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)

Because of its unique DNA-cleaving and strand-passing activities, topoisomerase II is involved in many aspects of DNA metabolism, including replication, transcription, recombination, and repair. The cytotoxic potential of topoisomerase II-targeted drugs, such as etoposide, is related to their ability to stabilize covalently linked enzyme-DNA complexes, which are intermediates in the enzyme's catalytic cycle. Epidermal growth factor receptor is expressed on the cell surface of the majority of squamous cell carcinomas, and epidermal growth factor binding is known to stimulate a number of cellular transduction pathways, including tyrosine kinase, protein kinase C, and phospholipase C. Because topoisomerase II is a proliferation-dependent protein and has been shown to be a high-affinity substrate for many of these cellular transduction pathways, the effects of epidermal growth factor on cellular regulation and sensitivity to etoposide were studied with the human oral cavity squamous cell line, KB. Topoisomerase II catalytic activity was rapidly and transiently inhibited after the addition of epidermal growth factor to the cellular growth media. Western blot on nuclear extracts did not demonstrate alterations in topoisomerase II polypeptide levels to account for changes in catalytic activity. Epidermal growth factor treatment also led to the formation of stabilized, covalently linked enzyme-DNA complexes. Furthermore, epidermal growth factor-induced, topoisomerase II-mediated DNA strand breaks were additive to those induced by etoposide. This study indicates that epidermal growth factor specifically regulates the catalytic and DNA-cleaving activities of topoisomerase II in KB cells. This may direct clinical strategies for circumventing the intrinsic cellular resistance to chemotherapy commonly observed in squamous cell carcinomas of the head and neck.
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PMID:Epidermal growth factor regulates topoisomerase II activity and drug sensitivity in human KB cells. 864 3

Broadly defined, phytoestrogens include isoflavones, coumestans, and lignans. A number of these compounds have been identified in fruits, vegetables, and whole grains commonly consumed by humans. Soybeans, clover and alfalfa sprouts, and oilseeds (such as flaxseed) are the most significant dietary sources of isoflavones, coumestans, and lignans, respectively. Studies in humans, animals, and cell culture systems suggest that dietary phytoestrogens play an important role in prevention of menopausal symptoms, osteoporosis, cancer, and heart disease. Proposed mechanisms include estrogenic and antiestrogenic effects, induction of cancer cell differentiation, inhibition of tyrosine kinase and DNA topoisomerase activities, suppression of angiogenesis, and antioxidant effects. Although there currently are no dietary recommendations for individual phytoestrogens, there may be great benefit in increased consumption of plant foods.
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PMID:Dietary phytoestrogens. 924 Sep 32

In an effort to identify novel antileukemic agents that can bypass the mechanisms of multidrug resistance, we found that cyclosporin A ([CyA] 5 mumol/L) produced a median cell kill of 69% (range, 47% to 85%) in seven B-lineage acute lymphoblastic leukemia (ALL) cell lines (OP-1, SUP-B15, KOPN-55bi, RS4;11, NALM6, REH, and 380) and three T-lineage ALL cell lines (MOLT4, CCRF-CEM, and CEM-C7) after 4 days of culture. At 10 mumol/L, median CyA toxicity was 99% (range, 88% to > 99%). CyA was equally toxic to both a multidrug-resistant cell line, CEM-VLB100, which overexpresses gp-170 P-glycoprotein, and one resistant to topoisomerase II inhibitors, CEM-VM1-5, which has a mutation in the topoisomerase II gene. CyA was also toxic to primary leukemic cells maintained in stroma-based culture, a system that substantially prolongs in vitro cell survival. Against lymphoblasts from 21 patients with B-lineage ALL, the compound (at 5 mumol/L) reduced the leukemic cell number by a median of 87% (range, 27% to > 99%) compared with results for parallel control cultures lacking CyA. Seven of these samples were from cases with unfavorable genetic features (e.g., Philadelphia-chromosome or MLL gene rearrangements); three were obtained at relapse. Against T lymphoblasts (from six patients), the median reduction in cell number was 79% (range, 30% to > 99%). At 10 mumol/L, the cell kill exceeded 97% in all cases studied. The mechanism of CyA cytotoxicity was found to be the activation of apoptosis, which was suppressed by phorbol myristate acetate but not by inhibitors of ceramide-mediated apoptosis, phosphatidyl inositol-3 kinase activity, or tyrosine kinase activity. These findings demonstrate high levels of CyA-induced toxicity against ALL cells at concentrations achievable in vivo, thus providing a strong rationale for clinical testing of this agent in patients with ALL.
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PMID:Cyclosporin A induces apoptosis in childhood acute lymphoblastic leukemia cells. 944 62

