Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer continues to be the most frequently diagnosed cancer in men in the United States. Despite aggressive intervention, a significant number of men with prostate cancer will not be cured of their disease and will face the possibility of metastatic disease. Thus, development of potent prevention strategies to diminish or eliminate this threat is in order. Cellular exposure to chronic oxidative stress may be 1 possible etiologic factor in the development of many cancers, including prostate cancer. Oxygen radicals can attack DNA directly and result in the accumulation of potentially promutagenic oxidized DNA bases such as 8-hydroxydeoxyguanosine. In addition, chronic oxidant stress may also result in lipid peroxidation and the subsequent generation of a range of reactive products that can damage DNA. Disruption of certain genes may result in cellular tolerance to oxidative genomic injury. GSTP1 is an enzyme that helps catalyze the conjugation reaction between potentially damaging electrophiles and glutathione. Inactivation of GSTP1 has been documented to occur in nearly 100% of human prostate cancers; it is also frequently inactivated in prostatic intraepithelial neoplasia lesions. This inactivation may leave the cell vulnerable to oxidative DNA damage and/or tolerant to accumulation of oxidized DNA base adducts. These base adducts can be measured by several quantitative methods, such as gas chromatography-mass spectrometry with selected ion monitoring. These sophisticated methods can be readily integrated into prostate cancer chemoprevention studies of new and developing prevention agents by providing quantitative assessment of oxidative DNA damage before and after administration of these candidate chemopreventive drugs. The combination of genetic information, state-of-the-art assessment tools, and novel agents will allow rational, directed prostate cancer chemoprevention studies to be performed and, together, will help determine the role of chronic oxidative stress in the carcinogenic process of prostate cancer.
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PMID:Oxidative stress in chemoprevention trials. 1129 12

Evidence that somatic inactivation of GSTP1, encoding the human pi-class glutathione S-transferase, may initiate prostatic carcinogenesis is reviewed along with epidemiological evidence implicating several environment and lifestyle factors, including the diet and sexually transmitted diseases, as prostate cancer risk factors. An integrated model is presented featuring GSTPI function as a 'caretaker' gene during the pathogenesis of prostate cancer, in which the early loss of GSTPI activity renders prostate cells vulnerable to genome damage associated with chronic prostatic inflammation and repeated exposure to carcinogens. The model predicts that the critical prostate carcinogens will be those that are substrates for GSTP1 detoxification and are associated with high prostate cancer risk diet and lifestyle habits.
Cancer Metastasis Rev 2002
PMID:The diet, prostate inflammation, and the development of prostate cancer. 1240 Sep 93

We determined whether the glutathione S-transferase GSTP1 Ile105 --> Val105 substitution is associated with response to androgen ablation therapy in patients with advanced prostate cancer. As response may be associated with tumor grade, Gleason score, clinical T stage and presence of metastases we also determined if GSTP1 genotypes were associated with these prognostic parameters. We speculated that GSTP1 Ile105/Ile105 would be linked with good response to androgen ablation therapy and, low/moderate tumor grade, 1/2 clinical T-stage, Gleason score < 6 and, no metastases. Genotype frequencies in cases and controls were not significantly different (P = 0.70) indicating that allelism in GSTP1 is not associated with susceptibility. There was no association between GSTP1 (Ile105/Ile105 versus Ile105/Val105 and Val105/Val105) and grade (P = 0.28, OR = 0.92), Gleason score (P = 0.84, OR = 0.94) or metastatic state (P = 0.68, OR = 0.88) though the frequency of GSTP1 Ile105/Ile105 was higher in cases with stage 1/2 tumors than those with stage 3/4 tumors (P = 0.03, OR = 1.89). GSTP1 Val105/Val105 was also associated with response to hormone ablation therapy. Thus, the GSTP1 Ile105/Ile105 frequency was significantly higher in 86/118 patients who demonstrated a good response than in those with poor response (P = 0.03, OR = 2.70). We speculate that the association of GSTP1 with response results from an effect of the gene product early in carcinogenesis.
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PMID:Glutathione S-transferase GSTP1 genotypes are associated with response to androgen ablation therapy in advanced prostate cancer. 1251 68

