Effect of transfection of a Drosophila topoisomerase II gene into a human brain tumour cell line intrinsically resistant to etoposide

Asano, Takeshi; Zwelling, Leonard A.; An, Taeha; McWatters, Amanda; Herzog, Cynthia E.; Mayes, Janice; Loughlin, Susan M.; Kleinerman, Eugenie S.

doi:10.1038/bjc.1996.261

Cited by 16 publications

(11 citation statements)

References 14 publications

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“…It has previously been reported that amplification of TOP2A may account for chemosensitivity to anthracycline therapy in breast cancer [18]. Further, invitro studies using different experimental methods have previously proved that sensitivity to the TOP2A inhibitors depends on the level of expression of TOP2A in cancer cells-cells with a low concentration of TOP2A protein are less sensitive to TOP2A-inhibiting drugs than cells containing a high concentration of TOP2A [11,13,[27][28][29][30][31]. Similar results for astrocytomas have not yet been reported in the literature.…”

Section: Discussionmentioning

confidence: 98%

Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor

et al. 2011

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The search for molecular markers which predict response to chemotherapy is an important aspect of current neuro-oncology research. MGMT promoter methylation is the only proved marker of glioblastoma. The purpose of this study was to assess the effect of topoisomerase expression on glioblastoma survival and study the mechanisms involved. The transcript levels of all isoforms of the topoisomerase family in all grades of diffuse astrocytoma were assessed. A prospective study of patients with glioblastoma treated by a uniform treatment procedure was performed with the objective of correlating outcome with gene expression. The ability of TOP2A enzyme to relax the super coiled plasmid DNA in the presence of temozolomide was evaluated to assess its effect on TOP2A. The temozolomide cyctotoxicity of TOP2A-silenced U251 cells was assessed. The transcript levels of TOP2A, TOP2B, and TOP3A are upregulated significantly in GBM in comparison with lower grades of astrocytoma and normal brain samples. mRNA levels of TOP2A correlated significantly with survival of the patients. Higher TOP2A transcript levels in GBM patients predicted better prognosis (P = 0.043; HR = 0.889). Interestingly, we noted that temozolomide inhibited TOP2A activity in in-vitro enzyme assays. We also noted that siRNA knock down of TOP2A rendered a glioma cell line resistant to temozolomide chemotherapy. We demonstrated for the first time that temozolomide is also a TOP2A inhibitor and established that TOP2A transcript levels determine the chemosensitivity of glioblastoma to temozolomide therapy. Very high levels of TOP2A are a good prognostic indicator in GBM patients receiving temozolomide chemotherapy.

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Section: Discussionmentioning

confidence: 98%

Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor

et al. 2011

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“…It is know that the activity of DNA topoisomerase II can be interrupted by enzyme binders ( e.g ., Etoposide) or DNA lesions ( e.g ., abasic sites) to produce topoisomerase II‐mediated DNA damage. In‐vitro studies have also demonstrated that the forced expressions of topoisomerase by ectopic transfection could enhance the therapeutic effect of Etoposide in drug‐resistant breast and brain cancer cell lines 44, 45. In this study, we showed that Etoposide could sensitize HCC cells to doxorubicin‐induced cell death.…”

