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)

Chemotherapy is the principal strategy to systemically challenge metastasized cancers of genitourinary origin. Unfortunately, the efficacy of chemotherapy is often hampered by multidrug resistance, the resistance to a variety of structurally and functionally distinct cytotoxic agents. Multidrug resistance can be either intrinsic or acquired, and can be caused by several mechanisms. The so-called classical multidrug resistance, mediated by the MDR1 gene product P-glycoprotein, has been held mainly responsible for inferring the multidrug resistance phenotype on urologic malignancies. However, several other multidrug resistance pathways have been identified. Multidrug resistance can be caused by the membrane-bound multidrug-resistance-associated protein, the detoxifying glutathione metabolism, the antiapoptotic protein BCL2, and changes in levels or activity of the topoisomerase enzymes. Strategies to overcome multidrug resistance of genitourinary tumors have arisen from the better understanding of the biologic and molecular mechanisms of multidrug resistance, and have been studied in experimental and clinical settings. However, attempts to modulate multidrug resistance in clinical renal cell, bladder, prostate, and testicular cancer have not been very rewarding so far, despite the optimism that had arisen from experimental data. Nevertheless, application of novel therapies to reverse multidrug resistance and to increase efficacy of chemotherapy for urologic cancers should be further pursued, within the setting of controlled clinical trials, to improve on current strategies.
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PMID:Circumvention of multidrug resistance in genitourinary tumors. 953 94

To study the development of drug resistance in childhood hepatoblastoma (HB) using a model closely related to in vivo conditions, we cultivated HB xenografts from 3 patients into mice and treated these tumors with either adriamycin (ADR) or cisplatin (CIS). Determination of the relative expression levels of various resistance associated genes by a cDNA-PCR approach showed: a) Significantly enhanced MDR1 gene expression levels after treatment with ADR in each case. b) Significantly enhanced glutathione S-transferase mu (GST mu) gene expression levels after treatment with CIS in 2/3 xenografts. c) Significantly decreased levels of topoisomerase IIa (TOPO IIa) in tumors of the same two patients after treatment with either ADR or CIS. These findings give evidence that the MDR1-, GST mu- and TOPO IIa-gene products may contribute to drug resistance in HB.
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PMID:Altered expression of resistance associated genes in hepatoblastoma xenografts incorporated into mice following treatment with adriamycin or cisplatin. 971 21

Protoberberines are a new class of organic cations that are dual poisons of topoisomerases I and II. Certain protoberberines exhibit greater in vitro cytotoxicity against cell lines derived from solid tumors than from leukemias. Using a group of seventeen different protoberberine analogs, the structural basis for selective cytotoxicity toward sensitive SF-268 glioblastoma cells as compared with resistant RPMI 8402 lymphoblast cells was explored. The selective cytotoxicity is associated with the presence of an imminium ion and other structural features of protoberberines, and is not shared by drugs such as camptothecin, doxorubicin, vinblastine, and etoposide, which are either equally or more cytotoxic against RPMI 8402 cells than SF-268 cells. The selective cytotoxicity of protoberberines against SF-268 over RPMI 8402 cells is not due to differences in topoisomerase levels or known drug efflux systems such as multidrug resistance (MDR1) and multidrug-resistance protein (MRP). Comparative in vitro studies of the accumulation of coralyne, a fluorescent protoberberine, into sensitive and resistant cells demonstrated a correlation between drug accumulation and selective cytotoxicity. Inhibitors of coralyne uptake included several protoberberine-related compounds. Of these, palmatine, a minimally cytotoxic protoberberine, both inhibited coralyne accumulation and reduced cytotoxicity against SF-268 cells, but not against RPMI 8402 cells. Despite the structural resemblance of protoberberines to catecholamines, our experiments using inhibitors and cells expressing biogenic amine uptake systems have ruled out the involvement of biogenic amine uptake1, uptake2, and vesicular monoamine transport systems. Uptake systems remaining as candidates, supported by preliminary data, include transport via vesicles derived from specialized membrane invaginations and selected carrier-mediated organic amine transport systems.
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PMID:Selective cytotoxicity of topoisomerase-directed protoberberines against glioblastoma cells. 980 26

We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide. In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.
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PMID:Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening. 986 68

