Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug selection, the key for chemotherapy, is one of the most difficult decision-making in clinic for the treatment of malignant tumors. How to choose is undetermined. Here a new strategy--predictive molecule-targeted chemotherapy (PMTC)--is put forward to choose relatively sensitive chemotherapeutic drugs and to avoid relatively resistant traditional drugs according to the expression of predictive molecules in individual tumor tissue. For example, paclitaxel is regarded as a relatively sensitive drug and may be chosen for the tumors with high expression of p53, while it is predicted as relatively resistant drug and should be avoided for the tumors with high expression of P-glycoprotein (P-gp). Here, we reviewed the predictive values of a variety of molecules, such as p53, P-gp, topoisomerase-1, topoisomerase-2, MSI, BRCA-1, ERCC1, FANC, hMHL1/2, XPD, Bcl-2, ErbB-2, MGMT, dihydropyridine dehydrogenase (DPD), thymidylate synthetase (TS), deoxycytidine kinase (dCK), Ras, Bax, Cyclin A, tubulin proteins, and so on, for the efficacy of some traditional chemotherapeutic drugs, such as platinum, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, methotrexate, 5-flurouracil, gemcitabine, vincristine, vinorelbine, paclitaxel, etoposide, irinotecan, topotecan, and so on.
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PMID:[Routine chemotherapeutic drug treatment effectiveness predictive molecules and chemotherapeutic drug selection]. 1716 91

Increasingly, multimodal treatment protocols are being employed to improve the survival of patients with locally advanced adenocarcinomas of the upper gastrointestinal tract; however, only 30%-40% of the patients respond to 5-fluoro-uracil (5-FU) and cisplatin-based neoadjuvant chemotherapy. The goal of our studies is the identification of reliable genetic markers--on the genomic DNA, messenger RNA (mRNA), or protein level-that could predict response of upper gastrointestinal carcinomas prior to neoadjuvant chemotherapy. In esophageal carcinomas, a higher gene expression of methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism, was more frequently found in responding patients. In addition high gene expression of caldesmon and of the two drug carrier proteins MRP1 and MDR1 was associated with response to therapy. By performing a genome-wide profiling on the protein level in a small group of patients, new potential markers were identified that will have to be validated in ongoing studies. In gastric carcinomas, mutations of the p53 gene revealed no association with response or survival, but tumors with a high rate of loss of heterozygosity, as determined by microsatellite analysis, showed a better response to a cisplatin-based chemotherapy. Analysis of the expression of 5-fluorouracil (5-FU) (TS, DPD, TP)- and cisplatin (ERCC1, ERCC4, GADD45A, KU80)-related genes demonstrated an association of DPD expression with response and survival. The combined consideration of TP and GADD45 gene expression showed the most obvious association with therapy response in this tumor. Our studies point to promising markers with potential use for chemotherapy response prediction of adenocarcinomas of the upper gastrointestinal tract, but prospective studies for validation are necessary.
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PMID:Prediction of response to neoadjuvant chemotherapy in carcinomas of the upper gastrointestinal tract. 1760 14

Both genetic variants and messenger RNA (mRNA) expression of DNA repair and tumor suppressor genes have been investigated as molecular markers for therapy outcome. However, the phenotypic impact of genetic variants often remained unclear, thus the rationale of their use in risk prediction may be limited. We therefore analyzed genetic variants together with anthropometric and lifestyle factors to see how these affect mRNA levels of ERCC1, MDM2 and TP53 in primary blood lymphocytes. mRNA expression was measured in 376 prostate cancer patients by quantitative real-time polymerase chain reaction after reverse transcription, and ERCC1 rs11615 T>C, ERCC1 rs3212986 C>A, MDM2 rs2279744 T>G and TP53 rs17878362 (p53PIN3) polymorphisms were determined. Considerable interindividual differences in mRNA expression were found (coefficients of variation: ERCC1, 45%; MDM2, 43% and TP53, 35%). ERCC1 expression was positively correlated with plasma levels of beta-carotene (P = 0.03) and negatively correlated with canthaxanthin (P = 0.02) and lutein (P = 0.02). Overall, the polymorphisms affected mRNA expression only weakly. Carriers of a distinct ERCC1 haplotype (CC) showed, however, significantly lower expression values than non-carriers (P = 0.001). Applying logistic regression, we found that CC haplotype carriers had a 1.69-fold increased odds ratio (95% confidence interval: 1.06-2.71) for reduced ERCC1 mRNA levels. This low ERCC1 expression might be associated with reduced DNA repair and better therapy response. In summary, the association we have found between ERCC1 genotype and mRNA expression supports recent clinical observations that genetic variation in ERCC1 can affect treatment outcome and prognosis. Our study further revealed a modulating effect by nutritional factors.
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PMID:A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients. 1833 46

