Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The examination of topoisomerase II alpha content by Western blot analysis or topoisomerase II catalytic activity by decatenation of kDNA requires a large number of cells, but it is difficult to collect sufficient cells for these biochemical analyses from lung cancer patients by transbronchial brushing or aspiration. In this study, we explored the relationship between these biochemical analyses and topoisomerase II immunostaining in cytospin preparations of three lung adenocarcinoma cell lines. The levels of topoisomerase II alpha content were about 8.4 for A549, 2.9 for PC-3 and 1 for RERF-LC-MS, and the levels of topoisomerase II catalytic activity were about 4, 2, and 1, respectively. The percentages of strongly positive cells for topoisomerase II immunostaining were 60.9% for A549, 33.3% for PC-3, and 14.3% for RERF-LC-MS, and these were compatible with the levels of topoisomerase II alpha content or topoisomerase II catalytic activity. Our results indicate that topoisomerase II immunostaining can be utilized in place of biochemical analysis.
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PMID:Quantitative immunocytochemical assays of topoisomerase II in lung adenocarcinoma cell lines. Correlation to topoisomerase II alpha content and topoisomerase II catalytic activity. 869 54

Topoisomerase II is a key target of many anticancer drugs used to treat lung cancer. We measured the expression of topoisomerase II alpha and beta mRNA's and also the levels of cellular topoisomerase II alpha and beta protein and concluded that topoisomerase II alpha levels are important in cellular resistance to the topoisomerase II inhibitors examined. This can be clearly seen in pairs of matched cell lines. However, when looking at a panel of cell lines with a range of histological types the importance of the enzyme can be masked by other cellular characteristics such as repair and detoxification mechanisms.
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PMID:Relationship between topoisomerase II levels and resistance to topoisomerase II inhibitors in lung cancer cell lines. 871 77

Anthracenyl-amino acid conjugates (AAC) represent a novel class of topoisomerase (topo) inhibitor. The relationship between mechanism of enzyme inhibition and in vitro cytotoxicity has been investigated in a panel of 5 Chinese hamster ovary (CHO) and 2 human ovarian cancer cell lines (A2780) shown to possess different drug resistance phenotypes associated with altered expression of topo I and topo II. From a total of 13 compounds, 4 displayed broad-spectrum activity (IC50 ranging from 3.5-29.7 microM). NU/ICRF 500 (topo II catalytic inhibitor) was 1.4-fold more active against CHO ADR-1, which overexpresses topo II and was essentially noncross-resistant in CHO ADR-r (13.9-fold resistant to doxorubicin (DOX)) and 2780AD (1,460-fold resistant to DOX). NU/ICRF 505, which stabilises topo I cleavable complexes, was noncross-resistant in CHO ADR-3 (3,4-fold resistant to camptothecin) and only 1.8-fold cross-resistant in 2780AD. Hypersensitivity was recorded in ADR-r that overexpresses topo I. The most active compound was NU/ICRF 506, a dual catalytic inhibitor of topo I and II. Hypersensitivity was observed in ADR-r (1.4-fold) but not ADR-1, indicating that topo I is the likely nuclear target, and a low level of resistance was seen in the CHO ADR-6 drug transport mutant and 2780AD. The topo II catalytic inhibitor NU/ICRF 513 only produced hypersensitivity in ADR-r. These data suggest that NU/ICRF 500, 505, and 506 induce cell death, at least partly, through topo inhibition. NU/ICRF 513 appears to be cytotoxic via a nontopo mechanism of action. In addition, NU/ICRF 505 significantly inhibited the growth of two human xenografts (HT-29 colon cancer and NX002 nonsmall-cell lung cancer) in nude mice after i.p. administration at a dose of 25 mg/kg. The important properties of noncross-resistance and in vivo antitumour activity merit further development of AAC as potential new anticancer drugs.
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PMID:Development of anthracenyl-amino acid conjugates as topoisomerase I and II inhibitors that circumvent drug resistance. 883 16

