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Title: STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma

Abstract

Purpose: Glioblastoma multiforme (GBM) is a devastating brain neoplasm that is essentially incurable. Although radiation therapy prolongs survival, GBMs progress within areas of irradiation. Recent studies in invertebrates have shown that STI571 (Gleevec; Novartis, East Hanover, NJ) enhances the cytotoxicity of ionizing radiation. In the present study, the effectiveness of STI571 in combination with radiation was studied in mouse models of GBM. Methods and Materials: Murine GL261 and human D54 GBM cell lines formed tumors in brains and hind limbs of C57BL6 and nude mice, respectively. GL261 and D54 cells were treated with 5 {mu}mol/L of STI571 for 1 h and/or irradiated with 3 Gy. Protein was analyzed by Western immunoblots probed with antibodies to caspase 3, cleaved caspase 3, phospho-Akt, Akt, and platelet-derived growth factor receptor (PDGFR) {alpha} and {beta}. Tumor volumes were assessed in mice bearing GL261 or D54 tumors treated with 21 Gy administered in seven fractionated doses. Histologic sections from STI571-treated mice were stained with phospho-Akt and phospho-PDGFR {beta} antibodies. Kaplan-Meier survival curves were used to study the response of mice bearing intracranial implants of GL261. Results: STI571 penetrated the blood-brain barrier, which resulted in a reduction in phospho-PDGFR in GBM. STI571-induced apoptosis in GBM wasmore » significantly enhanced by irradiation. STI571 combined with irradiation induced caspase 3 cleavage in GBM cells. Glioblastoma multiforme response to therapy correlated with an increase in tumor growth delay and survival when STI571 was administered in conjunction with daily irradiation. Conclusion: These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [3]
  1. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States)
  2. Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN (United States)
  3. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States) and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN (United States) and Vanderbilt-Ingram Cancer Center, Nashville, TN (United States). E-mail: Dennis.Hallahan@mcmail.vanderbilt.edu
Publication Date:
OSTI Identifier:
20788294
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 64; Journal Issue: 1; Other Information: DOI: 10.1016/j.ijrobp.2005.08.025; PII: S0360-3016(05)02387-4; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANTIBODIES; BLOOD-BRAIN BARRIER; BRAIN; GLIOMAS; GROWTH; GROWTH FACTORS; INVERTEBRATES; IONIZING RADIATIONS; IRRADIATION; LIMBS; MICE; RADIATION SOURCE IMPLANTS; RADIOTHERAPY; RECEPTORS; SURVIVAL CURVES; TOXICITY

Citation Formats

Geng Ling, Shinohara, Eric T., Kim, Dong, Tan Jiahuai, Osusky, Kate, Shyr, Yu, and Hallahan, Dennis E. STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma. United States: N. p., 2006. Web. doi:10.1016/J.IJROBP.2005.0.
Geng Ling, Shinohara, Eric T., Kim, Dong, Tan Jiahuai, Osusky, Kate, Shyr, Yu, & Hallahan, Dennis E. STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma. United States. doi:10.1016/J.IJROBP.2005.0.
Geng Ling, Shinohara, Eric T., Kim, Dong, Tan Jiahuai, Osusky, Kate, Shyr, Yu, and Hallahan, Dennis E. Sun . "STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma". United States. doi:10.1016/J.IJROBP.2005.0.
@article{osti_20788294,
title = {STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma},
author = {Geng Ling and Shinohara, Eric T. and Kim, Dong and Tan Jiahuai and Osusky, Kate and Shyr, Yu and Hallahan, Dennis E.},
abstractNote = {Purpose: Glioblastoma multiforme (GBM) is a devastating brain neoplasm that is essentially incurable. Although radiation therapy prolongs survival, GBMs progress within areas of irradiation. Recent studies in invertebrates have shown that STI571 (Gleevec; Novartis, East Hanover, NJ) enhances the cytotoxicity of ionizing radiation. In the present study, the effectiveness of STI571 in combination with radiation was studied in mouse models of GBM. Methods and Materials: Murine GL261 and human D54 GBM cell lines formed tumors in brains and hind limbs of C57BL6 and nude mice, respectively. GL261 and D54 cells were treated with 5 {mu}mol/L of STI571 for 1 h and/or irradiated with 3 Gy. Protein was analyzed by Western immunoblots probed with antibodies to caspase 3, cleaved caspase 3, phospho-Akt, Akt, and platelet-derived growth factor receptor (PDGFR) {alpha} and {beta}. Tumor volumes were assessed in mice bearing GL261 or D54 tumors treated with 21 Gy administered in seven fractionated doses. Histologic sections from STI571-treated mice were stained with phospho-Akt and phospho-PDGFR {beta} antibodies. Kaplan-Meier survival curves were used to study the response of mice bearing intracranial implants of GL261. Results: STI571 penetrated the blood-brain barrier, which resulted in a reduction in phospho-PDGFR in GBM. STI571-induced apoptosis in GBM was significantly enhanced by irradiation. STI571 combined with irradiation induced caspase 3 cleavage in GBM cells. Glioblastoma multiforme response to therapy correlated with an increase in tumor growth delay and survival when STI571 was administered in conjunction with daily irradiation. Conclusion: These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival.},
doi = {10.1016/J.IJROBP.2005.0},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 1,
volume = 64,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}