TY - JOUR
T1 - Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF121/rGel
AU - Hsu, Andrew R.
AU - Cai, Weibo
AU - Veeravagu, Anand
AU - Mohamedali, Khalid A.
AU - Chen, Kai
AU - Kim, Sehoon
AU - Vogel, Hannes
AU - Hou, Lewis C.
AU - Tse, Victor
AU - Rosenblum, Michael G.
AU - Chen, Xiaoyuan
PY - 2007/3/1
Y1 - 2007/3/1
N2 - Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF121/rGel) composed of the VEGF-A isoform VEGF121 linked with a G4S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI),MRI, and PET. Methods: Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with 64Cu-1,4,7,10-tetraazacyclododedane-N,N′,N″,N‴- tetraacetic acid (DOTA)-VEGF121/rGel was performed before VEGF 121/rGel treatment. 18F-Fluorothymidine ( 18F-FLT) scans were obtained before and after treatment to evaluate VEGF121/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses. Results: Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with 64Cu-DOTA- VEGF121/rGel before treatment revealed a tumor accumulation (mean ± SD) of 11.8 ± 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF121. PET with 18F-FLT revealed significant a decrease in tumor proliferation in VEGF121/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF121/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity. Conclusion: The results of this study suggest that future clinical multimodality imaging and therapy with VEGF121/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF121/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.
AB - Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF121/rGel) composed of the VEGF-A isoform VEGF121 linked with a G4S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI),MRI, and PET. Methods: Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with 64Cu-1,4,7,10-tetraazacyclododedane-N,N′,N″,N‴- tetraacetic acid (DOTA)-VEGF121/rGel was performed before VEGF 121/rGel treatment. 18F-Fluorothymidine ( 18F-FLT) scans were obtained before and after treatment to evaluate VEGF121/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses. Results: Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with 64Cu-DOTA- VEGF121/rGel before treatment revealed a tumor accumulation (mean ± SD) of 11.8 ± 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF121. PET with 18F-FLT revealed significant a decrease in tumor proliferation in VEGF121/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF121/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity. Conclusion: The results of this study suggest that future clinical multimodality imaging and therapy with VEGF121/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF121/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.
KW - Angiogenesis
KW - Gelonin
KW - Glioblastoma multiforme
KW - VEGF
KW - VEGFR-2 (Flk-1/KDR)
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UR - http://www.scopus.com/inward/citedby.url?scp=34247208168&partnerID=8YFLogxK
M3 - Article
C2 - 17332623
AN - SCOPUS:34247208168
SN - 0161-5505
VL - 48
SP - 445
EP - 454
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 3
ER -