The molecular cytogenetic techniques of comparative genomic hybridization (CGH) and reverse in situ hybridization (REVISH) allow the entire genomes of tumours to be screened for genetic changes without the requirement for specific probes or markers. In order to define the ability of REVISH to detect and map regions of amplification associated with drug resistance, we investigated a panel of cell lines selected for resistance to doxorubicin and intrinsic sensitivity to topoisomerase II-inhibitory drugs. We have defined a modified REVISH protocol, which involves double hybridizations with genomic DNA from the test cell lines and chromosome-specific whole chromosome paints to identify the chromosomes to which the amplicons localize. Sites of amplification are then mapped by fractional length measurements (Flpter), using published genome databases. Our findings show that amplification of the topoisomerase II alpha gene is readily detected and mapped, as is amplification of the MDR and MRP loci. Interestingly, REVISH detected a new amplicon in the doxorubicin-resistant lung cancer cell line, GLC4-ADR, which mapped to chromosome 1q. REVISH is therefore ideally suited to characterize genetic changes specific for drug resistance within a background of genetic anomalies associated with tumour progression.
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PMID:Identification of genetic changes associated with drug resistance by reverse in situ hybridization. 901 38

Twenty tumoral and peritumoral tissues from patients with lung cancer were analyzed immunohistochemically for the drug resistance-related proteins P-glycoprotein (P-170), topoisomerase II (Topo-II), glutathione S-transferase-pi (GST-pi), metallothionein (MT), heat shock protein-70 (HSP-70) and the putative regulators of resistance (ErbB1, Fos and Jun). Protein expression of Topo-II, GST-pi, MT, HSP-70, ErbB1, Fos and Jun was elevated in tumor tissue in comparison to normal tissue. The different expression of the proteins between tumoral and normal tissues was statistically significant for Topo-II (P = 0.05), MT (P = 0.03), and HSP-70 (P = 0.01), whereas ErbB1 showed a borderline significance. The expression of the proteins was frequently increased in smokers in comparison to non-smokers. In general, the increase of the proteins of smokers corresponded in tumoral and non-tumoral tissue. Different expression was only found with MT and HSP-70 which were higher in tissues of smokers.
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PMID:Expression of resistance-related proteins in tumoral and peritumoral tissues of patients with lung cancer. 901 91

The acquisition of drug-resistant tumour cells is the main problem in the medical treatment of a range of malignant diseases. In recent years, three new classes of anti-cancer agents, each with a novel mechanism of action, have been brought forward to clinical trials. These are the topoisomerase I (topo I) poisons topotecan and irinotecan, which are both camptothecin derivatives, the taxane tubulin stabilizers taxol and taxotere and, finally, the antimetabolite gemcitabin, which is active in solid tumours. The process of optimizing their use in a combination with established agents is very complex, with numerous possible drug and schedule regimens. We describe here how a broad panel of drug-resistant small-cell lung cancer (SCLC) cell lines can be used as a model of tumour heterogeneity to aid in the selection of non-cross-resistant regimens. We have selected low-fold (3-10x) drug-resistant sublines from a classic (NCI-H69) and a variant (OC-NYH) SCLC cell line. The resistant cell lines include two sublines with different phenotypes towards alkylating agents (H69/BCNU and NYH/CIS), two sublines with different phenotypes against topo I poisons (NYH/CAM and NYH/TPT) and three multidrug resistant (MDR) sublines (H69/DAU, NYH/VM, and H69/VP) with combinations of mdr1 and MRP overexpression as well as topoisomerase II (topo II) down-regulation or mutation. Sensitivity to 20 established and new agents was measured in a standardized clonogenic assay. Resistance was highly drug specific. Thus, none of the cell lines was resistant to all drugs. In fact, all resistant cell lines exhibited patterns of collateral sensitivity to various different classes of drugs. The most intriguing pattern was collateral sensitivity to gemcitabin in two cell lines and to ara-C in five drug-resistant cell lines, i.e. in all lines except the lines resistant to topo I poisons. Next, all sensitivity patterns in the nine cell lines were compared by correlation analysis. A high correlation coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous.
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PMID:In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin. 906 9

Data obtained from multiple sources indicate that no single mechanism can explain the drug resistance and the poor prognosis of patients with lung cancer. The resistance-related proteins P-glycoprotein, glutathione-dependent enzymes, topoisomerase II, metallothioneins, O-6-alkylguanine-DNA alkyltransferase, thymidylate synthase, dihydrofolate reductase and heat shock proteins have been found in lung carcinomas, but these alone cannot explain the drug-resistant phenotype. Cell cycle-related proteins, angiogenic factors, protooncogenes, and tumor suppressor genes also play a role in the phenotype that is resistant lung cancer. A key future challenge involves determining the relative quantitative contributions of each of these mechanisms to overall resistance.
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PMID:Resistance mechanisms and their regulation in lung cancer. 925 4

