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Combined administration
of imatinib mesylate and ionizing radiation leads to increased radiosensitivity
in the human glioblastoma cell line RuSi RS1
M. Holdhoff, K. A. Kreuzer, C. Appelt, R. Scholz, A. Jordan, B. Hildebrandt,
C. A. Schmidt, R. A. Van Etten, B. Dörken, P. Le Coutre
Charité, Campus Virchow, Humboldt University, Berlin, Germany;
Center of Biological Nanotechnology (CBN), Berlin, Germany; MORI, Tufts-New
England Medical Center, Boston, MA.
Background. The selective tyrosine kinase
inhibitor imatinib mesylate (Gleevec) effectively inhibits the activity of the
abl, PDGF receptor (PDGFR) and c-kit tyrosine kinases.
Because of the specific target profile of this orally available and generally
well tolerated drug, imatinib is under intensive investigation for the potential
treatment of other diseases.
Malignant gliomas frequently show a high expression of PDGF receptor which is
involved in tumorigenesis by formation of an autocrine loop.
A role in DNA repair carried out through c-abl and c-kit was previously
described both for c-abl and c-kit.
In this study we address the potential use of imatinib mesylate and concomitant
ionizing radiation (IR) to improve the radiosensitivity of the glioblastoma cell
line RuSi RS1.
Methods.
Cells of the primary
glioblastoma cell line RuSi RS1, as well as of the colon cancer cell line WiDr
and of BT20, a human breast cancer cell line, were incubated with different
concentrations of imatinib mesylate 30 minutes prior to irradiation (doses
between 0 and 16 Gy).
Western blots were done comparing the different expression of c-abl, PDGFR alpha
and beta, and c-kit in the different cell lines.
Immunoprecipitation was performed to assess inhibition of the different kinases
by imatinib mesylate.
Results. Under combined treatment with
imatinib and IR a significant shift of the IC50 (dose needed to reduce the
survival fraction by 50%) was detected in RuSi RS1 compared to IR alone.
This effect was not seen in WiDr or BT20.
RuSi RS1 showed an overexpression of PDGFR beta.
Inhibition of tyrosine kinase phosphorylation by imatinib could be shown for
PDGFR beta and c-abl (the IP failed for c-kit).
Conclusion. Concomitant administration
of imatinib mesylate and ionizing radiation increases the radiosensitivity of
the glioblastoma cell line RuSi RS1.
This effect might partly be due to disruption of an autocrine loop of the
PDGF/PDGFR system.
Inhibition of DNA repair mechanisms in which the tyrosine kinase activity of
c-abl and c-kit is involved might be important causes of this observed
phenomenon as well.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-002655,00.asp
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