Tiazofurin, an oncolytic drug, reduces PI kinase activity and arrests chiefly in S phase. Genistein, an inhibitor of PIP kinase, tyrosine kinase, and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both tiazofurin and genistein reduce second messenger IP3 concentration in ovarian carcinoma cells. Because genistein and tiazofurin attack different enzymic targets and arrest the cell cycle at different phases, we tested the hypothesis that tiazofurin might be synergistic with genistein. Human ovarian carcinoma OVCAR-5 cells were grown in flasks in monolayers. In growth inhibition assay for tiazofurin and genistein the IC50s were 26 and 18 microM, respectively, and in clonogenic assays the LC50s were 17 and 4 microM, respectively. Various combinations of the two drugs were tested. The best protocol took into consideration that tiazofurin decreased GTP concentration in cells by 50% at 12 h after administration. Tiazofurin (20 microM) and genistein (20 microM) as single agents reduced cell counts to 60% and 50%, respectively. The predicted value, as a sum of the effect of two drugs, would have been 30% of controls. However, genistein added 12 h after tiazofurin decreased cell counts to 8%, showing synergistic action of the two drugs for growth inhibition. Similar results were observed in the clonogenic assays, which also revealed synergistic cytotoxicity. The protocol yielding synergism might be of value in the clinical treatment of human ovarian carcinoma.
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PMID:Synergistic action of tiazofurin and genistein in human ovarian carcinoma cells. 970 Jul 22

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), an oncolytic drug, inhibits IMP DH (inosine 5'-monophosphate dehydrogenase, EC 1.1.1.205), reduces signal transduction activity and IP3 (inositol 1,4,5-trisphosphate) concentration and arrests the cell cycle chiefly in S phase. Genistein (4',5,7-trihydroxyisoflavone), an inhibitor of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase, EC 2.7.1.68), tyrosine kinase and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both drugs, as single agents, induce differentiation. Since tiazofurin and genistein attack different enzymic targets and arrest the cell cycle at different phases and they each induce differentiation, we tested the hypothesis that tiazofurin might be synergistic with genistein in inducing differentiation. Human leukemic K-562 cells were grown in suspension culture and were seeded in 24-well culture plates. In growth inhibition assays for tiazofurin and genistein IC50s (drug concentration that inhibits 50% of cell proliferation) were 7 and 37 microM, respectively. For tiazofurin and genistein the concentrations of drug that induce differentiation in 50% of the cells were 35 and 45 microM, respectively. Various combinations of these two drugs were tested. Since tiazofurin decreased GTP concentration in cells by 50% at 12 hr after administration, genistein (10 to 30 microM) was added 12 hr after tiazofurin (5 to 15 microM). Synergistic action on differentiation was obtained from all tiazofurin and genistein combinations and in most combinations on growth inhibition. The percent of differentiating cells induced by genistein (10 microM) and tiazofurin (10 microM) as single agents increased 1.1- and 2.8-fold, respectively, of the control values. The two drugs together caused 5.9-fold elevation in inducing differentiation. Similar action was observed on inhibition of proliferation.
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PMID:Synergistic action of tiazofurin and genistein on growth inhibition and differentiation of K-562 human leukemic cells. 983 41

