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 aim of the present study was to clarify the relationship between topoisomerase-I (topo-I) activity and sensitivity to second-line chemotherapy consisting of cisplatin and camptothecin-11 (CPT-11) in patients with ovarian cancer. Thirty Japanese women with relapsed epithelial ovarian cancer who received treatment at Tottori University Hospital or Kurume University Hospital between 1992 and 1997 were included in this study. All patients had initially undergone chemotherapy consisting of cisplatin, doxorubicin and cyclophosphamide (CAP). All subjects exhibited measurable lesions and received second-line chemotherapy consisting of 50 to 60 mg/m(2) CPT-11 on days 1, 8 and 15 and 60 mg/m(2) cisplatin on day 1. Tumor samples were obtained in the period between initial and second-line chemotherapy. Topo-I activity was assayed by relaxation of supercoiled plasmid substrate DNA. Of the 30 patients, 18 responded to second-line chemotherapy and 12 did not. We found no significant difference in patient characteristics in responders and non-responders. The interval from the end of the initial course of chemotherapy to the beginning of the second-line chemotherapy did not significantly differ in the 2 groups. The minimum amount of extraction showing complete DNA relaxation in non-responders was significantly greater than that in responders (201.7 +/- 92.5 vs. 124.1 +/- 59.4 ng; p = 0.0164). In 8 cases whose samples could be obtained before and after CAP, the amount of protein significantly decreased after CAP therapy (286.4 +/- 142.1 vs. 138.5 +/- 97.8 ng; p = 0.0294). Topo-I activity, which is enhanced by CAP therapy, can play an important role in sensitivity to CPT-11.
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PMID:Topoisomerase-I activity and response to second-line chemotherapy consisting of camptothecin-11 and cisplatin in patients with ovarian cancer. 1050 31

Physiological cell conditions, such as glucose deprivation and hypoxia, play a role in developing drug resistance in solid tumors. These tumor-specific conditions cause decreased expression of DNA topoisomerase IIalpha (topo IIalpha), rendering cells resistant to topo II-targeted drugs, such as etoposide and doxorubicin. We show here that inhibition of proteasome attenuated drug resistance by inhibiting topo IIalpha depletion induced by glucose starvation and hypoxia. topo IIalpha restoration was seen only at the protein levels, indicating that the topo IIalpha protein depletion occurred through a proteasome-mediated degradation mechanism. The stress-induced etoposide resistance was effectively prevented in vitro by the proteasome inhibitor lactacystin in both intrinsically resistant and sensitive tumor cells (colon cancer HT-29 and ovarian cancer A2780 cells, respectively). Furthermore, lactacystin effectively enhanced the antitumor activity of etoposide in the refractory HT-29 xenograft. These results indicate that lactacystin could serve as a new therapeutic agent to circumvent resistance to topo II-targeted chemotherapy in solid tumors.
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PMID:Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. 1081 Nov 20

Multidrug resistance (MDR) and more specifically the expression of P-glycoprotein (Pgp) have been studied extensively in vitro. Unfortunately, it appears that the predictive value of MDR recognized in vitro is mostly an incorrect measure to determine the responsiveness of a particular tumour in the clinic. This misunderstood or overvalued role of MDR might explain the failure of strategies to reverse Pgp function by the use of modulators in solid tumours. To obtain more insight in in vivo drug resistance we investigated a panel of 15 human ovarian cancer xenografts consisting of the most common histological subtypes known in ovarian cancer patients. The response rate to cisplatin, cyclophosphamide and doxorubicin in the xenografts resembled the results of phase II trials with these agents in ovarian cancer patients. This resemblance justifies drug resistance studies in this experimental in vivo human tumour system. We determined the expression levels of MDR 1, MRP 1, LRP and topoisomerase IIalpha mRNA by the RNase protection assay and the presence of MRP1 and LRP proteins by immunohistochemistry. The S-phase fraction was investigated as a separate parameter by flow cytometry. In none of the 15 ovarian cancer xenografts was MDR 1 expression detectable. The expression levels of MRP 1 and LRP were low to moderate and resembled the presence of the MRP1 and LRP proteins. There was a weak, inverse relationship between the expression levels of LRP and sensitivity to cisplatin and cyclophosphamide (r = -0.44 and -0.45), but not to doxorubicin. The levels of topoisomerase IIalpha varied among the xenografts (0.73-2.66) and failed to correlate with doxorubicin resistance (r = 0.14). The S-phase fraction, however, showed a relation with the sensitivity to cisplatin (r = 0.66). Among the determinants studied in ovarian cancer in vivo, LRP mRNA and the S-phase fraction were the best predictive factors for drug response and most specifically for the activity of cisplatin.
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PMID:Drug resistance features and S-phase fraction as possible determinants for drug response in a panel of human ovarian cancer xenografts. 1097 Jun 95

