Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently shown that several pancreatic carcinoma cell lines are resistant to topoisomerase IIalpha inhibitors due to elevated basal nuclear factor kappaB (NF-kappaB) activity, and blockade of this activity by various means strongly increased chemosensitivity. In search of possible mechanisms leading to exaggerated NF-kappaB activity, we identified interleukin (IL)-1beta as a key mediator of this activation in two of the chemoresistant cell lines (A818-4 and PancTu-1). These cells express and secrete high levels of IL-1beta, as demonstrated by reverse transcription-PCR, immunocytochemistry, and ELISA. Culture supernatants from both cell lines induced NF-kappaB activity in chemosensitive PT45-P1 pancreatic carcinoma cells and significantly attenuated etoposide-induced apoptosis in a NF-kappaB-dependent fashion, similar to that seen in PT45-P1 cells treated with recombinant IL-1beta. Treatment of these cells with IL-1beta also changed the DNA damage characteristics toward those observed in A818-4 and PancTu-1 cells. NF-kappaB activation and the gain of chemoresistance in PT45-P1 cells on treatment with supernatants from both chemoresistant cell lines was abolished in the presence of a blocking anti-IL-1 receptor (I) antibody. Furthermore, this antibody decreased the resistance of A818-4 and PancTu-1 cells to etoposide treatment along with reduced NF-kappaB activity. Blockade of NF-kappaB activation by MG132, sulfasalazine, or an IkappaBalpha superrepressor disrupted the IL-1beta-mediated amplification loop and the accompanying chemoresistance. Our data provide insights into an autocrine mechanism involving IL-1beta by which pancreatic carcinoma cells develop chemoresistance that could serve as a molecular target in anticancer therapy.
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PMID:Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. 1183 May 51

Berberrubine, a protoberberine alkaloid that exhibits antitumor activity in animal models, has been identified as a specific poison of DNA topoisomerase II in vitro. To better understand the mechanisms of cellular response to berberrubine, human colorectal carcinoma cells (AMC5) were selected for resistance to berberrubine. The resulting cell line (AMC5/B1) was 5.3-fold resistant to berberrubine in the absence of MDR1 overexpression. The AMC5/B1 line was cross-resistant to topoisomerase II-targeted drugs but showed no cross-resistance to other antitumor drugs. The patterns of cross-resistance to various drugs led us to examine the cellular contents of topoisomerase II. Topoisomerase II activity was approximately 2.8-fold lower in AMC5/B1 cells compared with parental cells. The AMC5/B1 line contained approximately 5-fold decrease in topoisomerase IIalpha protein level and approximately 2.5-fold decrease in topoisomerase IIalpha mRNA level. A comparison of the degradation kinetics of topoisomerase IIalpha mRNA demonstrated that there was no difference in mRNA stability between the two cell lines. Furthermore, the activity of topoisomerase IIalpha promoter in AMC5/B1 cells was about 25% of that in AMC5 parental cells when transient transfection experiments were performed with the promoter-luciferase reporter gene. These results indicate that down-regulation of topoisomerase IIalpha in AMC5/B1 cells occurs at the transcriptional level. Nucleotide sequencing of the topoisomerase IIalpha promoter regions revealed no mutations in AMC5/B1 cells. In summary, resistance to berberrubine in AMC5 cells is associated with decreased level of catalytically active topoisomerase IIalpha, suggesting that topoisomerase IIalpha is the cellular target of berberrubine in vivo.
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PMID:Down-regulation of DNA topoisomerase IIalpha in human colorectal carcinoma cells resistant to a protoberberine alkaloid, berberrubine. 1190 Dec 27

Hybridization with cDNA arrays was used to obtain expression profiles of 214 protein-tyrosine kinase, protein-tyrosine phosphatase, dual-specific phosphatase, and other genes for kidney carcinomas (KC) and normal kidney tissues of 34 patients and for seven carcinoma cell lines. Computer analysis revealed three clusters of genes coexpressed in KC. A proliferating-cell gene cluster included MET, VIM, MYC, TOP2A, PCNA, etc. A neoangiogenesis and blood-cell gene cluster included LCK, HCK, FGR, MMP9, CSFR1, VEGF, FLT1, and KDR. A cluster corresponding to normal, differentiated kidney cells included ERBB2 (HER2) for receptor protein-tyrosine kinase, several phosphatase genes (PTPRE, PTPRB, DUSP9), and EGF. The results suggested that MET, DUSP9, PCNA, TOP2A, and VIM may serve as diagnostic and prognostic markers in KC. Tubulin and topoisomerase II were assumed to be promising targets for cell proliferation inhibitors in KC.
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PMID:[Molecular portrait of human kidney carcinomas: the gene expression profiling of protein-tyrosine kinases and tyrosine phosphatases which controlled regulatory signals in the cells]. 1206 34

