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)

Combination of selecting agents that act on different cellular mechanisms is a common strategy in cancer chemotherapy. GL331 is a new potent topoisomerase II (Topo II) poison; distinctly, paclitaxel is a microtubule-interfering cancer chemotherapeutic agent. In this study, we intended to evaluate the efficacy of combining GL331 with paclitaxel in cell killing and apoptotic induction in nasopharyngeal carcinoma NPC-TW01 cells. By MTT and internucleosomal DNA cleavage assays, we found that pretreatment or simultaneous treatment of NPC-TW01 cells with GL331 could significantly interfere with paclitaxel's cell killing and apoptosis-inducing activity. When the administration schedule was reversed, the cytotoxicity of GL331 was attenuated by paclitaxel pretreatment. The anti-cancer activity produced by combining GL331 with paclitaxel was obviously lower than the addition of the activities of two individual agents. NPC-TW01 cells were treated with GL331 and 3H-labeled paclitaxel simultaneously or with GL331 before 3H-labeled paclitaxel. In both conditions, GL331 did not reduce the [3H]paclitaxel level in the cells, suggesting that GL331's interference with paclitaxel's cell-killing and apoptosis-inducing efficacy did not result from any inhibition of cellular uptake or retention of paclitaxel. In addition, we found that GL331-induced perturbation of cell cycle progression dramatically over-rode the patterns of mitotic arrest induced by paclitaxel, and the mechanism could be the inhibition of cyclin B1/CDC2 kinase and MAD2 checkprotein activities.
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PMID:Evaluation of GL331 in combination with paclitaxel: GL331's interference with paclitaxel-induced cell cycle perturbation and apoptosis. 1129 Aug 73

The transcription factor NF-kappaB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that differ in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 microM) and doxorubicin (0.3 microM): Highly sensitive T3M4 [corrected] and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kappaB activity in all cell lines, whereas basal NF-kappaB binding was nearly undetectable in T3M4 [corrected] and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-kappaB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkappaBalpha super-repressor, strongly enhanced the apoptotic effects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-kappaB activity rather than the transient induction of NF-kappaB by some anti-cancer drugs. Blockade of basal NF-kappaB activity by well established drugs efficiently reduces chemoresistance of pancreatic cancer cells and offers the potential for improved therapeutic strategies.
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PMID:Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. 1131 19

Apoptosis and necrosis need to be differentiated in order to distinguish drug-induced cell death from spontaneous cell death due to hypoxia. The ability to differentiate between these two modes of cell death, especially at an early stage in the process, could have a significant impact on accessing the outcome of anticancer drug therapy in the clinic. Nuclear magnetic resonance spectroscopy was used to distinguish apoptosis from necrosis in human cervical carcinoma (HeLa) cells. Apoptosis was induced by treatment with the topoisomerase II inhibitor etoposide, whereas necrosis was induced by the use of ethacrynic acid or cytochalasin B. We found that the intensity of the methylene resonance increases significantly as early as 6 h after the onset of apoptosis, but that no such changes occur during necrosis. The spectral intensity ratio of the methylene to methyl resonances also shows a high correlation with the percentage of apoptotic cells in the sample (r2=0.965, P<0.003).
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PMID:Detection of drug-induced apoptosis and necrosis in human cervical carcinoma cells using 1H NMR spectroscopy. 1131 4

Inhibitors of topoisomerases are widely used in the treatment of cancer, including inhibitors of topoisomerase I (camptothecin analogs such as irinotecan and topotecan) and topoisomerase II (etoposide and doxorubicin). The novel bis-phenazine, XR5944, is a joint inhibitor of topoisomerase I and II as shown by the stabilization of topoisomerase-dependent cleavable complexes. XR5944 demonstrated exceptional activity against human and murine tumor cells in vitro and in vivo. In a range of cell lines XR5944 (IC50 0.04-0.4 nM) was significantly more potent than TAS-103, originally proposed as a joint topoisomerase I and II inhibitor, as well as agents specific for topoisomerase I or II (topotecan, doxorubicin and etoposide). In addition, XR5944 was unaffected by atypical drug resistance and retained significant activity in cells overexpressing P-glycoprotein or multidrug resistance-associated protein. Antitumor efficacy of XR5944 was demonstrated in human carcinoma xenograft models (H69 small cell lung cancer and HT29 colon). In the HT29 model, which is relatively unresponsive to chemotherapy, XR5944 (15 mg/kg i.v., q4dx3) induced tumor regression in the majority of animals (six of eight), whereas TAS-103, dosed at its maximum tolerated dose (45 mg/kg i.v., q7dx3), only induced a delay in tumor growth compared with control animals. In the H69 model, low doses of XR5944 (5 mg/kg i.v., qdx5/week for 2 weeks or 10-15 mg/kg i.v., q4dx3), induced complete tumor regression in the majority of animals. In contrast, topotecan (20 mg/kg i.v., q4dx3) or etoposide (30 mg/kg i.v., q5dx5) only slowed the tumor growth rate. These studies show that XR5944 is a highly active novel anticancer agent that is well tolerated at efficacious doses.
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PMID:Antitumor activity of XR5944, a novel and potent topoisomerase poison. 1133 93

