Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: experimental and clinical evidence.
OBJECTIVE
This study aimed to examine the effect of the novel recombinant human endostatin (rh-Endo) protein on tumor vasculature, and to explore and evaluate the optimal scheduling of rh-Endo and radiotherapy (RT).


METHODS
Tumor-perfusion parameters and hypoxia were monitored after rh-Endo treatment in 10 non-small cell lung-cancer (NSCLC) patients. Eight-week female C57BL/6J mice were randomized to receive rh-Endo or control (saline) once daily for 12 days when Lewis lung carcinoma (LLC) reached approximately 100-150 mm(3). On planned days, tumors were measured for cell apoptosis, microvessel density, pericytes, blood-vessel morphology, and tumor hypoxia. The tumor response under different combinations of rh-Endo and RT schedules was evaluated.


RESULTS
Tumor hypoxia was significantly reduced 5 days after rh-Endo in NSCLC patients, and a similar result was found in the LLC mouse model. The anti-tumor effect was markedly enhanced when RT was administered within the remodeling period compared to any other treatment schedule. rh-Endo treatment remodeled the tumor vasculature after 5 days by reducing microvessel density and increasing pericytic coverage of the vessel endothelium.


CONCLUSIONS
This study demonstrated decreased hypoxia in animals and patients upon rh-Endo treatment, which also enhanced the radioresponse within the vasculature-remodeling period. The optimal clinical combination of rh-Endo and RT warrants further investigation.
Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Mao-Bin
MB
Meng
Xiao-Dong
XD
Jiang
Lei
L
Deng
Fei-Fei
FF
Na
Jia-Zhuo
JZ
He
Jian-Xin
JX
Xue
Wen-Hao
WH
Guo
Qing-Lian
QL
Wen
Jie
J
Lan
Xian-Ming
XM
Mo
Jin-Yi
JY
Lang
You
Y
Lu
D000199:Actins / Q000032:analysis / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000532:radiotherapy*; D015687:Cell Hypoxia; D043169:Endostatins / Q000494:pharmacology*; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
C541116:ACTA2 protein, human; D000199:Actins; D043169:Endostatins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins