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Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma

Cited 83 time in Web of Science Cited 93 time in Scopus
Authors
Kubo, Tadahiko; Piperdi, Sajida; Rosenblum, Jeremy; Antonescu, Cristina R.; Chen, Wen; Kim, Han-Soo; Huvos, Andrew G.; Sowers, Rebecca; Meyers, Paul A.; Healey, John H.; Gorlick, Richard
Issue Date
2008-03-15
Publisher
Wiley-Blackwell
Citation
Cancer. 2008 ;112(10):2119-29.
Keywords
AdolescentAdultAgedBlotting, WesternBone Neoplasms/*drug therapy/metabolism/secondaryCell Survival/drug effectsChildFemaleHumansImmunoenzyme TechniquesImmunoprecipitationMaleMiddle AgedMitogen-Activated Protein Kinases/metabolismOsteosarcoma/*drug therapy/metabolism/pathologyPhosphorylationPiperazines/*therapeutic usePlatelet-Derived Growth Factor/metabolismPrognosisProtein Kinase Inhibitors/*therapeutic useProtein-Tyrosine Kinases/antagonists & inhibitorsProto-Oncogene Proteins c-akt/metabolismPyrimidines/*therapeutic useRNA, Messenger/genetics/metabolismReceptor, Platelet-Derived Growth Factor alpha/genetics/*metabolismReceptor, Platelet-Derived Growth Factor beta/genetics/*metabolismReverse Transcriptase Polymerase Chain ReactionTumor Cells, CulturedTumor Markers, Biological/genetics/*metabolism
Abstract
The purpose of this review was to determine whether imatinib mesylate (STI571, Gleevec) has a role in the treatment of osteosarcoma. The expression of platelet-derived growth factor (PDGF) receptor and its ligand was examined in a panel of surgical specimens obtained from 54 osteosarcoma patients, and then the expression was compared with prognosis. The effects of imatinib mesylate on growth and molecular events in 10 patient-derived osteosarcoma cell cultures were investigated. Immunohistochemical studies demonstrated frequent expression of PDGF-AA (80.4%) and PDGF-alpha receptor (79.6%) and their correlation with inferior event-free survival (P < .05). PDGF-B-B and PDGF-beta-receptor expressions were also frequent (75.4% and 86%, respectively); however, statistically significant inferior event-free survival was not demonstrated (P = .15). In vitro studies demonstrated that imatinib mesylate had a variable cytotoxic effect on various osteosarcoma primary cultures, with an IC(50) of 5.6 microM to 9.5 microM, and blocked the PDGF-induced intracellular signal transduction as well as inhibition of downstream Akt phosphorylation. Mitogen-activated protein kinase (MAPK) was constitutively activated despite PDGF stimulation and imatinib mesylate treatment in 7 of 10 osteosarcoma cultures, perhaps explaining uncontrolled proliferation and relative unresponsiveness to imatinib. Imatinib mesylate could not be viewed as having a role as a single agent at current conventional doses for the treatment of osteosarcoma. These findings predicted activity in osteosarcoma clinical trials and suggested that in vitro model systems predict clinical behavior and that PDGF and its receptor expression could potentially be used for determining prognosis of osteosarcoma.
ISSN
0008-543X (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18338812

https://hdl.handle.net/10371/63619
DOI
https://doi.org/10.1002/cncr.23437
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College of Medicine/School of Medicine (의과대학/대학원)Orthopedic Surgery (정형외과학전공)Journal Papers (저널논문_정형외과학전공)
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