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

  

Authors:	Kubo, T.; Piperdi, S.; Rosenblum, J.; Antonescu, C. R.; Chen, W.; Kim, H. S.; Huvos, A. G.; Sowers, R.; Meyers, P. A.; Healey, J. H.; Gorlick, R.
Article Title:	Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma
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 yvere investigated. Immunohistochemical studies demonstrated frequent expression of PDGF-AA (80.4%) and PDGF-α receptor (79.6%) and their correlation yyith inferior event-free survival (P < .05). PDGF-B-B and PDGF-β-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 IC30 of 5.6 μM to 9.5 μM, 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. © 2008 American Cancer Society.
Keywords:	immunohistochemistry; osteosarcoma; signal transduction; mitogen activated protein kinase; protein kinase b; adolescent; adult; cancer survival; child; protein phosphorylation; aged; bone neoplasms; middle aged; clinical trial; review; cisplatin; doxorubicin; cancer growth; methotrexate; drug megadose; cell survival; imatinib; platelet derived growth factor alpha receptor; receptor, platelet-derived growth factor alpha; tumor markers, biological; cancer cell culture; cytotoxicity; enzyme activation; in vitro study; drug effect; tumor cells, cultured; platelet derived growth factor receptor; pyrimidines; phosphorylation; ifosfamide; protein kinase inhibitors; immunoenzyme techniques; blotting, western; reverse transcriptase polymerase chain reaction; rna, messenger; drug response; platelet-derived growth factor; proto-oncogene proteins c-akt; ligand; immunoprecipitation; immunoblotting; dna flanking region; protein-tyrosine kinases; piperazines; receptor blocking; muramyl tripeptide; ic 50; mitogen-activated protein kinases; platelet derived growth factor beta receptor; receptor, platelet-derived growth factor beta; imatinib mesylate; gleevec; platelet-derived growth factor receptor (pdgf); sti-571
Journal Title:	Cancer
Volume:	112
Issue:	10
ISSN:	0008-543X
Publisher:	Wiley Blackwell
Date Published:	2008-05-15
Start Page:	2119
End Page:	2129
Language:	English
DOI:	10.1002/cncr.23437
PUBMED:	18338812
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-43049095679&partnerID=40&md5=20f484816cf18927d281ca107102c32c
Notes:	--- - "Cited By (since 1996): 23" - "Export Date: 17 November 2011" - "CODEN: CANCA" - "Source: Scopus"

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