Section: Discussionmentioning

confidence: 99%

TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance

Wong

Park

Wong

et al. 2008

Intl Journal of Cancer

172

119

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Genomic gain represents an important mechanism in the activation of proto-oncogenes. In many instances, induced oncogenes hold clinical implications both as prognostic markers and targets for therapeutic design. In hepatocellular carcinoma (HCC), although chromosomal gains are common, information on underlying oncogenes induced remains minimal. Here, we examined 7 causal sites of HCC for overexpressed genes by array-based transcriptional mapping. In 22 HCC cell lines and early passages of cultures studied, clusters of up-regulated genes were indicated, where TOP2A expression ranked the highest. Distinct TOP2A transcriptions were confirmed in an independent series of HCC tumors relative to adjacent non-tumoral liver (p 5 0.0018). By tissue microarray analysis of 172 HCC, we found TOP2A expressions correlated with advance histological grading (p < 0.001), microvascular invasion (p 5 0.004) and an early age onset of the malignancy (≤40 years; p 5 0.007). In conjunction with P-gp and MRP1, TOP2A were further assessed for its association with chemotherapy responsiveness and survival in 148 patients who entered our recently reported Phase III prospective randomized study. In 73 chemoresistant and 75 nonresistant patients, only TOP2A positivity correlated with chemoresistance (p 5 0.029) and shorter patients survival (p < 0.0001). The potential therapeutic value in targeting TOP2A by Etoposide, as a single agent, and in combination with Doxorubicin was also explored. In vitro cytotoxic studies suggested Etoposide at IC 20 readily reduced IC 50 values of Doxorubicin by a magnitude of~3.5 to 10-fold compared to Doxorubicin alone (p < 0.028). Our study highlighted for the first time the prognostic value of TOP2A in HCC and the potential use of TOP2A reactive agents in therapy.

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“…have previously proven that the sensitivity to topoII-inhibitors is dependent on the expression level of topoIIα in cancer cells; Namely, the cells with a low concentration of topoIIα protein are less sensitive to topoII-inhibiting drugs than cells containing a high concentration of topoIIα, i.e. the molecular target of the drugs [162][163][164][165][166][167][168].…”

Section: Topoisomerase Iiα α α α / Top2amentioning

confidence: 99%

“…The response to topoII-inhibitor chemotherapy, in turn, is made in the nucleus of each individual tumor cell depending on the expression level of topoIIα, i.e. whether the drug can find its molecular target, topoIIα, there [2,[162][163][164][165][166][167][168]170]. Thus, the topoIIα IHC can only be used as a proliferation marker when cancer diagnostics are considered (i.e.…”

Section: H E R -2 and T O P 2 A Diagnostic Test For Herceptin -Topo Imentioning

confidence: 99%

Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase IIα (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer

Järvinen¹,

Liu²

2006

CCDT

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The HER-2 (also known as ERBB2/ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also amplified in other forms of cancer. Beside its important role in tumor induction, growth and progression, HER-2 is also a target for new therapeutic approaches such as Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, which is in a wide clinical use for HER-2 amplified breast cancer, a number of various HER-2 directed immunological and genetic strategies, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) simultaneously, have demonstrated promising pre-clinical activity in HER-2 amplified carcinomas. Moreover, the HER-2 amplicon is known to contain more than 30 genes with altered copy numbers that could be therapeutic targets for chemotherapy. The topoisomerase IIalpha gene, TOP2A, is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted (with equal frequency) in a great majority of HER-2 amplified primary breast tumors and also in tumors without HER-2 amplification. Recent experimental as well as numerous, large, multi-center trials suggest that amplification (and/or deletion) of TOP2A may account for both sensitivity or resistance to commonly used cytotoxic drugs, i.e. topoII-inhibitors (anthracyclines etc.), depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding, and a number of therapeutic strategies targeting either the HER-2 or its signaling pathways in cancer therapy are being investigated. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostic tests such as those ascertaining TOP2A status, may be helpful for the ideal selection of patients for the combination therapy of an HER-2 targeting drug together with a cytotoxic drug such as topoII-inhibitor especially in the case of TOP2A amplification.

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Effect of transfection of a Drosophila topoisomerase II gene into a human brain tumour cell line intrinsically resistant to etoposide

Cited by 16 publications

References 14 publications

Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor

Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor

TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance

Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase IIα (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer

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Effect of transfection of a Drosophila topoisomerase II gene into a human brain tumour cell line intrinsically resistant to etoposide

Cited by 16 publications

References 14 publications

Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor

Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor

TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance

Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase II&#945; (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer

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Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase IIα (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer