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Effects of chronic oral
administration of the pan VEGF-R kinase inhibitor, CEP-7055, alone and in
combination with temozolomide (TMZ), on primary tumor growth, neurological
dysfunction, and survival in an orthotopic model of human glioblastoma in nude
mice
Susan E. Jones-Bolin, Hugh Zhao, Kathryn Hunter, Bruce
Ruggeri
Cephalon, Inc., West Chester, PA
Primary brain tumors of the central nervous system are the fifth
most common primary neoplasm.
Approximately 50% of these brain tumors are astrocytomas, of which 50% are
well-vascularized glioblastoma multiforme (GBM).
Despite aggressive therapy including surgery, radiation and chemotherapy, the
median reported survival for GBM patients is less than a year.
The role of VEGF-VEGF-R signaling in the growth, progression, and invasiveness
of GBM has been well established.
A series of studies using a U87MG human GBM orthotopic model were performed
evaluating the effects of chronic oral administration of CEP-7055, a potent and
selective pan VEGF-R kinase inhibitor [1], alone and in combination with
temozolomide (TMZ), on neurological dysfunction, GBM invasiveness, and
survival.
U87MG glioblastoma cells (5 x 10^5/mouse) were implanted stereotactically into
the caudate putamen of the right cerebrum 1.2 mm posterior and 1.9 mm lateral to
the bregma in nude mice under light anesthesia.
Treatment was initiated 3 days post-implantation.
The administration of CEP-7055 (23.8 mg/kg/dose, p.o., BID) and TMZ
administration (56-day cycles of 68 mg/kg/dose, p.o., QD for 5-days) in
combination resulted in a significant improvement in median survival of
GBM-bearing mice versus mice receiving TMZ monotherapy (241 days versus 212
days, respectively; p< 0.05).
In a parallel dose-response study still in-life in this model (day 233), chronic
oral administration of CEP-7055 alone at 23.8, 59, and 95 mg/kg/dose, p.o., BID
demonstrates a dose-related reduction in brain edema and hemorrhagic lesions in
GBM-bearing mice, and a trend for increased survival in mice receiving CEP-7055
and TMZ in combination versus those receiving TMZ monotherapy (217 versus 186
days, respectively).
Significant reductions in neurologic dysfunction have been observed in
GBM-bearing mice receiving CEP-7055 alone, TMZ alone, and to a greater degree,
the combination of CEP-7055 and TMZ versus vehicle-treated mice in both studies
to date.
Collectively, these data indicate a significant improvement in survival, and
marked reductions in apparent neurological deficit and brain edema/hemorrhagic
lesions, in mice bearing orthotopic GBM following the combined administration of
the pan VEGF-R kinase inhibitor, CEP-7055 and TMZ versus TMZ monotherapy.
CEP-7055 is currently in phase I trials in patients with solid tumors.
[1] Proc. Am. Assoc. Cancer Res. 43: 2601 and 5347 (2002).
Copyright © 2003 American Association for Cancer Research. All rights reserved.
Source: http://aacr03.agora.com/planner/displayabstract.asp?presentationid=3039
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