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Friday, March 25
Vascular Endothelial Growth Factor: A Therapeutic Target for Tumors of the Ewing's Sarcoma Family
by
Barry Sugarman
on Fri 25 Mar 2005 04:51 PM PST
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15788688
Clin Cancer Res. 2005 Mar 15;11(6):2364-2378.
Vascular Endothelial Growth Factor: A Therapeutic Target for Tumors of
the Ewing's Sarcoma Family.
Dalal S, Berry AM, Cullinane CJ, Mangham DC, Grimer R, Lewis IJ,
Johnston C, Laurence V, Burchill SA.
Candlelighter's Children's Cancer Research Laboratory, Departments of
Pathology and Paediatric Oncology, Cancer Research UK Clinical Centre,
St. James's University Hospital, Leeds, United Kingdom and Department of
Musculoskeletal Pathology and Royal Orthopaedic Hospital, Birmingham,
United Kingdom.
PURPOSE: We have reported previously that intratumoral microvessel
density (MVD) is a significant prognostic indicator of event-free
survival in the Ewing's sarcoma family of tumors (ESFT). Here, the
angiogenic growth factor expression profile and its relationship with
MVD has been investigated in ESFT.Experimental Design and RESULTS: Using
ESFT model systems, the potential of these factors as therapeutic
targets has been evaluated. A significant correlation (P = 0.02) was
observed between vascular endothelial growth factor (VEGF) expression
and MVD, consistent with the hypothesis that VEGF regulates the
development of microvessels in ESFT. There was no correlation between
MVD and any of the other growth factors studied. All six ESFT cell lines
studied produced and secreted VEGF; five of six cell lines also secreted
placental growth factor, one cell line (A673) at high levels. Tumor
conditioned medium induced proliferation of human umbilical vein
endothelial cells. Expression of VEGF receptors Flt-1 and Flk-1/KDR was
heterogeneous across the cell lines. Both receptor tyrosine kinase
inhibitors SU6668 (targets Flk-1/KDR, platelet-derived growth factor
receptor-beta, and fibroblast growth factor receptor 1) and SU5416
(targets Flk-1/KDR) as well as anti-VEGF agents rhuMAb-VEGF
(bevacizumab) and VEGF Trap delayed s.c. growth of ESFT in mice compared
with untreated groups: SU6668 (100 mg/kg/d), SU5416 (25 mg/kg/d),
rhuMAb-VEGF (10 mg/kg twice weekly), and VEGF Trap (2.5 or 25 mg/kg
twice weekly).CONCLUSIONS: These data suggest that VEGF is the single
most important regulator of angiogenesis in ESFT and may be exploited
for therapeutic advantage.
PMID: 15788688 [PubMed - as supplied by publisher]
Friday, March 11
Herceptin Down-Regulates HER-2/neu and Vascular Endothelial Growth Factor Expression and Enhances Taxol-Induced Cytotoxicity of Human Ewing's Sarcoma Cells In vitro and In vivo
by
Barry Sugarman
on Fri 11 Mar 2005 09:24 AM PST
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=15756027&dopt=Abstract
Clin Cancer Res. 2005 Mar 1;11(5):2008-17.
http://clincancerres.aacrjournals.org/cgi/content/abstract/11/5/2008
Herceptin Down-Regulates HER-2/neu and Vascular Endothelial Growth
Factor Expression and Enhances Taxol-Induced Cytotoxicity of Human
Ewing's Sarcoma Cells In vitro and In vivo.
Guan H, Jia SF, Zhou Z, Stewart J, Kleinerman ES.
Eugenie S. Kleinerman, Division of Pediatrics, Unit 87, University of
Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX
77030. Phone: 713-792-8110; Fax: 713-794-5042; E-mail:
ekleiner@mail.mdanderson.org
Division of Pediatrics and Department of Pathology, University of Texas
M.D. Anderson Cancer Center, Houston, Texas.
We have previously shown that high levels of HER-2/neu protein were
overexpressed in human Ewing's sarcoma cells (TC71, SK-ES1) relative to
normal human osteoblasts. The purpose of this study was to determine
whether herceptin alone or in combination with chemotherapeutic agents
could inhibit the growth of Ewing's sarcoma in vitro and in vivo.
Western blot analysis showed that the protein levels of HER-2/neu were
decreased following herceptin treatment. Cell growth was also inhibited
by herceptin in a dose-dependent manner with an IC(50) of 4 mg/mL in
TC71 and SK-ES1 cell line, whereas human immunoglobin had no effect.
Northern blot and ELISA showed the RNA expression and protein levels of
vascular endothelial growth factor were also inhibited by herceptin
treatment with no alteration in HIF-1alpha protein and topoisomerase
IIalpha expression. Furthermore, Ewing's sarcoma tumor growth was
significantly delayed by 100 mg/kg herceptin treatment in our Ewing's
sarcoma xenograft mouse model. Combining taxol with herceptin resulted
in additive cytotoxicity, whereas herceptin-etoposide, doxorubicin, and
9-nitrocamptothecin combinations did not. Taxol-herceptin enhanced
growth inhibition in TC71 cells in vitro compared with either agent
alone. Ewing's sarcoma growth was also delayed in vivo and mean tumor
size was significantly lower in mice treated with herceptin plus taxol
than in those receiving taxol or herceptin alone. These data suggest
that herceptin in combination with taxol may be a therapeutic option in
the treatment of Ewing's sarcoma.
PMID: 15756027 [PubMed - in process]
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