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)

Metastatic cancer in adults usually has a fatal outcome. In contrast, advanced testicular germ cell tumours are cured in over 80% of patients using cisplatin-based combination chemotherapy [1]. An understanding of why these cells are sensitive to chemotherapeutic drugs is likely to have implications for the treatment of other types of cancer. Earlier measurements indicate that testis tumour cells are hypersensitive to cisplatin and have a low capacity to remove cisplatin-induced DNA damage from the genome [2] [3]. We have investigated the nucleotide excision repair (NER) capacity of extracts from the well-defined 833K and GCT27 human testis tumour cell lines. Both had a reduced ability to carry out the incision steps of NER in comparison with extracts from known repair-proficient cells. Immunoblotting revealed that the testis tumour cells had normal amounts of most NER proteins, but low levels of the xeroderma pigmentosum group A protein (XPA) and the ERCC1-XPF endonuclease complex. Addition of XPA specifically conferred full NER capacity on the testis tumour extracts. These results show that a low XPA level in the testis tumour cell lines is sufficient to explain their poor ability to remove cisplatin adducts from DNA and might be a major reason for the high cisplatin sensitivity of testis tumours. Targeted inhibition of XPA could sensitise other types of cells and tumours to cisplatin and broaden the usefulness of this chemotherapeutic agent.
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PMID:Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. 1007 55

Over 80% of patients with advanced metastatic testis tumors can be cured using cisplatin-based combination chemotherapy. This is unusual as metastatic cancer in adults is usually incurable. Cell lines derived from testis tumors retain sensitivity to cisplatin in vitro. We previously investigated 2 testis tumor cell lines with a low capacity to remove cisplatin-induced DNA damage and found that they had low levels of the DNA nucleotide excision repair proteins XPA, ERCC1 and XPF. To determine whether low levels of XPA, ERCC1 and XPF proteins are characteristic of testis tumor cell lines, we investigated 35 cell lines derived from cancers to determine whether groups of cell lines from diverse tissue origins differ from one another in constitutive levels of these NER proteins. Quantitative immunoblotting was used to compare groups of cell lines representing prostate, bladder, breast, lung, cervical, ovarian and testis cancers. Only the 6 testis tumor cell lines showed significantly lower mean levels of XPA (p = 0.001), XPF (p = 0.001) and ERCC1 (p = 0.004) proteins from the other groups. Our results encourage further investigation of the possibility that low levels of these nucleotide excision repair proteins could be related to the favorable response of testis tumors to cisplatin-based chemotherapy.
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PMID:Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. 1509 99

Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable interindividual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.
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PMID:Pharmacogenomics of fluorouracil, irinotecan, and oxaliplatin in hepatic metastases of colorectal cancer: clinical implications. 1572 86

Approximately half of lung cancer patients present with metastases, and a large proportion will develop recurrent disease, with median survival to cisplatin-based chemotherapy of 11 months. No predictive factor of response to cisplatin-based chemotherapy is yet available in clinical practice. The nucleotide excision repair system plays a major role in repairing a variety of distorting lesions, notably platinum-induced DNA adducts. ERCC1 is a leading gene in repairing cisplatin DNA damage. We carried out three different studies examining individually the role of ERCC1, RRM1, and then both, mRNA expression in paraffin-embedded pretreatment bronchial biopsies from gemcitabine/cisplatin-treated advanced non-small-cell lung cancer (NSCLC) patients. Median survival was significantly prolonged in patients with low levels of ERCC1 or RRM1. BRCA1 is involved in homologous recombination repair, and we observed that low levels of BRCA1 mRNA significantly increased survival in gemcitabine/cisplatin-treated patients. Our observations lead us to recommend that tumors be regularly assessed for ERCC1 and BRCA1 mRNA expression in order to customize gemcitabine/cisplatin treatment.
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PMID:Pharmacogenomics and gemcitabine. 1680 41