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.
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PMID:Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. 1278 63

Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.
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PMID:Hypermethylation of CpG islands in primary and metastatic human prostate cancer. 1502 33

Glutathione S-transferase (GST) enzymes catalyse the detoxification of by-products of reactive oxygen species and are thus important in cellular defence mechanisms. The GSTs are polymorphic with allelic variants encoding isoforms with functional differences. GST polymorphism has been associated with susceptibility and clinical outcome in patients with cancer. In this retrospective cohort, we have investigated associations between common GSTM1, GSTM3 and GSTP1 polymorphisms with factors known to influence clinical out-come and patient survival in colorectal cancer. Significant linkage disequilibrium was demonstrated between GSTM1 and GSTM3 alleles (P< or =0.001). We identified no significant associations between the GSTP1(Ile105Val105) polymorphism and any clinical outcome parameters or patient survival. However significant associations were demonstrated with mu class GSTs. Those patients who were GSTM1 null presented less frequently with poorly-differentiated tumours (P=0.038). Furthermore, patients who were GSTM3 AA were less likely to present with advanced stage tumours (T-stage, P=0.036 and Dukes' classifications, P=0.012) or distant metastases (P=0.017) when examined alone. Upon further examination of the effect of linkage disequilibrium, we found that, in GSTM1 null individuals, GSTM3 AA (compared with other GSTM3 genotypes combined) had longer disease-free survival (HR=0.54, 95% CI 0.30-0.98, P=0.044). Thus, the GSTM3 AA genotype is associated with improved prognosis especially in those with GSTM1 null. Our findings suggest that the GST mu gene cluster mediates tumour characteristics and survival in patients with colorectal cancer.
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PMID:Polymorphisms in the glutathione S-transferase mu cluster are associated with tumour progression and patient outcome in colorectal cancer. 1632

Our aim was to evaluate the role of C-69T in GSTA1, Ile105Val in GSTP1, null allele in GSTT1 and GSTM1 in the prediction of toxicity in patients treated with 5-Fu/CPT-11/Lv regimens in metastatic CRC patients. Fifty-one patients with CRC metastatic disease were analysed. All patients had bidimensionally measurable disease according to WHO criteria. The gender distribution was 37 (74%) males and 13 (26%) females; age ranged from 41 to 71 years; performance status was in all patients > or = 80 (Karnofsky index). The analysis of gene polymorphism was performed in lymphocytes by using PCR-RFLP (GSTA1, GSTP1), PCR (GSTT1, GSTM1) and sequencing analysis (UGT1A1 *28). An appreciable significant association was observed between the GSTT1-null and toxicity: 57% developed gastrointestinal toxicity grade III versus 23% of patients with GSTT1-present genotype (p = 0.053). The other polymorphisms analysed did not show any significant relation with toxicity. Our data suggest that GSTT1-null is associated with a greater probability of developing toxicity to 5-Fu/CPT-11/Lv treatments, indicating a potential application of this genetic analysis in predicting adverse effects of this regimen.
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PMID:Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients. 1686 49

Promoter hypermethylation is responsible for gene inactivation during carcinogenesis. It has been proposed that there is some degree of specificity in the set of genes that become altered by this mechanism in distinct tumor types. To understand whether promoter hypermethylation may differentiate the site of origin, 49 lung adenocarcinomas from 31 lung primaries and 18 metastases from colorectal primaries, respectively, were tested for the presence of this alteration in the APC, CDH1, DAPK, GSTP1, MLH1, MGMT, P14, P16, RARbeta2, RASSF1, sFRP1 and WIF-1 genes. A distinct profile was apparent for the 2 groups of lung tumors and the frequencies of promoter hypermethylation at sFRP1 and WIF-1, 2 genes involved in Wnt signaling, and at CDH1 were significantly higher in colorectal metastases than in lung primaries, whereas methylation of the APC promoter was significantly more common in lung primary adenocarcinomas. Some tumors showed concomitant APC, sFRP1 and WIF-1 gene inactivation, indicating that multiple DNA methylation events must have occurred to definitively down-regulate the signaling through Wnt. However, promoter hypermethylation at the APC and CDH1 genes tended to be mutually exclusive (Fisher's exact test, p = 0.006), suggesting a similar role in carcinogenesis. In conclusion, we propose that inactivation by promoter hypermethylation at the APC, CDH1, sFRP1 and WIF-1 genes may contribute to the discrimination of lung primary adenocarcinomas from colorectal metastasis to the lung, and report the simultaneous presence of methylation at the promoters of multiple genes involved in the Wnt signaling. This may have biological consequences for carcinogenesis.
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PMID:Wnt signaling promoter hypermethylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung. 1699 Nov 25

