title: Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor.
abstract: 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.
authors.affiliation: Department of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India.
authors.forename: A
authors.initials: A
authors.lastname: Arivazhagan
authors.forename: Durairaj Mohan
authors.initials: DM
authors.lastname: Kumar
authors.forename: Vinay
authors.initials: V
authors.lastname: Sagar
authors.forename: Irene Rosita Pia
authors.initials: IR
authors.lastname: Patric
authors.forename: S
authors.initials: S
authors.lastname: Sridevi
authors.forename: Balaram
authors.initials: B
authors.lastname: Thota
authors.forename: Mallavarapu R
authors.initials: MR
authors.lastname: Srividya
authors.forename: K
authors.initials: K
authors.lastname: Prasanna
authors.forename: K
authors.initials: K
authors.lastname: Thennarasu
authors.forename: Neelima
authors.initials: N
authors.lastname: Mondal
authors.forename: A S
authors.initials: AS
authors.lastname: Hegde
authors.forename: B A
authors.initials: BA
authors.lastname: Chandramouli
authors.forename: V
authors.initials: V
authors.lastname: Santosh
authors.forename: M R S
authors.initials: MR
authors.lastname: Rao
authors.forename: P
authors.initials: P
authors.lastname: Kondaiah
authors.forename: K
authors.initials: K
authors.lastname: Somasundaram
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015331:Cohort Studies; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005909:Glioblastoma / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008297:Male; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D000077204:Temozolomide; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D059005:Topoisomerase II Inhibitors; D003606:Dacarbazine; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; D002166:Camptothecin; D000077204:Temozolomide
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