Activation of Src, which has an intrinsic protein tyrosine kinase (PTK) activity, has been demonstrated in human solid tumors, such as colorectal and breast cancers. To investigate the role of activated Src in drug resistance, we evaluated the effect of v-src on the resistance to various anti-cancer drugs using v-src-transfected HAG-1 human gallbladder adenocarcinoma cells. Compared with parental or mock-transfected HAG-1 cells, v-src-transfected HAG/src3-1 cells showed a 3.5-fold resistance to cis-diamminedichloroplatinum (II) (CDDP) but not to doxorubicin, etoposide or 5-fluorouracil. By contrast, activated H-ras, which acts downstream of src, failed to induce resistance to either of these drugs. Furthermore, wortmannin, a phosphatidylinositol (PI) 3-kinase inhibitor, and H7, a protein kinase C (PKC) inhibitor, did not alter CDDP resistance. Evaluation of the kinetics of the removal of DNA interstrand cross-links (ICLs), measured by alkaline elution, showed a significant increase in this removal in HAG/src3-1 cells as compared with mock-transfected cells, though no differences were found in the formation of DNA ICLs between these cell lines. CDDP resistance in v-src-transfected cells was reversed, if not completely, by either herbimycin A or radicicol, specific inhibitors of Src-family PTKs, suggesting that Src tyrosine kinase activity induces CDDP resistance. Moreover, significant reduction in the repair of CDDP-induced DNA ICLs was observed upon treatment with radicicol. The intracellular glutathione content and mRNA expression of topoisomerase II and metallothionein were virtually identical between these cell lines, except for topoisomerase I mRNA. Our data strongly suggest that the ability of activated src, but not ras, to induce CDDP resistance is mediated by augmentation of DNA repair through Src to downstream signal-transduction pathways distinct from either the Ras, PI 3-kinase or PKC pathway.
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PMID:v-src induces cisplatin resistance by increasing the repair of cisplatin-DNA interstrand cross-links in human gallbladder adenocarcinoma cells. 1004 75

Asian men have much lower incidences of prostate cancer and possibly of benign prostatic hyperplasia (BPH) than their Western counterparts. Vegetarian men also have a lower incidence of prostate cancer than omnivorous males. Both Asian and vegetarian men consume low-fat, high-fibre diets which provide a rich supply of weak dietary oestrogens. These plant or phyto-oestrogens have been proposed as chemopreventive agents, particularly for Asian men and to a lesser extent, for vegetarian men also. The three principal classes of phyto-oestrogens are the isoflavonoids, flavonoids and lignans. Many foods of plant origin contain varying amounts of these compounds and hundreds of plants manifest some degree of oestrogenic activity. Soya, a dietary staple in many parts of Asia, is a major source of the isoflavonoids, daidzein and genistein. Flavonoids are present in high concentration in many fruits, vegetables and crop species. In particular, apigenin and kaempferol are regarded as major flavonoids because of their common occurrence in plants, and their significant concentrations when present. Apples, onions and tea-leaves are excellent sources of flavonoids. Plant lignans are present in many cereals, grains, fruits and vegetables, and give rise to the mammalian lignans, enterodiol and enterolactone; however, the richest source is linseed (flaxseed) and other oilseeds. In addition to their oestrogenic activity, many of these plant compounds can interfere with steroid metabolism and bioavailability, and also inhibit enzymes, such as tyrosine kinase and topoisomerase, which are crucial to cellular proliferation.
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PMID:Diet and its preventive role in prostatic disease. 1032 92

We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b) Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c) Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.
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PMID:Establishment of a drug sensitivity panel using human lung cancer cell lines. 1035 21

In this study, simultaneous administration of certain inhibitors of topoisomerase I and topoisomerase II produced synergistic cytotoxicity in a series of human glioma cell lines. Camptothecin (CPT) and etoposide (VP-16) produced combination indices (CI) <1.0 in all glioma cell lines tested, including those that were relatively resistant to the two topoisomerase inhibitors individually. In contrast, CPT and VP-16 produced additive cytotoxicity in HT-29 and SW-620 colon carcinoma cell lines. To explore the molecular basis for synergy in glioma cells, we focused on one glioma cell line (U87) in which even sub-cytotoxic doses of CPT potentiated the action of VP-16. Except for genistein (a topo II agent with tyrosine kinase inhibitory function), all topo II inhibitors tested (doxorubicin, ellipticine, and m-AMSA) were synergistic with CPT. While CPT and VP-16 produced cytotoxicity and protein-linked DNA breaks (PLDB) that were supra-additive in U87 glioma cells, CPT and genistein produced additive results. Pretreatment of U87 cells with the tyrosine kinase inhibitor tyrphostin-A23 or the tyrosine phosphatase activator O-phospho-L-tyrosine (OPLT) reduced combination PLDB from synergistic to additive levels, but had no effect on the formation of PLDB induced by either CPT or VP-16 alone. CPT and VP-16 also produced a synergistic accumulation of sub-G0 (apoptotic) cells which was blocked by tyrphostin-A23. No significant increase in topoisomerase protein levels could be detected in response to combination treatment. Thus, synergistic effects between topoisomerase I and topoisomerase II inhibitors in U87 glioma cells may depend upon phosphorylation of cellular proteins other than the topoisomerases themselves.
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PMID:Synergistic cytotoxicity, apoptosis and protein-linked DNA breakage by etoposide and camptothecin in human U87 glioma cells: dependence on tyrosine phosphorylation. 1035 42

Overexpression of the c-erbB-2 (HER-2/neu) oncogene, which encodes a transmembrane receptor tyrosine kinase, has been shown to be associated with poor prognosis in ovarian and breast cancer. Recent studies indicate that c-erbB-2 may also be involved in determining the chemosensitivity of human cancers. In the present study, we examined the role of c-erbB-2 for chemoresistance in ovarian cancer. Overexpression of c-erbB-2 mRNA in tumor tissue was associated with a shorter survival of patients with primary ovarian cancer (P = 0.0001; n = 77) and was an independent prognostic factor in the proportional-hazard model adjusted for International Federation of Gynecologists and Obstetricians stage, residual disease, chemotherapy, and age (P = 0.035). A significant association between expression of c-erbB-2 mRNA and survival was obtained for the subgroup of patients who received a standard chemotherapy with carboplatin or cisplatin and cyclophosphamide (P = 0.0003), whereas only a nonsignificant trend was observed for patients who did not receive a standard chemotherapy (P = 0.124). In addition, the application of a standard chemotherapy improved the survival of patients with relatively low c-erbB-2 expression (P = 0.013) but not of patients with overexpression of c-erbB-2 (P = 0.359). Expression of c-erbB-2 mRNA correlated with expression of topoisomerase IIalpha mRNA determined by a reverse semiquantitative PCR technique (P = 0.009), whereas expression of c-erbB-2 and topoisomerase IIbeta mRNA did not correlate (P = 0.221). To examine the hypothesis that coamplified and/or coregulated topoisomerase IIalpha contributes to the resistance of c-erbB-2-overexpressing carcinomas, we established a chemosensitivity assay using primary cells from an ovarian carcinoma that overexpressed both c-erbB-2 and topoisomerase IIalpha. The combination of carboplatin with nontoxic concentrations of the topoisomerase II inhibitors etoposide or novobiocin enhanced the toxicity of carboplatin. In contrast, the tyrosine kinase inhibitor emodin exhibited no chemosensitizing effect in cells of this individual carcinoma. In conclusion, overexpression of c-erbB-2 was associated with poor prognosis and poor response to chemotherapy. The data suggest that topoisomerase IIlalpha, which correlates with c-erbB-2 expression, contributes to the resistance of c-erbB-2-overexpressing carcinomas.
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PMID:Contribution of c-erbB-2 and topoisomerase IIalpha to chemoresistance in ovarian cancer. 1039 67


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