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Title: AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells

Abstract

Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G{sub 2}-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 andmore » irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7. Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.« less

Authors:
; ;  [1];  [2];  [1];  [1];  [3];  [2];  [1];  [3]
  1. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)
  2. Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada)
  3. (United States)
Publication Date:
OSTI Identifier:
22149649
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 84; Journal Issue: 4; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; APOPTOSIS; CARCINOMAS; CELL CYCLE; DNA; DNA REPAIR; EVALUATION; IN VITRO; IN VIVO; IONIZING RADIATIONS; IRRADIATION; LUNGS; LYMPH NODES; METASTASES; MICE; RADIATION DOSES; RADIOSENSITIVITY; RADIOSENSITIZERS; RADIOTHERAPY; STRAND BREAKS

Citation Formats

Raghavan, Pavithra, Tumati, Vasu, Yu Lan, Chan, Norman, Tomimatsu, Nozomi, Burma, Sandeep, Simmons Comprehensive Cancer Center, Dallas, Texas, Bristow, Robert G., Saha, Debabrata, E-mail: debabrata.saha@utsouthwestern.edu, and Simmons Comprehensive Cancer Center, Dallas, Texas. AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells. United States: N. p., 2012. Web. doi:10.1016/J.IJROBP.2012.05.035.
Raghavan, Pavithra, Tumati, Vasu, Yu Lan, Chan, Norman, Tomimatsu, Nozomi, Burma, Sandeep, Simmons Comprehensive Cancer Center, Dallas, Texas, Bristow, Robert G., Saha, Debabrata, E-mail: debabrata.saha@utsouthwestern.edu, & Simmons Comprehensive Cancer Center, Dallas, Texas. AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells. United States. doi:10.1016/J.IJROBP.2012.05.035.
Raghavan, Pavithra, Tumati, Vasu, Yu Lan, Chan, Norman, Tomimatsu, Nozomi, Burma, Sandeep, Simmons Comprehensive Cancer Center, Dallas, Texas, Bristow, Robert G., Saha, Debabrata, E-mail: debabrata.saha@utsouthwestern.edu, and Simmons Comprehensive Cancer Center, Dallas, Texas. Thu . "AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells". United States. doi:10.1016/J.IJROBP.2012.05.035.
@article{osti_22149649,
title = {AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells},
author = {Raghavan, Pavithra and Tumati, Vasu and Yu Lan and Chan, Norman and Tomimatsu, Nozomi and Burma, Sandeep and Simmons Comprehensive Cancer Center, Dallas, Texas and Bristow, Robert G. and Saha, Debabrata, E-mail: debabrata.saha@utsouthwestern.edu and Simmons Comprehensive Cancer Center, Dallas, Texas},
abstractNote = {Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G{sub 2}-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7. Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.},
doi = {10.1016/J.IJROBP.2012.05.035},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 4,
volume = 84,
place = {United States},
year = {2012},
month = {11}
}