The combination of a novel topoisomerase II inhibitor, S16020, and ionizing radiation (IR) was investigated with the aim of assessing normal tissue tolerance using a mouse mucosal lip model and antitumor activity in a human carcinoma (HEP2) cell line. No increase of acute mucosal reactions was seen when combining S16020 with IR as compared with IR alone. Using clonogenic cell survival assay, a marked enhancement of HEP2 cell killing was found when S16020 was combined with irradiation. Additional in vivo combination of S16020-IR was able to increase markedly the antitumor efficacy as compared with S16020 or irradiation alone. Interestingly, the radiosensitization effect in vivo was observed at relatively low and nontoxic concentrations of S16020, and no dose-effect relationship was found beyond 30 mg/kg. In conclusion, the combination of IR and S16020 seems promising to enhance antitumor activity without increasing deleterious effect in normal tissues and to provide the basis for a new radio-chemotherapy combination.
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PMID:The olivacine S16020 enhances the antitumor effect of ionizing radiation without increasing radio-induced mucositis. 1144 28

The relationship between expression and function of the epidermal growth factor (EGF) family of receptors and chemosensitivity remains controversial. We studied the chemosensitivity to various anticancer agents of human cervical squamous carcinoma ME180 cells, and two resistant subclones, ME180/TNF and ME180/Pt, which also differ in their EGF receptor (EGFR) expression. Compared with ME180 cells, EGFR is overexpressed sixfold in ME180/TNF cells and is barely detectable in ME 180/Pt cells. Cell cycle analysis by flow cytometry and BrdU incorporation into DNA showed a correlation between EGFR expression and percentage of cells in S phase and active DNA replication (35% in high EGFR-expressing ME180/TNF cells, 19% in non-EGFR-expressing ME180/Pt cells and 23% in parental, intermediate-level EGFR-expressing ME 180 cells). By MTT assay and compared with parental, intermediate-level EGFR-expressing ME180 cells, high EGFR-expressing ME180/TNF cells had a three- to fourfold increased sensitivity to cisplatin, camptothecin (CPT), and topotecan, and low EGFR-expressing ME180/Pt cells had a five- to ninefold reduced sensitivity to the same agents. In contrast, the degree of cross-resistance with the topoisomerase II inhibitors doxorubicin and etoposide was minimal and the pattern of sensitivity to the anti-microtubulin agents vinblastine and paclitaxel was different, with a two- to fourfold decreased sensitivity in the high EGFR-expressing ME180/TNF cells and only a 1.5-fold decreased sensitivity in the low EGFR-expressing ME180/Pt cells. Neither alterations in intracellular CPT levels nor changes in topoisomerase I expression or activity, measured as ability to form DNA-protein complexes, were found to explain the differences in sensitivity to CPT among the three cell lines. Co-treatment with CP358774, a specific EGFR tyrosine kinase inhibitor, reduced the enhanced sensitivity of high EGFR-expressing ME180/TNF cells to the values observed in intermediate EGFR-expressing ME180 cells, but only reduced modestly the sensitivity of intermediate expressing ME180 cells. As a result, the resistance index of low EGFR-expressing ME180/Pt cells compared with intermediate EGFR-expressing ME180 cells was reduced only from five- to fourfold for cisplatin and from seven- to fourfold for CPT when ME180 cells were exposed to CP358774. CP358774 did not affect the sensitivity to either agent in low EGFR-expressing ME180/Pt cells. These results provide evidence that changes in EGFR expression or function may play a role in determining chemosensitivity to platinum and topoisomerase I poisons in some human tumor systems, and that the EGFR-related changes in chemosensitivity may vary depending on the level of EGFR expression and/or function.
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PMID:Sensitivity to topoisomerase I inhibitors and cisplatin is associated with epidermal growth factor receptor expression in human cervical squamous carcinoma ME180 sublines. 1145 99

