Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor gene product p53 can bind to and inhibit the helicase activity of the multisubunit transcription-repair factor TFIIH. We previously reported that p53-mediated apoptosis is attenuated in primary human fibroblasts from individuals with Xeroderma Pigmentosum (XP) that harbor mutations in the TFIIH DNA helicases XPD or XPB. In this study we show that apoptosis is reduced and delayed in three XPD lymphoblastoid cell lines (LCLs), but not in an XPD heterozygote LCL, after exposure to doxorubicin, a DNA-damaging agent and topoisomerase II inhibitor frequently used in cancer therapy. Apoptosis was assessed by quantitation of Annexin V binding to exposed phosphatidylserine residues and by caspase-mediated cleavage of Poly(ADP)Ribose Polymerase (PARP). Apoptosis induced by doxorubicin was suppressed in LCLs retrovirally transduced with the Human Papillomavirus 16 E6 oncoprotein, consistent with the hypothesis that this is a p53-dependent process. PARP cleavage was not delayed in XPD LCLs in response to anti-Fas (CD95) antibody-mediated apoptosis, thus, the defect in the apoptotic pathway in these cells lies upstream of caspase activation. Similar changes in the expression of apoptosis-effector genes, p53, and p53-responsive genes p21Cip1/WAF-1/Sid1 (p21), gadd45, bcl-2 and bax were observed in normal and XPD LCLs after treatment with doxorubicin, indicating that delayed apoptosis was not a consequence of defective transcription of these genes. Thus, our studies provide further support to the hypothesis that XPD and p53 can functionally interact in a p53-mediated apoptotic pathway.
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PMID:Drug-induced apoptosis is delayed and reduced in XPD lymphoblastoid cell lines: possible role of TFIIH in p53-mediated apoptotic cell death. 1046 15

Cisplatin or carboplatin is commonly used with gemcitabine, docetaxel, paclitaxel or vinorelbine as chemotherapy doublets in the treatment of advanced non-small cell lung cancer. Several randomized trials have failed to identify major differences in survival between any of these doublets. This lack of evidence for improvement in survival with any chemotherapy regimen has created a tabula rasa in which no more large randomized trials should be conducted with out including a genetic analysis. Patients see survival as their major concern, and other considerations, such as cost of treatment and qualify of life, are relegated to lower positions. Genetic alterations related to the transcription-coupled repair pathway of the nucleotide excision repair system (TC-NER) have revealed the subset of patients who are resistant to cisplatin. TC-NER involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. For a long time, ERCC1 mRNA levels have been known to correlate with DNA repair capacity in various tissues. Levels of DNA cisplatin adducts in peripheral blood and buccal mucosa cells predict chemotherapy response, and high ERCC1 mRNA levels have been related to chemoresistance in ovarian cancer and in malignant lymphocytes from chronic lymphocytic leukemia. Moreover , in some instances, mRNA expression has been correlated with polymorphisms. Overexpression of ERCC1 correlates with poor survival gemcitabine/cisplatin-treated non-small cell lung cancer patients. An ongoing customized ERCC1-based chemotherapy trial has been established on this knowledge. Patients are randomized to the control arm of cisplatin/docetaxel is combined with cisplatin or gemcitabine according to ERCC1 levels. To date, 80 patients have been included. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. Some XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to disease progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; p = 0.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biological redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings indicate that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival. This highlights the possibilities of individually tailored chemotherapy. However, in patients treated with cisplatin/vinorelbine, the opposite effect has been observed. Patients with Lys751Lys had a longer time to progression. When docetaxel was added to gemcitabine/cisplatin, patients with Lys751Lys also had better survival. Our findings indicate that TC-NER status can help to decide between cisplatin/gemcitabine and docetaxel/ cisplatin. TC-NER-dependent activity is similar to other anticancer agents that cause DNA-binding enzymes to kill cells (topoisomerase inhibitors). At least 50% of non-small cell lung cancer patients harbor Lys751Lys and can benefit from docetaxel/ cisplatin treatment. Genes involved in spindle formation, centrosome functions and mRNA transport along the microtubule tracks should provide further information on potential markers of docetaxel resistance.
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PMID:Influence of genetic markers on survival in non-small cell lung cancer. 1466 33

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

Doxorubicin, a widely used anthracycline anticancer agent, acts as a topoisomerase II poison but can also form formaldehyde-mediated DNA adducts. This has led to the development of doxorubicin derivatives such as doxoform, which can readily form adducts with DNA. This work aimed to determine which DNA repair pathways are involved in the recognition and possible repair of anthracycline-DNA adducts. Cell lines lacking functional proteins involved in each of the five main repair pathways, mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end-joining (NHEJ) were examined for sensitivity to various anthracycline adduct-forming treatments. The treatments used were doxorubicin, barminomycin (a model adduct-forming anthracycline) and doxoform (a doxorubicin-formaldehyde conjugate). Cells with deficiencies in MMR, BER and NHEJ were equally sensitive to adduct-forming treatments compared to wild type cells and therefore these pathways are unlikely to play a role in the repair of these adducts. Some cells with deficiencies in the NER pathway (specifically, those lacking functional XPB, XPD and XPG), displayed tolerance to adducts induced by both barminomycin and doxoform and also exhibited a decreased level of apoptosis in response to adduct-forming treatments. Conversely, two HR deficient cell lines were shown to be more sensitive to barminomycin and doxoform than HR proficient cells, indicating that this pathway is also involved in the repair response to anthracycline-DNA adducts. These results suggest an unusual damage response pathway to anthracycline adducts involving both NER and HR that could be used to optimise cancer therapy for tumours with either high levels of NER or defective HR. Tumours with either of these characteristics would be predicted to respond particularly well to anthracycline-DNA adduct-forming treatments.
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PMID:DNA repair in response to anthracycline-DNA adducts: a role for both homologous recombination and nucleotide excision repair. 1796 7

Doxorubicin (DOX), a member of the anthracycline group, is a widely used drug in cancer therapy. The mechanisms of DOX action include topoisomerase II-poisoning, free radical release, DNA adducts and interstrand cross-link (ICL) formation. Nucleotide excision repair (NER) is involved in the removal of helix-distorting lesions and chemical adducts, however, little is known about the response of NER-deficient cell lines to anti-tumoral drugs like DOX. Wild type and XPD-mutated cells, harbouring mutations in different regions of this gene and leading to XP-D, XP/CS or TTD diseases, were treated with this drug and analyzed for cell cycle arrest and DNA damage by comet assay. The formation of DSBs was also investigated by determination of gammaH2AX foci. Our results indicate that all three NER-deficient cell lines tested are more sensitive to DOX treatment, when compared to wild type cells or XP cells complemented by the wild type XPD cDNA, suggesting that NER is involved in the removal of DOX-induced lesions. The cell cycle analysis showed the characteristic G2 arrest in repair-proficient MRC5 cell line after DOX treatment, whereas the repair-deficient cell lines presented significant increase in sub-G1 fraction. The NER-deficient cell lines do not show different patterns of DNA damage formation as assayed by comet assay and phosphorylated H2AX foci formation. Knock-down of topoisomerase IIalpha with siRNA leads to increased survival in both MRC5 and XP cells, however, XP cell line still remained significantly more sensitive to the treatment by DOX. Our study suggests that the enhanced sensitivity is due to DOX-induced DNA damage that is subject to NER, as we observed decreased unscheduled DNA synthesis in XP-deficient cells upon DOX treatment. Furthermore, the complementation of the XPD-function abolished the observed sensitivity at lower DOX concentrations, suggesting that the XPD helicase activity is involved in the repair of DOX-induced lesions.
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PMID:Effect of the anti-neoplastic drug doxorubicin on XPD-mutated DNA repair-deficient human cells. 1992 38