A meta-analysis of recent data from the literature underscores the considerable body of present knowledge concerning prostate carcinogenesis, in part due to the numerous molecular biology tools now at our disposal. As concerns early events, much interest is being paid to modifications in the expression of GSTP1 and NKX3.1 occurring in totipotent stem cell populations. The discovery of fusion genes implicating TMPRSS2 and ERG (and, on rare occasions, other ETS family transcription factors) constitutes a major advance. Under physiological androgenic stimulation, the presence of these fusion genes leads to overexpression of genes involved in cell growth and differentiation. Concomitantly, alterations in numerous signalling pathways (growth factors, Wnt-beta catenine, PI3K/Akt) are responsible for the onset of an aggressive tumor phenotype. Hormono-independence is currently explained by an amplification of, or mutations in, androgenic receptors. These are facilitated by genomic instabilities linked to alterations in proteins which regulate gene expression, such as EZH2, and by the influence of the tumor microenvironment. Disturbances in the interactions between tumor cells and the microenvironment contribute to local extension of the tumor. Changes in the expression of E-cadherin are responsible for modifications in cell adhesion to the extracellular matrix. The expression of metalloproteases and of angiogenic factors favors tumor dissemination. Finally, the bone tropism in prostate metastases is probably linked to osteomimetic properties of prostate tumor cells which are capable of expressing certain proteins involved in bone remodelling, such as Runx-2, BSP (bone sialoprotein) and BMP (bone morphogenetic protein). Numerous studies remain to be carried out in order to correlate the identified genetic profiles and molecular anomalies with tumor prognosis. Nevertheless, the possibility of decrypting these anomalies for use in therapeutic applications is encouraging.
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PMID:[Molecular aspects of prostate cancer: recent data from the literature]. 1784 97

Metastasis is a multi-step process involving many biomolecular changes and DNA methylation is one such molecular change. Although differences in DNA methylation have been reported in matched primary and metastatic mammary carcinoma, no such differences have been reported in gastric carcinoma. Accordingly, to investigate whether DNA methylation profiles in metastatic gastric carcinoma differ from those of their primary counterparts, we investigated the DNA methylation of eleven genes, ADAM23, CDH1, FHIT, FLNC, GSTP1, ITGA4, LOX, RUNX3, THBS1, TIMP3, and UCHL1 in 74 matched human primary gastric carcinomas, lymph node metastases, non-neoplastic gastric mucosal, and uninvolved lymph node tissues by utilizing methylation-specific PCR. Seven of these genes (ADAM23, FLNC, ITGA4, LOX, RUNX3, TIMP3, and UCHL1) showed cancer-specific methylation, and three (CDH1, FHIT, and THBS1) showed cancer-unrelated methylation. GSTP1 was rarely methylated in any tissue type. Of the seven genes that showed cancer-specific methylation, FLNC was more frequently methylated in metastatic gastric carcinomas than in their primary counterparts (p=0.004). In addition, the average number of methylated genes in metastatic tumors was greater than that in primary tumors (p=0.004). The high-methylation group (cases with three or more genes methylated in primary tumors) was found to contain more women (p=0.031) and diffuse type tumors by Lauren classification (p=0.022). DNA methylation profiles were not found to affect prognosis. We suggest that promoter methylation of FLNC may be involved in the lymph node metastasis of gastric carcinoma and that the DNA methylation statuses of metastatic tumors should be considered in node-positive gastric carcinoma.
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PMID:Comparative analysis of DNA methylation between primary and metastatic gastric carcinoma. 1936 Mar 1


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