder cancer is in the process of being defined. However, the frequency of occult or clinically evident renal insufficiency in this patient population may limit ifosfamide's role in this disease.
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PMID:Ifosfamide in the treatment of bladder cancer. 867 50

The activity of ifosfamide in genitourinary malignancies has been documented in testicular cancer and bladder cancer. The use of ifosfamide in germ cell tumors spans 20 years and has involved three distinct clinical settings: as a component of salvage therapy in cisplatin-resistant or recurrent disease, as part of initial therapy for patients with poor-risk disease, and as part of an ablative regimen for patients undergoing high-dose therapy with stem cell support. The use of ifosfamide in salvage therapy is well established, with approximately 40% to 50% of patients treated with a second-line ifosfamide-based regimen expected to achieve a complete response; however, only 25% of these patients will be long-term disease-free survivors. The drug's incorporation into standard-dose first-line regimens in patients with poor-risk disease has failed to improve the efficacy of therapy over standard, less toxic regimens. The value of ifosfamide as a component of high-dose salvage therapy with stem cell support in patients with refractory disease or of its increasing use as first-line therapy in patients with poor-risk features remains to be demonstrated. In urothelial carcinoma, data on the activity of ifosfamide are more sparse. Older trials in previously untreated patients in Japan and Egypt suggest an overall response rate of 30% to 40%, while a recent Eastern Cooperative Oncology Group trial in patients with prior chemotherapy reported a response rate of 20%. Ifosfamide has therefore been identified as one of six new active agents in urothelial cancer, and trials of combination regimens including ifosfamide are under way. The vinblastine/ifosfamide/gallium nitrate (VIG) combination was tested in a pilot study at Indiana University with a 67% overall response rate and in a confirmatory Eastern Cooperative Oncology Group phase II trial with a 56% response rate. Trials of ifosfamide plus paclitaxel with or without cisplatin are ongoing, but the role of ifosfamide in the routine therapy of urothelial malignancies remains to be determined.
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PMID:The role of ifosfamide in the treatment of testicular and urothelial malignancies. 871 97

At present, a combination of cisplatin, methotrexate, vinblastine and doxorubicin is the most widely used chemotherapy for metastatic bladder cancer. However, long-term follow-up shows that this combination may have little effect on survival. In addition, this regimen is toxic. New agents are needed which combine efficacy with good safety profiles. Agents which have been investigated include gallium nitrate, interferon-alpha and paclitaxel both as single agents and in combination with established cytotoxic drugs. A number of studies have been conducted in bladder cancer with the novel nucleoside analogue, gemcitabine. Response rates of up to 33% have been recorded in two phase II studies. Gemcitabine was well tolerated in both studies with few of the side-effects normally associated with cytotoxic drugs. A third study is ongoing.
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PMID:Metastatic bladder cancer: advances in treatment. 916 96

In this study sensitivity of human transitional cancer cells to the anticancer agent paclitaxel, an antimicrotubular drug, and to gallium nitrate, a group IIIa metal, was compared to that of the standard MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) drugs. The reduction of cell proliferation was evaluated after 48 h of incubation of six different cell lines with each agent using the mean transit time (MTT) assay. We investigated both monolayers and spheroids. Paclitaxel showed significantly higher growth inhibitory effects on monolayers than vinblastine, both agents targeting the antimicrotubular apparatus. This could not be reproduced on spheroids, where a survival fraction of 50% was observed even at high concentrations (10 microM). High concentrations of gallium nitrate were needed to achieve sufficient toxicity. These concentrations are beyond the concentration achievable by systemic application. Our findings suggest that paclitaxel may be a clinically useful agent for systemic and intravesical use in bladder cancer.
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PMID:In vitro investigations of new therapeutic agents on bladder tumor cell lines. 928 32

Because of demonstrated superiority in multiple randomized trials, MVAC has become the standard therapy for metastatic or unresectable bladder cancer. However, the disappointing long-term results with this regimen have prompted the development of newer agents and regimens for this disease. These include novel antifolates, gemcitabine, taxanes, ifosfamide, and gallium nitrate. Each of these agents leads to objective responses, including complete responses in both untreated and previously treated patients. More recent reports of combination regimens using these agents suggest that response rates are equivalent to those seen with MVAC but that there is significantly less toxicity. These observations, if confirmed in randomized trials, would signify an important advance in the therapy of metastatic bladder cancer.
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PMID:New chemotherapy regimens for advanced bladder cancer. 950 79


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