Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of soft-tissue sarcoma.
OBJECTIVE
Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS).


METHODS
Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed.


RESULTS
The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm(3) after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis.


CONCLUSIONS
SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.
Yoon
Sam S
SS
Department of Surgery, Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. syoon@partners.org
Stangenberg
Lars
L
Lee
Yoon-Jin
YJ
Rothrock
Courtney
C
Dreyfuss
Jonathan M
JM
Baek
Kwan-Hyuck
KH
Waterman
Peter R
PR
Nielsen
G Petur
GP
Weissleder
Ralph
R
Mahmood
Umar
U
Park
Peter J
PJ
Jacks
Tyler
T
Dodd
Rebecca D
RD
Fisher
Carolyn J
CJ
Ryeom
Sandra
S
Kirsch
David G
DG
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D011758:Pyrroles / Q000627:therapeutic use*; D011897:Random Allocation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis; D012509:Sarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib