STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma.
OBJECTIVE
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
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 micromol/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.


CONCLUSIONS
These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival.
Geng
Ling
L
Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN 37232-5671, USA.
Shinohara
Eric T
ET
Kim
Dong
D
Tan
Jiahuai
J
Osusky
Kate
K
Shyr
Yu
Y
Hallahan
Dennis E
DE
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis; D001549:Benzamides; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000532:radiotherapy*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000737:chemistry / Q000188:drug therapy / Q000532:radiotherapy*; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases