Multimodality imaging of IL-18--binding protein-Fc therapy of experimental lung metastasis.
OBJECTIVE
Interleukin (IL)-18 plays important roles in cancer progression and metastasis. The goal of this study is to identify cell lines that are most sensitive to stand alone IL-18-binding protein (IL-18bp)-Fc treatment, to study the pharmacokinetics and tumor targeting efficiency of IL-18bp-Fc, and to evaluate the efficacy of IL-18bp-Fc in treating breast cancer experimental lung metastasis by multimodality imaging.


METHODS
Reverse transcription-PCR, ELISA, and other cell-based assays were done on murine 4T1, CT-26, and B16F10 cells. The most IL-18bp-Fc-sensitive 4T1 cells were stably transfected with firefly luciferase (fLuc) and injected i.v. into female BALB/C mice to establish the experimental lung metastasis model. Tumor targeting efficiency and pharmacokinetics of IL-18bp-Fc was assessed by (64)Cu-DOTA-IL-18bp-Fc positron emission tomography (PET) and biodistribution studies. Two groups of fLuc-4T1 experimental lung metastasis tumor-bearing mice were each given saline or IL-18bp-Fc (1 mg/kg) daily i.p. Bioluminescence imaging, (18)F-FDG PET, and computed tomography scans were done to evaluate the treatment efficacy. Ex vivo experiments were also carried out to validate the imaging results.


RESULTS
IL-18bp-Fc had high and specific accumulation in the fLuc-4T1 lung metastasis tumor as evidenced by both PET and biodistribution studies. Bioluminescence imaging, (18)F-FDG PET, and computed tomography scans all revealed that IL-18bp-Fc treatment was effective in inhibiting the lung metastasis tumor progression, validated by ex vivo examination of the lung.


CONCLUSIONS
IL-18bp-Fc therapy can inhibit 4T1 breast cancer experimental lung metastasis. Noninvasive multimodality molecular imaging is a powerful tool for evaluating the tumor targeting efficiency/pharmacokinetics of the drug and effective monitoring of the therapeutic response.
Cao
Qizhen
Q
The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305, USA.
Cai
Weibo
W
Niu
Gang
G
He
Lina
L
Chen
Xiaoyuan
X
D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D020382:Interleukin-18 / Q000737:chemistry* / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology* / Q000628:therapy*; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods; D014057:Tomography, X-Ray Computed / Q000379:methods
D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein