Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
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The glutathione transferase mu gene (GST1) and the debrisoquine hydroxylase gene (CYP2D6) are known to be polymorphic in the human population and have been associated with increased susceptibility to cancer. Smokers with low lymphocyte GST mu activity are at higher risk for lung cancer, while low debrisoquine hydroxylase activity has been correlated with lower risk for lung and bladder cancer. Phenotypic characterization of these polymorphisms by lymphocyte enzyme activity (GST) and urine metabolite ratios (debrisoquine) is cumbersome for population studies. Recent cloning and sequencing of the mutant alleles of these genes has allowed genotyping via the polymerase chain reaction (PCR). Advantages of PCR approaches are speed, technical simplicity, and minimal sample requirements. This article reviews the PCR-based methods for detection of genetic polymorphisms in human cancer susceptibility genes.
Environ Mol Mutagen 1991
PMID:Detection of DNA sequence polymorphisms in carcinogen metabolism genes by polymerase chain reaction. 168 53

P-Benzoquinone dioxime (BQD) appears to be a sex-specific rat carcinogen inducing tumours of the urinary bladder in female rats. The present paper shows that BQD is a direct-acting mutagen in Salmonella typhimurium TA98, confirming published data. In contrast to this in vitro data, negative results were obtained after oral administration of BQD to female rats in both the bone marrow micronucleus test and the in vivo liver UDS test. BQD did, however, induce a marked effect upon S-phase synthesis in the livers of female rats between 14 and 48 hr after a single oral dose of 250 mg/kg. A similar effect was also observed in the livers of male rats. There was no evidence of hepatotoxicity (in terms of elevated liver enzyme levels) after treatment of female rats with the compound indicating that the increase in cell proliferation was due to a direct mitogenic effect of BQD in this organ. Some liver mitogens have been found to be liver carcinogens; this does not appear to be the case for BQD. Nevertheless, the mitogenic activity of this compound might play a contributory role to the induction of bladder cancer in rats if it also acted as a mitogen in this tissue. Further studies are indicated, measuring genotoxicity and cell-proliferative activity in the bladder in order to further elucidate the mechanism of action of this compound as a rodent carcinogen.
Environ Mol Mutagen 1992
PMID:In vivo genotoxicity studies with p-benzoquinone dioxime. 173 6

The use of biochemical markers may improve the potentialities of etiologic epidemiology. Exposure markers or markers of biologically effective dose allow better exposure assessment, therefore decreasing misclassification in epidemiological studies. Markers of individual susceptibility (such as metabolic polymorphism) permit the identification of subgroups of subjects at higher risk of cancer. In general, the integration of biochemical methods and an epidemiological design is helpful in the study of the sources of interindividual variability in response to carcinogenic stimuli. We review several investigations making use of biochemical measurements in the field of cigarette-induced bladder cancer.
Teratog Carcinog Mutagen 1990
PMID:Biochemical epidemiology: uses in the study of human carcinogenesis. 197 27

Schistosomiasis has long been associated with cancer. This association is most prevalent between Schistosoma hematobium and bladder cancer. Numerous theories have been proposed to explain the causal link between the parasite infestation and the ensuing neoplasia. One theory that has not received as much attention as others, however, is the role of genotoxins in the neoplastic process. Considering the substantial amount of supportive evidence for the cocarcinogenic effects of schistosomes, concern for the health effects resulting from exposure of infested individuals to either exogenous or endogenous genotoxins is certainly warranted.
Environ Mutagen 1985
PMID:Schistosome related cancers: a possible role for genotoxins. 389 33

Mutations in the tumor suppressor gene p53 play an important role in carcinogenesis and tumor progression. To assess the status of p53 from genomic DNA from bladder cancer samples a two stage polymerase chain reaction was employed. The technique provided material for subsequent detection of mutations by Single Strand Conformation Polymorphism (SSCP) analysis followed by DNA sequence analysis. SSCP analysis of exons 5 to 9 of p53 was performed using fragments from PCR end-labeled with 32P followed by autoradiography using an electrophoresis system with temperature control. This SSCP method improved resolution of mutations in exons 5, 7, and 8 and the sharpness of bands in exons 6 and 9. Bands with altered migration patterns were excised from the dried SSCP gels, reamplified by PCR, and sequenced. Mutations in conserved exons 5, 6, 7, 8, and 9 of the p53 gene were analyzed from bladder tumor biopsies. Our results are consistent with the literature in that mutations in p53 are predominantly found in high grade bladder cancer (Odds Ratio = 4.05, Fisher Exact P = 0.104); however, the results were not statistically significant due to small numbers. Eight of 35 (23%) tumor samples examined showed mutations in p53 (including two double mutations). Six of 13 (46%) grade III and IV tumors had p53 mutations vs. 2 of 17 (12%) grade I and II tumors. Normal individuals carried no p53 mutations. We found no correlation between pack years of smoking and mutation in p53. The spectrum of mutations confirmed a high proportion of G:C C:G transversions as well as the occurrence of double mutations.
Environ Mol Mutagen 1994
PMID:p53 mutations in human bladder cancer. 795 18

Dietary uracil at the 3% level induces urinary bladder tumors in rats through urolithiasis-dependent mechanical irritation. In the present study, comparison of lesions induced by uracil administration over the different periods of 36 weeks (middle-term) and up to 103 weeks (long-term) revealed significant elevation of both incidences and multiplicity of transitional cell carcinomas (TCCs) in the long-term group. Histopathological assessment in terms of tumor biology further demonstrated significantly higher grading on the basis of the degree of cellular and structural atypia, and greater depth of invasion in the long-term group. Application of markers for cell proliferation activities including proliferating cell nuclear antigen (PCNA) and silver-binding nucleolar organizer regions (AgNORs) also revealed significantly elevated AgNOR counts in the long-term group TCC. AgNOR counts and PCNA rates in TCCs showed relation to the histological grades. Thus the present study demonstrated that prolonged uracil-induced urolithiasis causes more biologically aggressive bladder carcinomas with invasive potential. Continuous stimulation of cell proliferation presumably has the potential to facilitate multiple genetic alterations leading to development of more malignant carcinomas. However, it should be borne in mind that the difference in bladder cancer development might also be related to the fact that the animals survived longer and that the early lesions therefore had more time to progress to more advanced stages.
Teratog Carcinog Mutagen 1994
PMID:Progressive growth of rat bladder carcinomas after exposure to prolonged uracil-induced urolithiasis. 799 27

Both K-ras and p53 gene mutations are found commonly in pancreatic tumors. Analysis of the mutational patterns may provide insight into disease etiology. To further describe the mutational patterns of pancreatic cancer and to assess the evidence to date, we performed a pooled analysis of the published data on genetic mutations associated with pancreatic ductal adenocarcinoma. We included data from studies that evaluated point mutations in the two genes most studied in pancreatic cancer, K-ras and p53. A majority of the 204 tumors had mutations in at least one gene, with 29% having both K-ras and p53 mutations, 39% with K-ras mutation alone, and 16% having p53 mutation alone. Sixteen percent of tumors lacked mutation in either gene. K-ras mutations were present in high frequencies in all tumor grades (>69%). A statistically significant trend was observed for p53 mutation with higher tumor grade (P = 0.04). For K-ras, G2 and G3 grades, combined, had notably higher prevalences of mutation than G1 (P = 0.004). CGT mutations in K-ras codon 12 were marginally associated with lower tumor grade (P for trend = 0.09), and these tumors were somewhat less likely to have a p53 mutation than tumors with other K-ras mutations (P = 0.06). In the 59 K-ras+/p53+ tumors, 64% had the same type of mutation (transition or transversion) in both genes, suggesting a common mechanism. The mutational pattern of p53 in pancreatic cancer is similar to bladder cancer, another smoking-related cancer, but not to lung cancer. Analyses of molecular data, such as that performed here, present new avenues for epidemiologists in the study of the etiology of specific cancers.
Environ Mol Mutagen 1999
PMID:Patterns of genetic alterations in pancreatic cancer: a pooled analysis. 1021 65