To enhance the therapeutic efficacy as well as to reduce the side effect, we attempted to liposomalize 4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53), a novel and effective topoisomerase II inhibitor. More than 90% of TOP-53 was efficiently incorporated into the liposomes composed of dipalmitoylphosphatidylcholine and cholesterol by remote-loading method. Anti-tumor activity of liposomal TOP-53 against solid tumor was examined in vivo using colon26 NL-17 carcinoma model mice. Three doses of liposomal TOP-53 (12 mg/kg/dose) showed significant tumor growth suppression (97.5% reduction determined at day 25) and the increase in life span (33%) of tumor-bearing mice. Furthermore, one mouse out of 5 was completely cured after treatment. Since similar efficacy was observed in the free TOP-53 treated group, liposomalization does not contribute much to the enhancement of therapeutic efficacy. However, a slight but measurable damage at the injection site was observed when free TOP-53 was injected, and the damage was diminished by the liposomalization. Taken together, liposomalization reduces the side effect rather than enhancing the therapeutic efficacy when TOP-53 is used.
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PMID:Potential usage of liposomal 4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53) for cancer chemotherapy. 1208 Nov 47

To identify mechanisms of camptothecin (CPT) resistance and the relationship between CPT-resistant cells and other anticancer agents, a CPT-resistant cell line (CPT30) and its partial revertant cell line (CPT30R) were established from a human nasopharyngeal carcinoma cell line (HONE-1). CPT30 and CPT30R cells displayed a 14- and 3.5-fold resistance to CPT compared with HONE-1 cells, respectively. The resistant and partial revertant cell lines showed cross-resistance to topotecan and increased sensitivity to cisplatin, carboplatin, and 1,3-bis(chloroethyl)-1-nitrosurea. The topoisomerase (Top) I catalytic activity of CPT30 and CPT30R cells was 30% and 200%, respectively, compared with that of HONE-1 cells. The expression of Top I protein and mRNA levels in CPT30 cells was 40% and 30% less than that in HONE-1 cells, respectively, whereas in CPT30R cells, the levels of Top I protein and mRNA were 50% and 20% higher, respectively, than that in HONE-1 cells. Both the resistant and revertant cell line whole-cell lysates demonstrated different levels of sensitivity to CPT in in vitro assays in comparison with that of HONE-1 cells. Furthermore, CPT exhibited 15- and 7-fold better binding affinity in stabilizing protein-linked DNA breaks in HONE-1 cells than in CPT30 and CPT30R cells, respectively. Direct DNA sequencing of the reverse transcription-PCR product and genomic DNA revealed a point mutation resulting in E418K mutation in the Top I of both CPT30 and CPT30R cells. Wild-type Top I RNA and genomic DNA were also detected in these two cell lines. A yeast system was used to examine whether this mutation could be responsible for CPT resistance. Our results showed that a single amino acid change (E418K) resulted in CPT resistance. Therefore, quantitative and qualitative changes in Top I were responsible for CPT resistance in CPT30 cells. CPT resistance in CPT30R cells was caused by mutation of Top I.
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PMID:Novel mutation of topoisomerase I in rendering cells resistant to camptothecin. 1209 80

Primary screening in vitro and study on the mode of action of oracin in Ehrlich ascites carcinoma cells have been performed. The measure of the cytotoxic effect was the degree of inhibition of 14C-adenine and 14C-valine incorporation into TCA insoluble fraction of Ehrlich ascites carcinoma (EAC) cells. The inhibitory effect was characterized by IC50 values. The biosynthesis of nucleic acides indicated by the incorporation of 14C-adenine was more sensitive (IC50 = 66 micromol/ l) than the biosynthesis of proteins indicated by the incorporation of 14C-valine (IC50 = 196 micromol/l). To elucidate the biochemical mode of action, the effect of oracin on dynamics of biosynthesis of macromolecules indicated by the incorporation rate of [14C] labeled precursors (adenine, thymidine, uridine, valine) into appropriate macromolecules of EAC cells was studied. Oracin inhibited incorporation of all four precursors into the trichloracetic acid - insoluble fraction of Ehrlich ascites cells. The extent of inhibition was dependent on both time and drug concentration. We found that oracin inhibited activity of topoisomerase II by 100% at concentration 5 to 15 micromol/l.
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PMID:Cytotoxicity and mode of action of the potential cytostatic drug oracin. 1209 2