Acute myelogenous leukemia (AML) represents 80% of adult acute leukemias. A standard-dose chemotherapy allows to obtain 52% to 72% of complete remission (CR). A major limitation for success in chemotherapy of AML is dominance of drug-resistant subpopulations of cells. Cytosine-arabinoside (Ara-C) is a basic drug in AML treatment. Myeloblasts resistance to Ara-C could be kinetic or pharmacological. The classical multidrug resistance (MDR) depends on presence in resistant myeloblasts ATP-dependent drug-efflux pump with ability to remove cytotoxic drugs from the cells. It is a product of MDR1 gene called P-glycoprotein (Pgp). Pgp is responsible for cell resistance to cytotoxic compounds of natural origin, such as anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, colchicine and amsacrine. There were also identified not Pgp-dependent multidrug resistance mechanisms (non-Pgp MDR) in AML. All mentioned above drugs are involved but not taxol. Non-Pgp MDR depends on topoisomerase II alfa activity alterations, multidrug resistance-associated protein (MRP) expression and lung resistance-related protein (LRP) expression. Pgp positive AML patients have poorer complete remission (CR) rate, decreased remission duration and overall survival. Pgp expression is detected among 70% AML patients older than 55. The most promising drugs in circumventing classical MDR seems cyclosporin A (CsA) and cyclosporin D (SDZ PCS 833). They are successfully used in refractory and relapsed AML.
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PMID:[The causes of treatment ineffectiveness in acute myelogenous leukemia--the role of blast resistance to cytotoxic drugs]. 1002 86

Clinical studies have suggested that both MDR1 and MRP may play a significant role in the chemosensitivity and outcome of neuroblastoma. To clarify the nature of multidrug resistance (MDR) in this tumour a series of six neuroblastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MRP, LRP and topoisomerase II genes using reverse transcription polymerase chain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed LRP and four expressed MDR1, but protein levels of each of these were variable. Chemosensitization to a range of MDR-associated drugs (vincristine, doxorubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cisplatin, melphalan) by three modulating agents, cyclosporin A, PSC 833 and the novel Biricodar (VX-710; Incel), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agents was evaluated using FACS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked sensitization to vincristine was observed in MDR1-positive lines, and a similar but less consistent effect was seen with taxotere, doxorubicin and etoposide. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory factors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.
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PMID:BIRICODAR (VX-710; Incel): an effective chemosensitizer in neuroblastoma. 1037 71

Combined modalities are currently used for cancer therapy, although their mechanisms of activity remain incompletely deciphered. The design of new drug combinations suffers from our inability to anticipate accurately their efficacy or toxicity. They can be evaluated in vivo, using human tumors grafted into immunodeficient mice, as we did here with combined protocols used in the clinical setting. Xenografts of small cell lung carcinoma (SCLC) from eight patients were used to test the tumor sensitivity to etoposide (VP16; 12-16 mg/kg/days, days 1, 2, and 3), cisplatin (CDDP; 6-9 mg/kg/day, day 1) and ifosfamide (IFO; 90-210 mg/kg/day, days 1, 2, and 3) as single agents and to evaluate the efficacy of the two-drug or three-drug combinations. Five xenografts came from untreated patients (SCLC-61, SCLC-6, SCLC-10, SCLC-41, and SCLC-96) and three after treatment (SCLC-74, SCLC-101, and SCLC-108). p53 was inactivated in all of them. Tumor growth inhibition, growth delay, and the survival rate of tumor-bearing mice reflected individual SCLC chemosensitivity. As single agents, IFO inhibited tumor growth in a dose-dependent manner, whereas CDDP and VP16 had little or no effect. Both CDDP and IFO potentiated VP16, inducing complete regressions in the most sensitive SCLCs; VP16-IFO was more effective than VP16-CDDP, with complete regressions in six versus three of the eight tumors tested, respectively. CDDP-IFO was less effective than VP16-IFO, with three of eight SCLCs giving complete regressions. The three-drug combination led to modest improvement over the best two-drug combination but only for sensitive SCLCs. Because drug-responses distinguished two classes of SCLCs, as sensitive or refractory, MDR1, glutathione S-transferase pi, lung-related multidrug resistance protein, multidrug resistance protein, and topoisomerase IIalpha mRNA expression was studied by semiquantitative reverse transcription. There was no correlation with SCLC sensitivity; topoisomerase IIalpha and multidrug resistance protein was expressed in all cases, lung-related multidrug resistance protein and glutathione S-transferase pie in seven of eight, and MDR1 gene in four of eight. In conclusion, these SCLC xenografts displayed a pattern of chemotherapy response close to that observed in patients. This model confirmed that in two-drug combinations, each component potentiated the effects of the other, with VP16-IFO tending to be the best two-drug combination, both of which were more effective than VP16-CDDP and better tolerated than CDDP-IFO. The addition of a third agent gave a modest, if any, therapeutic benefit in the responders but none in refractory SCLCs. There was no correlation between the extent of response and resistance markers.
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PMID:Distinctive potentiating effects of cisplatin and/or ifosfamide combined with etoposide in human small cell lung carcinoma xenografts. 1081 35