Interindividual differences in bladder cancer susceptibility may be partly mediated through polymorphic variability in the metabolism of carcinogens. N-acetyl transferase-2 (NAT2) has been extensively studied as a risk factor in this context, but the results are inconsistent. In some studies the failure to demonstrate a relationship may be a consequence of a lack of statistical power. To overcome lack of power, data from 21 published case-control studies were pooled in a meta-analysis using a random-effects model. The pooled odds ratio of bladder cancer associated with slow acetylator status was 1.31 (95% CI: 1.11-1.55). The results suggest that NAT2 slow acetylator status is associated with a modest increase in risk of bladder cancer. There was, however, heterogeneity between studies. It is clear from this overview that greater attention should be paid to the design of these types of study.
Environ Mol Mutagen 2000
PMID:N-acetyl transferase-2 and bladder cancer risk: a meta-analysis. 1104 3

Based on the research of less toxic anticancer therapies, we have looked for novel compounds with anticancer activity based on a proapoptotic mechanism. The described compounds are derivatives of ether, carbamate, urea, amide, or amine. Some of the prepared compounds decreased cell viability of various tumor cell lines in a time- and dose-dependent manner, and also induced DNA fragmentation, which indicated cell apoptosis. The potential antitumoral activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human mama, colon, and bladder cancer cell lines (MD-MBA-231, HT-29, and T-24). Compounds showing cytotoxic activity were subjected to an apoptosis assay. In addition, some of the synthesized compounds provoked a rapid and dose-dependent increase in the level of caspase-3, an enzyme, which is considered to be one of the principal executing caspases in which all of the biochemical routes involved in the apoptosis response converge. The most promising compounds, with respect to cytotoxicity and apoptosis induction capability, were the 4-nitrophenylcarbamate derivative of 2,2'-methylenebis(4-chlorophenyl) 3c, the naphthylurea derivative 4d, and the n-propylurea derivative 4c, from 4,4'-methylenebisphenyl, all of which displayed cytotoxic activity and showed very interesting levels of apoptosis. Furthermore, good levels of apoptosis induction were achieved for 3a and 4b in the T-24 cell line. Therefore, compounds such as 7b, a pyrido[2,3-d]pyrimidine derivative, show a significant in vitro cytotoxicity, with IC(50) values between 3 and 8 microm in the three cell lines tested. This compound also produced a rapid and dose-dependent increase of the caspase-3 level and induced apoptosis in HT-29 cells. Other profiles have been found, such as those presented by 5c and 7c, which are cytotoxic and apoptotic but do not provoke an increase in the level of caspase-3, or those presented by 1c, 1d, and 2a, which are cytotoxic, without showing any other activity. The different types of behavior of each compound are not necessarily parallel in the three cell lines tested. A great number of these compounds of interest show no cytotoxicity in nontumoral human cells such as CRL-8799, a nontumoral line of mama. Subsequent modulation of these lead structures permits advances in the design of potent cytotoxic and proapoptotic anticancer drugs.
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PMID:Synthesis and biological evaluation of new symmetrical derivatives as cytotoxic agents and apoptosis inducers. 1572 57

The burden of human infectious diseases remains a public health problem worldwide. At least 2 billion people are affected by viral infections, and a similar number by bacteria or helminths. The long-term effects of these maladies have raised particular concern since some infectious agents have been associated with chronic human diseases, especially cancer. It is estimated that 13-20% of the world cancer cases are associated with some virus, bacteria, or helminth, e.g., human papillomavirus, Helicobacter pylori, and Schistosoma haematobium that cause cervical, stomach, and urinary bladder cancer, respectively. Certain associations between infection and malignancy are strong and irrefutable; others are still speculative. This article reviews the infectious agents that have been associated with cancer and current knowledge about the mechanisms underlying these associations.
Environ Mol Mutagen
PMID:Role of infectious diseases in human carcinogenesis. 1574 42


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