Topoisomerases (Topo) I and II are cellular enzymes that catalyze the relaxation of topologically strained DNA and that are involved in a number of DNA-related processes. Their complete inhibition by Topo I and II inhibitors gives promise for improvements in the treatment of malignant diseases. However, preclinical studies showed down-regulation of Topo II protein expression by Topo I inhibitors, which may preclude the useful application of combined topoisomerase inhibition in the clinic. We investigated the efficacy of the combination of etoposide (ETP) and camptothecin (CPT) in human gastric and lung cancer cell lines with different sensitivity towards ETP. The cytotoxicity of different drugs was assessed by the sulforhodamine B assay. Drug interactions were evaluated by isobologram analysis. The polymerase chain reaction and flow cytometry were employed for examination of the mdr1 (multidrug resistance type 1) phenotype. As reported by others, incubation of the P glycoprotein (P-gp)-negative tumor cell lines with the Topo I inhibitor CPT resulted in a significant down-regulation of Topo II protein expression. This was obviously due to changes in the cell cycle distribution of the cells induced by the treatment, with a marked increase of cells in G2/M phase and a consecutive decrease of S phase cells. Despite these biochemical changes, isobologram analysis showed additive cytotoxic activity of CPT and ETP in all the cell lines, independent of whether the drug incubation was performed simultaneously or sequentially. These data indicate that down-regulation of Topo II protein by CPT does not prevent additive activity of CPT and ETP in vitro, and therefore combined Topo I and II inhibition may be useful for investigation in clinical trials.
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PMID:Down-regulation of topoisomerase II by camptothecin does not prevent additive activity of the topoisomerase II inhibitor etoposide in vitro. 931 43

Lung cancer, which is the leading cause of cancer mortality, remains a significant health-care problem among men and women in the United States, despite an overall 20-year decline in the incidence of cigarette smoking. Non-small cell lung cancer (NSCLC) comprises 75 to 80% of all lung cancer cases. The metastatic nature of this disease has been responsible for the poor survival statistics reported to date and emphasizes the need for effective systemic treatment. Prior to 1993, attempts to identify new chemotherapeutic agents and combinations with activity against NSCLC met with little success. Recently, however, several new compounds and classes of compounds have offered some hope for at least small improvements in response and survival while being relatively well tolerated in patients with this disease. This article presents current findings for some of these agents, including the taxanes paclitaxel and docetaxel, the topoisomerase inhibitors irinotecan and topotecan, and the novel pyrimidine analogue gemcitabine. In addition, the University of Southern California/Norris Cancer Center experience with the combination of carboplatin and paclitaxel is presented.
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PMID:Experience with new chemotherapeutic agents in non-small cell lung cancer. 943 88

A possible link between protein kinase C (PKC) and P-glycoprotein (P-gp)-mediated-multidrug resistance (MDR) was assumed from studies on MDR cell lines selected in vitro. The functional relevance of PKC for the MDR phenotype remains unclear, and the involvement of a particular PKC isozyme in clinically occurring drug resistance is not known. Recently, we have demonstrated significant correlations between the expression levels of the PKC eta isozyme and the MDR1 or MRP (multidrug resistance-associated protein) genes in blasts from patients with acute myelogenous leukaemia (AML) and in ascites cell aspirates from ovarian cancer patients. To extend these findings to further types of human tumours we analysed specimens from 64 patients with primary breast cancer for their individual expression levels of several MDR-associated genes (MDR1, MRP, LRP (lung cancer resistance-related protein), topoisomerase (Topo) II alpha/IIbeta, cyclin A and the PKC isozyme genes (alpha, beta1, beta2, eta, theta, and mu) by a cDNA-PCR approach. We found significantly enhanced mean values for MRP, LRP and PKC eta gene expression, but significantly decreased Topo II alpha and cyclin A gene expression levels in G2 tumours compared with G3. Remarkably, significant positive correlations between the MDR1, MRP or LRP gene expression levels and PKC eta were determined: MDR1/PKC eta (rs = +0.6451, P < 0.0001) n = 62; MRP/PKC eta (rs = +0.5454, P < 0.0001) n = 63; LRP/PKC eta (rs = +0.5436, P < 0.0001) n = 62; MRP/LRP (rs = +0.7703, P < 0.0001) and n = 62, MDR1/MRP (rs = +0.5042, P < 0.0001) n = 62. Our findings point to the occurrence of a multifactorial MDR in the clinics and to PKC eta as a possible key regulatory factor for up-regulation of a series of MDR-associated genes in different types of tumours.
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PMID:Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlations of PKC eta with MDR1, MRP and LRP gene expression. 945 50


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