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zoom RSS ガン放射線療法の効果を高める/POLQ遺伝子の抑制

<<   作成日時 : 2010/04/05 20:34   >>

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 ガン細胞を殺す放射線療法の能力を妨げる遺伝子が英国の研究者によって発見された。破損したDNAを修理する役割を持つPOLQ遺伝子の働きを抑えれば、放射線治療がもっと効果的となる。
 多数のガン患者が放射線治療を受けており、40%の症例でガン消失に寄与していると概算されている。
 POLQ遺伝子が特に正常な健康組織の中ではアクティブではなく、ガン細胞中に豊富に認められる。これを目標に治療薬の発見が期待される。
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Page last updated at 23:00 GMT, Friday, 2 April 2010 00:00 UK
Blocking gene boosts cancer killing radiotherapy
http://news.bbc.co.uk/2/hi/health/8596797.stm

画像Radiotherapy
Radiotherapy is a commonly used cancer treatment

A gene which hinders the ability of radiotherapy to kill cancer cells has been detected by UK researchers.

The team found that if they blocked the POLQ gene - which has a role in repairing damaged DNA - radiotherapy was more effective.
It is hoped that the discovery, which came about after a trawl through 200 candidate genes, could lead to new drugs to boost radiotherapy.
The findings are published in the journal Cancer Research.

Many thousands of cancer patients will have some form of radiotherapy as part of their treatment, and it is estimated to contribute to 40% of cases where cancer is eliminated.

The next stage is to translate this discovery into a treatment that will benefit patients
Professor Gillies McKenna

The researchers from the University of Oxford said tumours can differ widely in the way they respond to radiotherapy - but the reasons for these differences are largely unknown.
In order to find a potential target for increasing the chances that radiotherapy would work, they looked specifically at genes involved in repairing DNA damage.
After pinpointing the POLQ gene, they found that blocking it in several different types of cancer cell in the laboratory, including laryngeal and pancreatic tumours, rendered the cells more vulnerable to the effects of radiation.

Selective
Previous research had shown that the POLQ gene is not particularly active in normal healthy tissue.
Doing the same experiment in healthy cells, the team found that blocking the gene did not have any effect on the sensitivity of normal tissue to radiation.
The researchers said the fact that the POLQ seemed to more abundant in cancer cells than normal cells made it a good target for boosting the effects of radiotherapy.
Study leader Dr Geoff Higgins, a Cancer Research UK scientist at the Gray Institute for Radiation Oncology and Biology, said: "We've sieved through a vast pool of promising genetic information and identified a gene that could potentially be targeted by drugs to improve the effectiveness of radiotherapy.
"Blocking the activity of this gene resulted in a greater number of tumour cells dying after radiotherapy and provides new avenues for research."
Professor Gillies McKenna, director of the institute, added: "The next stage is to translate this discovery into a treatment that will benefit patients."

----------------------------------------------------
Cancer Research 70, 2984, April 1, 2010. Published Online First March 16, 2010;
doi: 10.1158/0008-5472.CAN-09-4040
(c) 2010 American Association for Cancer Research

A Small Interfering RNA Screen of Genes Involved in DNA Repair Identifies Tumor-Specific Radiosensitization by POLQ Knockdown
Geoff S. Higgins1, Remko Prevo1, Yin-Fai Lee1, Thomas Helleday1, Ruth J. Muschel1, Steve Taylor2, Michio Yoshimura1, Ian D. Hickson3, Eric J. Bernhard1 and W. Gillies McKenna1

Authors' Affiliations: 1 Gray Institute for Radiation Oncology and Biology, 2 Computational Biology Research Group, and 3 Genome Integrity Group, Oxford University, Oxford, United Kingdom

Corresponding Author: W. Gillies McKenna, Gray Institute For Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom. Phone: 44-1865-228963; Fax: 44-1865-222901; E-mail: gillies.mckenna@rob.ox.ac.uk.

The effectiveness of radiotherapy treatment could be significantly improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues. However, many of the key therapeutically exploitable mechanisms that determine intrinsic tumor radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumor cells (SQ20B) and irradiated normal tissue cells (MRC5). Using {gamma}H2AX foci at 24 hours after IR, we identified several genes, such as BRCA2, Lig IV, and XRCC5, whose knockdown is known to cause increased cell radiosensitivity, thereby validating the primary screening end point. In addition, we identified POLQ (DNA polymerase {theta}) as a potential tumor-specific target. Subsequent investigations showed that POLQ knockdown resulted in radiosensitization of a panel of tumor cell lines from different primary sites while having little or no effect on normal tissue cell lines. These findings raise the possibility that POLQ inhibition might be used clinically to cause tumor-specific radiosensitization. Cancer Res; 70(7); 2984--93

Key Words: High-throughput screen . siRNA . DNA repair . POLQ . Tumor radiosensitivity

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