The cytosine nucleoside analogue 2'-C-cyano-2'-deoxy-1-beta-d-arabino-pentofuranosylcytosine (CNDAC) causes DNA single-strand breaks after its incorporation into DNA. This investigation sought to determine if DNA excision repair pathways were activated to repair this damage. Neither the base excision repair nor the mismatch repair pathway seemed to be involved. Cells deficient in the CSB protein, which initiates transcription-coupled nucleotide excision repair (NER) pathway (TC-NER), exhibited increased clonogenic sensitivity to CNDAC, whereas cells deficient in XPC, which initiates global genome NER, were slightly resistant relative to wild-type cells. The cells lacking either helicase XPB, which unwinds 5' of the lesion, or endonuclease XPF, which incises 5' to a lesion, exhibited increased clonogenic sensitivity to CNDAC, as did cells lacking the XPF partner protein ERCC1. This sensitization was independent of p53 function. Repletion of XPF restored sensitivity comparable with the wild type. In contrast, cells lacking either XPD, the 3'-helicase, or the 3'-endonuclease XPG were equally as sensitive as wild-type cells. In comparison, cells deficient in XPF were not sensitized to other cytosine nucleoside analogues, troxacitabine and cytarabine. Thus, the single-strand nick caused by CNDAC is recognized and, in part, repaired by the TC-NER pathway. NER proteins that function in the 5' direction relative to the UV-induced lesion also participate in the repair of the CNDAC-induced nick, in contrast to proteins that process on the 3' side of the lesion.
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PMID:Repair of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine-induced DNA single-strand breaks by transcription-coupled nucleotide excision repair. 1848 73

Recent years have brought tremendous progress in the development of genomic and proteomic platforms to study cancer biology. Tests based on these platforms are helpful in early diagnosis, prognosis, and prediction of treatment benefit. Molecular studies performed on minimally invasive material (plasma, sputum) from individuals participating in longitudinal or case-control studies have approximately 70%-90% sensitivity and specificity to detect lung cancer. In operable non-small-cell lung cancer, genomic and proteomic studies yield better prognostic information than pathologic staging. There are several examples of successful identification of predictive assays for benefit from chemotherapy (ERCC1, RRM1, p27Kip1, and p53 expression) or targeted therapies (epidermal growth factor receptor [EGFR] gene copy number, EGFR activating mutations, EGFR protein expression, serum proteomic profile). These markers should be prospectively tested in clinical studies before they can be routinely used in the clinic.
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PMID:Advances in genomic and proteomic studies of non-small-cell lung cancer: clinical and translational research perspective. 1850 Oct 93

Ovarian cancer shows considerable variability in its chemoresponse, however, the prospect of individualized medicine holds high hopes for improving patient survival. The influence of interindividual genomic polymorphisms on drug response (pharmacogenomics) is well established, and a variety of candidate loci in ovarian tumors have been identified, including ERCC1, ABCB1 and p53 variants. Recently pharmacoepigenomic modulators of key genes and pathways, such as promoter methylation (MLH1 and BRCA1 genes) and microRNA regulation (PTEN/AKT and NF-kappaB pathways) have been implicated in ovarian cancer chemoresponse. Epigenomic studies have until now mainly focused on tumor-specific changes, although germ-line epigenetic change may also be of importance. However, assessing the relevance of these potential pharmaco(epi)genomic biomarkers in clinical trials requires well powered studies in homogeneous populations, with independent validation sets, to distinguish real associations from false-positives. In addition, the selection of one gene or locus as having sufficient phenotypic effect to impact on clinical outcome may be an oversimplification. Integrated approaches that identify stable pharmacogenomic and epigenomic patterns and their relationship with expression patterns and gene function will be increasingly necessary.
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PMID:Pharmaco(epi)genomics in ovarian cancer. 1907 41

The impact of DNA damage-induced replication blockage for early activation of stress kinases [stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)] is largely unknown. Here, we show that induction of dual phosphorylation of SAPK/JNK by the DNA polymerase inhibitor aphidicolin was not ameliorated by additional exposure to ultraviolet (UV) light, indicating that overlapping mechanisms participate in signaling to SAPK/JNK triggered by both agents. UV-induced DNA replication blockage, cyclobutane pyrimidine dimer formation and DNA strand break induction coincided with SAPK/JNK phosphorylation at early (< or =30 min) but not late (> or =2 h) time points after exposure. Genotoxin-stimulated SAPK/JNK activation was attenuated in nonproliferating cells, indicating that S phase-dependent mechanisms are involved in signaling to SAPK/JNK. Correspondingly, UV-induced phosphorylation of SAPK/JNK was higher in S-phase cells as compared with G(1)-phase cells. Activation of SAPK/JNK by genotoxins was below detection limit in nonproliferating human peripheral blood lymphocytes, whereas peripheral blood lymphocytes stimulated to proliferation displayed clear SAPK/JNK activation. UV-induced phosphorylation of SAPK/JNK was attenuated in XPC-defective cells, ameliorated in BRCA2 mutated cells and not changed in cells lacking ATM, DNA-PK, CSB, XPA, p53, ERCC1 or PARP as compared with the corresponding wild types. Based on these data, we suggest that DNA replication blockage caused by genotoxin-induced DNA damage contributes to early activation of SAPK/JNK.
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PMID:DNA replication arrest in response to genotoxic stress provokes early activation of stress-activated protein kinases (SAPK/JNK). 1910 74