A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently described in situ hybridization technique in archival samples (Meeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, March GE, De Marzo AM: Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. American Journal of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue microarrays containing a variety of noninvasive pancreatic ductal lesions. These included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B, 24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in 79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN-1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic pancreatitis, reduction of telomere signal was observed in all PanIN lesions, whereas atrophic and inflammatory ductal lesions retained normal telomere length. Telomere fluorescence intensity in PanIN lesions did not correlate with proliferation measured by quantitative Ki-67-labeling index or topoisomerase IIalpha expression. Thus, telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium. A critical shortening of telomere length in PanINs may predispose these noninvasive ductal lesions to accumulate progressive chromosomal abnormalities and to develop toward the stage of invasive carcinoma.
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PMID:Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. 1241 2

We established an NC-190-resistant cell line, FM/NC-R, from the murine mammary carcinoma cell line FM3A and examined some of its characteristics. FM/NC-R cells were prepared by mutagen treatment followed by exposure to NC-190 in the culture medium. FM/NC-R cells were 76.5 times more resistant against NC-190 than FM3A cells as measured by their growth in vitro. FM/NC-R cells also showed cross-resistance to etoposide with NC-190. Neither NC-190 nor etoposide increased the lifespan of FM/NC-R-bearing mice at doses that prolonged the lifespan of FM3A-bearing mice more than four times. This resistance was not due to the change in the concentration of NC-190 in the cells, and there was no change in the expression of P-glycoprotein, a drug efflux pump in the cells. NC-190 and etoposide are inhibitors of DNA topoisomerase II, but there was no difference in cellular content of DNA topoisomerase II between the two cell lines as determined by Western blot analysis. The stabilization of DNA-DNA topoisomerase II cleavable complexes induced by NC-190 was lost in FM/NC-R cells. It was found that Gly881, which is located in the ATP binding site, was replaced by Arg in topoisomerase IIalpha of FM/NC-R cells. These results indicate that the NC-190-resistant cell line FM/NC-R contains a mutated DNA topoisomerase IIalpha.
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PMID:Establishment and characterization of a mouse FM3A cell mutant resistant to topoisomerase II-inhibitor NC-190. 1243 94

DNA topoisomerase II has been shown to be an important therapeutic target in cancer chemotherapy. Here, we describe studies on the antitumor activity of a novel topoisomerase II inhibitor, ER-37328 [12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1- jk]carbazole-4,6,10(5H,11H)-trione hydrochloride]. ER-37328 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay and induced double-strand DNA cleavage within 1 h in murine leukemia P388 cells, in a bell-shaped manner with respect to drug concentration. The maximum amount of DNA cleavage was obtained at 2 microM. Like etoposide, ER-37328 (2 microM) induced topoisomerase II-DNA cross-linking in P388 cells. A spectroscopic study of ER-37328 mixed with DNA demonstrated that ER-37328 has apparent binding activity to DNA. ER-37328 showed potent growth-inhibitory activity against a panel of 21 human cancer cell lines [mean (50% growth-inhibitory concentration) GI50 = 59 nM]. COMPARE analysis according to the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of ER-37328 was similar to that of etoposide, but different from that of doxorubicin. Studies on etoposide-, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)]-, and camptothecin-resistant P388 cell lines showed that: (a) etoposide- and m-AMSA-resistant P388 cell lines were partially resistant to ER-37328 compared with the parental cell line; and (b) a camptothecin-resistant cell line showed no cross-resistance to ER-37328. In addition, ER-37328 overcame P-glycoprotein-mediated resistance. In vivo, ER-37328 produced potent tumor regression of Colon 38 carcinoma inoculated s.c., and its activity was superior to that of etoposide or doxorubicin. These results indicate that ER-37328 inhibits topoisomerase II activity through the formation of topoisomerase II-DNA cleavable complex and has potent antitumor activity both in vitro and in vivo.
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PMID:Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor. 1246 11

Fewer than 20% of patients with pancreatic cancer present with disease macroscopically confined to the pancreas, and approximately 40% already have locally advanced disease. Based on data from the Gastrointestinal Tumor Study Group, adjuvant therapy with radiation and 5-fluorouracil has become standard practice in the United States; however, in other countries, adjuvant treatment has not been as widely accepted. Other issues include the potential of neoadjuvant therapy and optimal systemic management. The issue of second-line therapy has also been raised in the treatment of pancreatic carcinoma, after the establishment of gemcitabine as a first-line standard treatment approach, in which it achieves a significant clinical benefit response. Other combination partners with gemcitabine under investigation include the antimetabolite 5-fluorouracil, the topoisomerase-I inhibitor irinotecan, the taxane docetaxel, the platinum oxaliplatin, the multitargeted antifolate pemetrexed, the farnesyl transferase inhibitor R-115777, the anti-HER2/neu antibody trastuzumab, and the epidermal growth factor inhibitor cetuximab. Combined-modality approaches with gemcitabine and radiation are also under active investigation.
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PMID:Future directions in the treatment of pancreatic cancer. 1257 31


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