Topoisomerases I and II unravel DNA during transcription, DNA replication and DNA repair. Inhibitors of both enzymes are important anticancer drugs, but only now are combined inhibitors becoming available for clinical use. In this study we have used an ATP-based chemosensitivity assay to determine the activity of XR5000 and possible combinations against ovarian cancer, a tumor sensitive to current topoisomerase inhibitors, and melanoma, an insensitive tumor. A further six tumors of other types were also tested. The results from 20 ovarian cancer and 18 melanoma biopsies show remarkably little difference between the tumor types in terms of IC50, IC90 or two summary indices of chemosensitivity based on all of the concentrations tested. XR5000 on its own shows a steep concentration-response curve in most tumors, only achieving high reduction (above 95%) of ATP levels at 2440 ng/ml (6 microM). The results were often similar to the combination of etoposide and topotecan, particularly at the higher concentrations tested. The combinations with greatest activity in ovarian cancer were with paclitaxel or cisplatin, while melanoma showed greatest improvement with paclitaxel or treosulfan. The results are encouraging for the clinical introduction of this agent, and suggest that it will be effective in combination with currently available drugs for both ovarian cancer and melanoma.
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PMID:Ex vivo activity of XR5000 against solid tumors. 1100 88

New drug development requires simple in vitro models that resemble the in vivo situation more in order to select active drugs against solid tumours and to decrease the use of experimental animals. In this paper, we review the characteristics and scope of a relatively simple cell-culture system with a three-dimensional organisation pattern - the multilayered postconfluent cell culture model. Solid tumour cell lines from diverse origins when grown in V-bottomed microtiter plates reach confluence in 3-5 days and then start to form multilayers. The initial exponential growth of the culture is followed by a plateau phase when cells reach confluence. This produces changes in the morphology of the cells. For some cell lines, it is possible to observe cell differentiation. A substantial advantage of the system is the use of the sulforodamine B (SRB) assay to determine relative cell growth or viability, which allows semiautomation of the experiments. Several experiments were performed to assess the differences and similarities between cells cultured as monolayers and multilayers, and eventually, compared with the results for solid tumours and some other models such as spheroids. Cell-cycle analysis for multilayers showed a lower S-phase arrest, which is accompanied by a decrease in the expression of cell-cycle-related proteins and a decrease in cellular nucleotide pools. Gene and protein expression of topoisomerase I, topoisomerase II and thymidylate synthase expression were lower for multilayers, but no substantial changes were observed for the expression of DT-diaphorase. P53 expression increased. Multilayer cultures present distinctive properties for drug transport across the membrane, drug accumulation and retention. In fact, the transport of antifolates across the membrane, accumulation of topotecan and gemcitabine-triphosphate are reduced in multilayers when compared with monolayers, which may be related to a decrease in drug penetration to the inner regions of the multilayers. Alteration of these pharmacodynamic parameters is directly related to a decrease in drug activity. The most powerful application of multilayers is in the assessment of cytotoxicity. Solid tumour cell lines from different origins have been treated with several conventional and investigational anticancer drugs. The data show that multilayers are more resistant to the drugs than the corresponding monolayers, but there are substantial differences between the drugs depending on culture conditions, e.g. the difference was rather small for a drug such as cisplatin, miltefosine and EO9, a drug, which is activated under hypoxic conditions. Gemcitabine was active against ovarian cancer but not against colon cancer, resembling the in vivo situation. This observation was not evident with monolayer experiments. Another interesting application is the possibility to perform drug combination studies. The combination of gemcitabine and cisplatin proved to produce selective cell kill in H322 cells (non-small cell lung cancer cell line). Neither of the drugs was independently able to produce similar effects. In summary, multilayer cultures are relatively simple three-dimensional systems to study the effect of microenvironmental conditions on anticancer drug activity. The model might serve as a base for a more rigorous secondary in vitro screening.
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PMID:The multilayered postconfluent cell culture as a model for drug screening. 1103 3

KILLER/DR5 is a death-domain-containing proapoptotic receptor that binds to the cytotoxic ligand TRAIL. It was originally reported that induction of KILLER/DR5 mRNA following DNA damage was p53-dependent, but some drugs that induce apoptosis can upregulate KILLER/DR5 mRNA expression in cell lines with mutated p53. We further extend those findings by classifying the capability of various apoptosis-inducing drugs to increase the expression of KILLER/DR5 mRNA in a p53-independent manner. beta-Lapachone, a topoisomerase inhibitor, increased KILLER/DR5 mRNA in colon cancer cell lines with wild-type p53 but not with mutant p53. In contrast, betulinic acid, a novel chemotherapeutic compound, induced apoptosis and KILLER/DR5 mRNA in melanoma and glioblastoma cells through a p53-independent mechanism. The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA. Finally, the cytokine interferon-gamma (IFN-gamma) induced apoptosis and KILLER/DR5 in cell lines with mutant p53, and the induction of KILLER/DR5 mRNA by IFN-gamma was delayed in cells lacking wild-type STAT1, a transcription factor implicated in IFN-gamma signaling. Similarly, the induction of KILLER/DR5 mRNA by the cytokine TNF-alpha was also delayed in cell lines with mutated STAT1. These findings suggest that KILLER/DR5 may play a role in p53-independent apoptosis induced by specific drugs and warrants further investigation as a novel target for chemotherapy of tumors lacking wild-type p53.
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PMID:p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. 1113 40