The crucial 'flaw' in the existing treatment paradigm for non-small cell lung cancer (NSCLC) is the 'one size fits all approach'. Consequently, adjuvant chemotherapy is given to all patients to benefit a minority and, in the metastatic setting doublet chemotherapy only provides modest improvements in response rates and survival. A personalized approach of treatment selection is therefore desperately needed. Genetic information is stored in the chemical structure of DNA. To maintain the structural integrity of DNA, an intricate network of DNA repair systems have evolved. One of these is the nucleotide excision repair (NER), a highly versatile and sophisticated DNA damage removal pathway. We show here that this DNA repair mechanism is instrumental in defining prognosis and response to treatment. ERCC1, one of the proteins in this pathway, is measured to assess its functional status of the NER pathway. In patients with early stage NSCLC, low ERCC1 predicts for relapse and selects for patients who will benefit from adjuvant cisplatin-based chemotherapy. Conversely, ERCC1-positive resected patients have a better intrinsic prognosis and are not likely to benefit from platinum based chemotherapy. In a phase II trial in metastatic disease, we show that by tailoring chemotherapy using ERCC1 and RRM1 we can obtain 1-year survival of 60% (versus approximately 36% in historical controls) and response rates of 42% (versus 25% in historical controls). This approach is currently being validated in a prospective phase III trial. In the future, assessment of NER function may play a central role in NSCLC treatment decision making.
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PMID:Nuclear excision repair-based personalized therapy for non-small cell lung cancer: from hypothesis to reality. 1760 Jul 54

The prognosis of patients with non-small cell lung cancer continues to be poor. Multimodality treatment strategies including chemotherapy are indicated for almost all stages of the disease. To be able to customize chemotherapy based on individual patients' clinical or biological markers is a priority for translational research. Several possible markers need to be validated. In this review, we will discuss the potential of ERCC1 (excision repair cross complementary group 1) to predict sensitivity to cisplatinum, of tubuline-beta, class III for vinca-alkaloids and taxanes, RRM1 (ribonucleotide transferase subunit 1) for gemcitabine and lastly demographic parameters as well biological parameters for erlotinib. Data will be presented separately for patients with metastatic disease and for those where it is localized.
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PMID:[Predicting the response to chemotherapy in patients with non-small cell lung cancer]. 1823 15

Nucleotide excision repair (NER) is a key node of resistance of tumour cells to the anticancer drug cisplatin. Testicular germ cell tumours (TGCT) show exquisite sensitivity towards cisplatin, and this has been connected to low levels of the NER proteins ERCC1 and XPF. Tumours of some patients with advanced head and neck squamous cell carcinoma (HNSCC) regress well under cisplatin chemotherapy but prediction of responsiveness is poor. Little is known about the levels of ERCC1-XPF in HNSCC tissues and cell lines. We investigated mRNA and protein levels of ERCC1 and XPF in 13 HNSCC cell lines and seven testis tumour cell lines and examined the correlation between levels of ERCC1 and XPF and cellular resistance towards cisplatin. No significant difference in mRNA expression of either ERCC1 or XPF in the HNSCC cell lines compared to the testis tumour cell lines was observed. Significantly higher XPF protein levels were found in HNSCC cell lines compared to testis tumour cell lines resulting in cellular cisplatin resistance. The data indicate a contribution of XPF protein for the cisplatin resistance observed in HNSCC cell lines. Subsequently, XPF and ERCC1 protein expression was investigated in cancer tissue of 34 patients. XPF levels were significantly higher in metastases of HNSCC patients than in primary cancer tissue. These findings indicate a contribution of XPF protein for the observed chemoresistance in some HNSCC tissue. XPF protein may be a predictive marker for cisplatin responsiveness of metastases in HNSCC patients.
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PMID:Metastases of squamous cell carcinoma of the head and neck show increased levels of nucleotide excision repair protein XPF in vivo that correlate with increased chemoresistance ex vivo. 2037 3

