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Top2a inhibition by temozolomide useful for predicting gbm patient's survival

A technology of temozolomide and prognosis, applied in medical preparations containing active ingredients, measuring devices, biological tests, etc., can solve problems such as poor median survival time

Active Publication Date: 2013-08-28
COUNCIL OF SCI & IND RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The highly heterogeneous and invasive nature of these tumors makes total resection practically impossible, resulting in poor median survival despite postoperative treatment modalities

Method used

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  • Top2a inhibition by temozolomide useful for predicting gbm patient's survival
  • Top2a inhibition by temozolomide useful for predicting gbm patient's survival
  • Top2a inhibition by temozolomide useful for predicting gbm patient's survival

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Collection of Tumor Samples

[0054] Tumor samples were collected from patients who underwent surgery at Sri Sathya Sai Institute of Higher Medical Sciences (SSSIHMS) and National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Normal brain tissue (anterior temporal lobe) obtained during surgery for intractable epilepsy was used as a control sample. The study was reviewed and approved by the ethics committees of both clinical centers, and patient consent was obtained before commencing the study in accordance with IEC guidelines and approvals.

Embodiment 2

[0056] Cell Lines, siRNA, and Transfection

[0057] U373, U138, LN18, LN229, U343, U87, K562, U251, and SVG cells were incubated at 37°C with 5% CO 2 They were cultured in DMEM containing 10% fetal bovine serum, penicillin and streptomycin in a humid atmosphere. Human TOP2A and cyclophilin siRNA duplexes were designed and synthesized by Dharmacon Research (Lafayette, CO). SMARTpool siRNA is a mixture of 4 different siRNA duplexes targeting different coding region sequences of TOP2A (Genbank TM accession number NM_001067). Dissolve the siRNA duplex in 1X universal RNA oligo buffer (20mM KCl, 6mM HEPES-KOH (pH7.5), 0.2mM MgCl 2 )middle. SiRNA transfection (20OnM) was performed using Dharmafect (Dharmacon Research) following the manufacturer's instructions.

Embodiment 3

[0059] Cell Viability Assay

[0060] For chemosensitivity assays, 24 h after plating, cells were treated with cytotoxic drugs and incubated at 37°C, 5% CO 2 Incubate for 45 hours. At this point, MTT (20 μl of 5 mg / mL) was added to the cells. Three hours after MTT addition, formazan crystals were dissolved in DMSO (200 μl) and measured as absorbance at 550 nm. All samples were normalized to control cells taking the absorbance generated by the illuminated cells as 100%. All assays were performed in triplicate.

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Abstract

The present invention provides a TOP2A inhibition by temozolomide useful for predicting glioblastoma patient's survival. Glioblastoma (GBM) is the most common, malignant primary adult brain tumor. The conventional treatments for GBM, include surgery, radiation, and chemotherapy which have only modestly improved patient survival. The patients with GBM expressing higher TOP2A transcript levels had better prognosis. More interestingly, the present invention reports that temozolomide is an inhibitor of TOP2A activity in vitro. The present invention further shows that siRNA knock down of TOP2A rendered a glioma cell line resistant to temozolomide chemotherapy.; Thus it is demonstrated for the first time that temozolomide is a TOP2A inhibitor and establishes that TOP2A transcript levels determines the chemosensitivity of glioblastoma to temozolomide therapy thus explaining the very high levels of TOP2A transcript being a good prognostic indicator in GBM patients receiving temozolomide chemotherapy.

Description

field of invention [0001] The present invention relates to inhibition of topoisomerase II alpha (TOP2A) by temozolomide for use in predicting survival of glioblastoma patients. [0002] More specifically, the present invention demonstrates that the level of TOP2A transcript determines the chemosensitivity of glioblastoma to temozolomide therapy, thereby explaining that very high level of TOP2A transcript is a good prognostic indicator for GBM patients receiving temozolomide chemotherapy. Background of the invention [0003] Glioblastoma (grade IV astrocytoma) is the most malignant and common primary adult brain cancer (Furnari et al., 2007). The highly heterogeneous and invasive nature of these tumors makes total resection practically impossible, resulting in poor median survival despite postoperative treatment modalities. While postoperative radiation therapy alone provided a slight survival benefit, radiation therapy plus nitrosourea-based chemotherapy produced a 6% incre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00
CPCC12Q2600/178A61K31/495G01N33/57407G01N2333/99G01N2800/52C12Q2600/158A61P35/00A61P43/00A61K39/00G01N33/00G01N33/574G01N33/68C12Q1/533
Inventor S·库玛拉维尔A·阿里玛帕玛甘K·斯纳拉苏A·S·海格德A·R·查德拉莫里S·瓦尼P·康戴哈S·R·曼查纳哈里朗加斯瓦梅
Owner COUNCIL OF SCI & IND RES
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