Recombinant human tumor necrosis factor (rHuTNF) is a cytokine, with some antitumor activity, released by stimulated monocytes-macrophages. In vivo and in vitro cytotoxicity studies testing the effectiveness of rHuTNF alone or in combination with chemotherapeutic agents have been carried out. We have evaluated the direct cytotoxic effect of rHuTNF on a human epithelial ovarian cancer cell line in vitro (A2774), alone or in combination with Etoposide (VP16) or Doxorubicin (Doxo), some topoisomerase II (Topo II) targeted drugs, or in combination with Cisplatin (CDDP), a not Topo II interactive drug. Our results suggest that rHuTNF is directly cytotoxic and that it is also able to induce a potentiation of VP16- or Doxo-cytotoxicity, but it is unable to potentiate CDDP-cytotoxicity. These data represent a reasonable basis for combining rHuTNF with Topo II inhibitors within phase I studies. The combination regimen could be tested in ovarian cancer patients.
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PMID:Synergistic cytotoxic effects of recombinant human tumor necrosis factor and Etoposide (VP16) or Doxorubicin on A2774 human epithelial ovarian cancer cell line. 1157 50

Irinotecan hydrochloride (CPT-11), a DNA topoisomerase-I inhibitor, is now widely used in the treatment of various solid tumors, including colorectal, gastric, breast, lung, and ovarian cancer. Despite the good response shown in the late phase-II study, CPT-11 was not often employed in the treatment of malignant lymphoma, mainly because of severe leukopenia and diarrhea caused by the recommended schedule: 40 mg/m2 of CPT-11 on days 1 to 3, 8 to 10, 15 to 17, then discontinued for at least 2 weeks. In clinical use, administration of CPT-11 had to be ceased on days 15 to 17 in almost all cases, and on days 8 to 10 in a considerable number of patients. Subsequently, a lower dose schedule (less than 40 mg/m2) was developed. Our phase II trial employing a reduced dose of CPT-11 on days 1 and 2, plus ADM on day 3 with 3-week interval in patients with refractory and relapsed NHL showed a fairly good response of relapsed B-cell lymphoma and a substantial response of T-cell lymphoma with acceptable toxicity. The combination of a topoisomerase-I inhibitor (CPT-11) and a topoisomerase-II inhibitor is an interesting concept for the treatment of NHL. Another phase II trial in combination with CPT-11 and other anti-cancer drugs, particularly cisplatin or topoisomerase-II inhibitors, is warranted. A superior salvage chemotherapy regimen could be found in the future by investigating combinations of low-dose CPT-11 and cisplatin or topoisomerase-II inhibitors.
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PMID:Chemotherapy with irinotecan (CPT-11), a topoisomerase-I inhibitor, for refractory and relapsed non-Hodgkin's lymphoma. 1169 85

In the present study, we examined die 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 (P = 0.035). A significant association between expression of c-erbB-2 mRNA und survival was obtained for the subgroup of patients who received a standard chemotherapy with carboplatin or cisplatin and cyclophosphamide (P = 0.0003). 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 und topoisomerase IIbeta mRNA dit not correlate (P = 0.221). The data suggest that topoisomerase IIalpha, which correlates with c-erbB-2 expression, contributes to the resistance of c-erbB-2-overexpressing carcinomas.
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PMID:[Expression of c-erbB-2 and topoisomerase II alpha in relation to chemoresistance in ovarian cancer]. 1207 Jul 98

XK469, a synthetic quinoxaline phenoxypropionic acid derivative, has been found to have selective activity against a broad panel of solid tumors including several drug-resistant cell lines and has been approved for phase I clinical evaluation. Recent studies suggested that XK469 is a selective topoisomerase IIbeta inhibitor, but the mechanism of XK469-induced cell death remains unknown. Here we investigate the ability of XK469 to induce apoptosis of human cancer cells. In the human ovarian cancer cell line PA1, XK469 caused the release of cytochrome c, activation of caspases including caspases 9, 7 and 3, cleavage of PARP, and subsequently cell death. Moreover, Bcl2 and Bax were cleaved in XK469 treated cells. PA1 cells expressing the dominant negative-caspase 9 were less sensitive to XK469. Importantly, in these PA1 cells expressing DN-casp 9, the activation of caspases including caspases 3, 7 and 9, and cleavage of Bax and Bcl2 were inhibited, suggesting that the activation of the mitochondrial pathway is required for XK469-induced anticancer activity. These results indicate that the induction of apoptosis by XK469 may account for its anti-tumor activity and such activity is required for the activation of the mitochondrial pathway. Thus, our study defines a possible mechanism, at least in part, underlying XK469-induced anti-cancer activity.
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PMID:Induction of apoptosis by the new anticancer drug XK469 in human ovarian cancer cell lines. 1208 31


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