ERCC1 plays a critical role in the repair of lesions in DNA induced by cisplatin. It has been demonstrated that, in patients with resected NSCLC, those with ERCC1-negative tumours had greater benefit from adjuvant chemotherapy than patients with ERCC1-positive tumours. On the other hand, patients with ERCC1-positive tumours have a better prognosis. ERCC1 can be evaluated either by the level of protein expression on immunohistochemical analysis or by quantification of its mRNA expression. At present ERCC1 appears to be a promising biomarker for predicting the benefit of cisplatin based chemotherapy and its modulation could allow sensitisation of tumour cells to this drug. Its use in daily clinical practice requires a further stage of prospective validation studies which are already in progress in patients both with completely resected NSCL or metastatic disease.
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PMID:[ERCC1 and lung cancer]. 2040 38

Patients with locally advanced/inflammatory breast cancer (LABC/IBC) face a high likelyhood of recurrence and prognosis for relapsed, or de novo stage IV metastatic breast cancer (MBC) remains poor. Estrogen (ER) and HER2 receptor expression on primary or MBC allow targeted therapies, but an estimated 10-18% of tumors do not exhibit these biomarkers and survival in these cases is even poorer. Variations in discordance rates for the expression of ER and HER2 receptors have been observed between primary and metastatic tumors and such discordances may lead to suboptimal treatment. Circulating tumor cells (CTCs) are considered the seeds of residual disease and distant metastases and their characterization could help guide treatment selection. To explore this possibility, we used multiple biomarker assessment of CTCs in comparison to primary and metastatic tumor sites. Thirty-six patients with LABC/IBC, or stage IV MBC were evaluated. Blood samples were procured prior to initiating or changing therapy. CTCs were identified based on presence of cytokeratin and nucleus staining, and the absence of CD45. A multimarker assay was developed to simultaneously quantify expression of HER2, ER, and ERCC1, a DNA excision repair protein. Novel fiber-optic array scanning technology (FAST) was used for sensitive location of CTCs. CTCs were detected in 82% of MBC and 62% LABC/IBC cases. Multiplex marker expression was successfully carried out in samples from18 patients with MBC and in 8 patients with LABC/IBC that contained CTCs. In MBC, we detected actionable discordance rates of 40 and 23%, respectively for ER and HER2 where a biomarker was negative in the primary or metastatic tumor and positive in the CTCs. In LABC/IBC, actionable discordances were 60 and 20% for ER and HER2, respectively. Pilot trials evaluating the effectiveness of treatment selections based on actionable discordances between biomarker expression patterns on CTCs and primary or metastatic tumor sites may allow for a prospective assessment of CTC-based individualized targeted therapies.
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PMID:Multiple biomarker expression on circulating tumor cells in comparison to tumor tissues from primary and metastatic sites in patients with locally advanced/inflammatory, and stage IV breast cancer, using a novel detection technology. 2149 85

Systemic combination chemotherapy, such as the methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) regimen, has shown certain activity in advanced bladder cancer, but is associated with a significant toxicity burden, with a treatment-related mortality of about 4%. Therefore, a great deal of interest has been focused on the gemcitabine-cisplatin (GC) combination chemotherapy which showed the same antitumor effect as MVAC chemotherapy with far less toxicity. Indeed, the GC regimen is now frequently administered as the first-line chemotherapy against metastatic bladder cancer. For the present, GC/MVAC regimens constitute alternative platform chemotherapy, until new evidence based strategy can be demonstrated. Accordingly it is important to be able to predict whether a regimen is effective in each patient with bladder cancer before the initiation of chemotherapy. Clinicopathological factors as the Karnofsky performance status and the presence of visceral metastases are well-established prognostic markers for poor survival. However, they are inadequate to predict the optimal therapeutic regimen for each individual patient. As for the predictive marker of cisplatin, ERCC1 may predict survival in bladder cancer treated by platinum-based therapy. The predictive potential of gemcitabine has not been previously considered in advanced bladder cancer treated by gemcitabine-combined systemic chemotherapy. In our retrospective study, the predictive value of a high expression level of hENT1 was assessed in bladder cancer treated by gemcitabine combined combination chemotherapy.
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PMID:[The prognostic significance of human equilibrative nucleoside transporter1 (hENT1) expression in metastatic bladder cancer patients treated with gemcitabine-cisplatin based combination chemotherapy]. 2158 90


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