Choroidal melanoma has a high mortality rate and responds poorly to existing chemotherapy, but unexpected ex vivo sensitivity of a subset of these tumours to topoisomerase II inhibitors has been noted. Since chemoresistance may be mediated by the molecular phenotype of tumours, immunohistochemistry has been used to study the expression of both isoforms of topoisomerase II (alpha and beta) in 29 choroidal melanomas for which chemosensitivity assay data for doxorubicin or mitoxantrone are also available. Of these, eight tumours were topoisomerase II beta-positive and 11 were topoisomerase II alpha-positive. Recent studies showing genetic abnormality (often monosomy of chromosome 3) in choroidal melanoma suggest that loss of immunostaining could be due to genomic loss rather than down-regulation of topoisomerase II beta in these tumours. There was no convincing excess of anthracycline resistance in the topoisomerase II beta-negative group. Addition of topoisomerase II alpha, MDR1 (11/17 positive), LRP (16/28 positive), and MRP (5/29 positive) data in multivariate analysis did not reliably predict sensitivity or resistance. Vincristine chemosensitivity showed no relation to MDR1, LRP or MRP in 18 tumours tested. While it is possible that some tumours which do express topoisomerase II beta may respond to anthracyclines, the molecular basis of resistance or sensitivity to anthracyclines or vincristine in uveal melanoma is complex and remains incompletely understood.
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PMID:Relationship between expression of topoisomerase II isoforms and chemosensitivity in choroidal melanoma. 1100 93

Renal Cell Carcinomas (RCCs) exhibit strong resistance to the most chemotherapeutic treatments probably due to the expression of various multidrug resistance (MDR) genes. Overexpression of P-glycoprotein (Pgp) is established as one such factor, but other mechanisms such as at-MDR, characterized by attenuated DNA-topoisomerase II (topoII) activity, may be functional as well. In addition, regulating proteins involved in apoptosis can exhibit multidrug resistant features. However, prevention of apoptosis as a mechanism of MDR has not yet been assessed in RCC, nor has the cytotoxicity of a variety of chemotherapeutic agents known to trigger apoptotic or necrotic cell death been tested in RCC in a systematic fashion. Using immunohistochemistry and Western blotting, Bcl-2 and Bax expression was determined in a panel of multidrug resistant RCC lines featuring Pgp and/or at-MDR. The results were related to apoptotic activity and kind of cell death in these cell lines, demonstrated by incubation with Hoechst 33342 and propidium iodide after treatment with various cytotoxic agents and quantitated by MTT. In the drug resistant sublines, some decreased Bax and strongly increased Bcl-2 expression was seen by immunohistochemistry indicating prevention of apoptosis as a distinct feature of MDR in RCC. This was confirmed by Western blotting. Sublines revealed significant resistance for all drugs, except for CC-313 and DiMIQ. However, these drugs induced necrotic cell death, in contrast to all other drugs tested, which induced apoptotic cell death. We conclude that, in chemoselected RCC sublines, multidrug resistance appears to be functional due to inhibition of apoptosis, apart from the MDR1 and at-MDR resistance mechanisms. CC-313 and DiMIQ are very potent cytotoxic agents in RCC, probably because they do not kill by induction of apoptosis.
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PMID:Inhibition of apoptotic proteins causes multidrug resistance in renal carcinoma cells. 1184 68

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


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