Endostatin improves radioresponse and blocks tumor revascularization after radiation therapy for A431 xenografts in mice.
OBJECTIVE
Clinical trials of antiangiogenic agents used alone for advanced malignancy have been disappointing but preclinical studies suggest that the addition of radiation therapy could improve antitumor efficacy. To test the hypothesis that antiangiogenic therapy combined with radiation therapy can overcome the limitations of antiangiogenic monotherapy, we studied the effects of endostatin combined with radiation on the growth and vascularization of A431 human epidermoid carcinomas growing intramuscularly in the legs of mice.


METHODS
Mice with established A431 human epidermoid leg tumors were treated with radiation, endostatin, both radiation and endostatin, or vehicle control. The experiment was repeated and mice from each group were killed at 2, 7, and 10 days after irradiation so that tumor tissue could be obtained to further analyze the kinetics of the antitumor, antivascular, and antiangiogenic response to therapy.


RESULTS
Endostatin enhanced the antitumor effects of radiation, and prolonged disease-free survival was observed in the combined treatment group. Endothelial cell proliferation was increased in tumors after irradiation but was blocked by the concurrent administration of endostatin, and the combination of endostatin with radiation enhanced endothelial cell apoptosis within 48 h after irradiation. Expression of vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-2 were increased in tumors after irradiation, and this increase was blocked by concurrent administration of endostatin.


CONCLUSIONS
These data indicate that endostatin can block tumor revascularization after radiation therapy and thereby augment radioresponse.
Itasaka
Satoshi
S
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Komaki
Ritsuko
R
Herbst
Roy S
RS
Shibuya
Keiko
K
Shintani
Tomoaki
T
Hunter
Nancy R
NR
Onn
Amir
A
Bucana
Corazon D
CD
Milas
Luka
L
Ang
K Kian
KK
O'Reilly
Michael S
MS
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000473:pathology / Q000532:radiotherapy*; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D043169:Endostatins / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011836:Radiation Tolerance; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D043169:Endostatins