Topoisomerase IIalpha is a target for many chemotherapeutic agents in clinical use. To define mechanisms of resistance and regions crucial for the function of topoisomerase IIalpha, drug-resistant cell lines have been isolated following exposure to topoisomerase II poisons. Two resistant sublines, T47D-VP and MCF-7-VP, were isolated from human carcinoma cell lines following exposure to 300 or 500 ng / ml etoposide (VP-16). Cytotoxicity studies confirmed resistance to etoposide and other topoisomerase II poisons. KCl-sodium dodecyl sulfate (K-SDS) precipitation assays using intact cells showed reduced DNA-topoisomerase II complex formation following VP-16 or amsacrine (m-AMSA). RNAse protection analysis identified a deletion of 200 base pairs in the topoisomerase IIalpha cDNA of T47D-VP and rising dbl quote, left (low)AA insertion" in the topoisomerase IIalpha cDNA of MCF-7-VP. Reduced topoisomerase IIalpha mRNA and protein levels were observed in both cell lines. It was somewhat surprising to find that nuclear extracts from T47D-VP and MCF-7-VP cells had comparable topoisomerase II activity to that of parental cells. Analysis of the extent of phosphorylation demonstrated that topoisomerase IIalpha from the resistant cells was relatively hypophosphorylated compared to that of parental cells. In these cell lines, hypophosphorylation secondary to loss of a portion of the C-terminal domain of topoisomerase IIalpha mediated the restored activity, despite a fall in topoisomerase IIalpha mRNA and protein, and this resulted in cross resistance to topoisomerase II poisons.
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PMID:Hypophosphorylation of topoisomerase IIalpha in etoposide (VP-16)-resistant human carcinoma cell lines associated with carboxy-terminal truncation. 1147 32

The substitution of gallic acid at the 3 position of (-)-epigallocatechin-3-O-gallate (EGCG) increased the inhibition against topoisomerase I from calf thymus gland and topoisomerase II from human placenta, and the substitution of a hydroxyl group at the 3' position increased the inhibition against the topoisomerase I. These results suggested that the 3 and 3' positions of the EGCG molecule play important roles in the process of inhibition of topoisomerases I and II. EGCG showed strong inhibition against topoisomerases I from wheat germ, calf thymus gland and Vero cells, and showed weak or no inhibition against topoisomerases I from carcinoma cells such as A549, HeLa and COLO 201 cells. EGCG differentially inhibited the topoisomerases I from different sources.
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PMID:Inhibitory activities of (-)-epigallocatechin-3-O-gallate against topoisomerases I and II. 1155 76

The human monoclonal antibody SC-1 was isolated from a patient with a diffuse-type adenocarcinoma of the stomach using somatic cell hybridization. The immunoglobulin (Ig)M antibody reacts specifically with diffuse- (70%) and intestinal-type (25%) gastric adenocarcinoma and induces apoptosis in vitro and in vivo. When used in clinical trials with stomach carcinoma patients, significant apoptotic and regressive effects in primary tumors have been observed with the antibody SC-1. The SC-1 receptor is a new 82 kd membrane-bound isoform of glycosylphosphatidylinositol (GPI)-linked CD55 (decay-accelerating factor, DAF). CD55 is known to protect cells from lysis through autologous complement and is coexpressed with the ubiquitously distributed 70 kd isoform. The SC-1-specific CD55 isoform is up-regulated shortly after antibody binding, followed by an internalization of the antibody/receptor-complex, whereas the membranous expression of wild-type CD55 remains unchanged. The apoptotic process is marked by cleavage of cytokeratin 18, indicating the involvement of caspase-6 in the apoptotic process. In contrast to other apoptotic pathways, a cleavage of poly(ADP-ribose)polymerase (PARP) is not observed. The expression of the cell-cycle regulator c-myc becomes up-regulated, whereas expression of topoisomerase IIalpha is down-regulated. Induction of apoptosis leads to an increase in the internal Ca(2+) concentration, which is not necessary for the apoptotic process but for the transport of newly synthesized SC-1-specific CD55 isoform to the membrane.
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PMID:Regulation of the new coexpressed CD55 (decay-accelerating factor) receptor on stomach carcinoma cells involved in antibody SC-1-induced apoptosis. 1170 63

Chronic lymphocytic leukemia (CLL) is rarely associated with secondary acute myelogenous leukemia (AML) usually due to chemotherapy or radiotherapy. No cases of concomitant CLL and acute promyelocytic leukemia (APL) have been found in the literature. Nevertheless, up to 12% of therapy-related AML cases are classified as APL. Of these latter, most are related to topoisomerase treatment, with a few acute cases occurring after radiotherapy. We report here a patient with an untreated CLL who developed APL 2 years after radiotherapy for prostate carcinoma.
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PMID:Acute promyelocytic leukemia developing after radiotherapy for prostate cancer in a patient with chronic lymphocytic leukemia. 1175 54


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