Chemotherapies are widely used in the treatment of lung cancer. However, little is known about their effect in the expression of different tissue markers. Seventeen lung cancer tissue blocks obtained by bronchoscopic biopsies together with their corresponding surgical biopsies after neoadjuvant chemotherapy were studied. They included 9 adenocarcinomas (ADC) and 8 squamous cell carcinomas (SCC). Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues to study the expression of Ki-67, p53, Bcl-2, Bax, Fas-ligand and ERCC1 (excision repair cross-complementation group 1). Out of 17 NSCLC 6 expressed proapoptotic markers and 4 expressed antiapoptotic markers, while in 7 cases the apoptotic markers did not show detectable changes after neoadjuvant chemotherapy. Six of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment. Eight bronchoscopic NSCLC tissues (6 SCC, 2 ADC) expressed ERCC1. All but one ADC became ERCC1 negative after neoadjuvant therapy. There was no newly expressed ERCC1 positive case in the surgical biopsy group. Platinum-based neoadjuvant chemotherapy had no effect on the apoptotic activity of 17 patients' tumor specimen, however, 6 of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment, in 3 cases the level of Ki-67 became decreased, while 8 cases had no detectable change of proliferation activity. The results of the present study suggest that platinum-based chemotherapy probably induces a selection of tumor cells with more aggressive phenotype, and also affects the expression of tissue marker (ERCC1) that could have predictive value.
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PMID:Platinum-based chemotherapy in lung cancer affects the expression of certain biomarkers including ERCC1. 1925 35

Platinum drugs are among the most active and widely used agents in the treatment of different cancers. However, the great individual variability in both outcome and toxicity of platinum chemotherapy requires the identification of genetic markers that can be used to screen patients before treatment. In this study, 21 polymorphisms in 10 genes, the protein activities of which may be addressed in different aspects of cisplatin metabolism, were tested for correlations with efficacy and toxicity of cisplatin-cyclophosphamide regimen in 104 ovarian cancer patients. The glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism was strongly associated with progression-free survival (chi(2)=12.12, P=0.002). The allelic status of the GSTA1 -69 C>T polymorphism correlated with the overall survival: patients with T/T genotype survived longer than C/C carriers (P=0.044). Thrombocytopenia, anemia and neuropathy were less frequent among patients with the GSTM1-null or GSTM3 intron 6 AGG/AGG genotypes. Severe neutropenia was associated with the TP53 72 Pro/Pro, XPD 312 Asp/Asn and XRCC1 399 Arg/Arg genotypes. A higher risk of nephrotoxicity was noted for patients with the heterozygous ERCC1 19007 T/C and 8092 C/A genotypes. No correlations were found between genotypes and complete tumor responses.
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PMID:Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients. 1978 80

Lung cancer is one of the most common cancers in the world. While historically, more men than women have died from lung cancer as a result of higher numbers of male smokers, the sex mortality ratio is now showing signs of narrowing. Tumors in women with lung cancer may be slightly different to those in men with lung cancer. This review focuses on biomarkers differentially expressed between female and male patients with lung cancer. There is variation in gene expression between men and women in some genes that encode carcinogen-metabolizing enzymes (CYP1A1, GSTM). Gastrin-releasing peptide (GRP), a bombesin-like peptide, is present in two actively transcribed alleles in women compared with men. Higher prevalence of infection with oncogenic variants human papilloma viruses (HPVs) HPV16 and HPV18 has been suggested in women. A higher frequency of G to T transversion was found in the p53 gene in lung tumors of women. KRAS mutation was found to be more frequent in women with resected non-small cell lung cancer (NSCLC) than in men with resected NSCLC. Epidermal growth factor receptor (EGFR) mutation is more frequently found in lung tumors from women, but the confounding effect of tobacco exposure may explain this difference. Lower levels of ERCC1 and BRCA1 have been reported in women with NSCLC. Lung tumors from women are more likely to express estrogen receptors than those from men. An in silico analysis of transcriptome datasets from lung cancer patients demonstrated that only seven genes (in at least two studies) had significantly different expression patterns in male versus female patients. All of these genes are localized on the sex chromosomes: one on chromosome X and six on chromosome Y. Many areas remain under debate and there are still significant gaps in our understanding, particularly how sex-linked factors relate to lung cancer risk, and to biological and clinical behaviors. Future research into lung cancer needs to address these gender differences more specifically.
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PMID:Differential expression of biomarkers in men and women. 1999 47


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