three-dimensional-angiogenesis-assay-system-using-co-culture

Three-dimensional Angiogenesis Assay System using Co-culture Spheroids Formed by Endothelial Colony Forming Cells and Mesenchymal Stem Cells

Studies in the field of angiogenesis have been aggressively growing in the last few decades with the recognition that angiogenesis is a hallmark of more ...

Korea Institute of Radiological & Medical Sciences

We investigated the relations between the cell uptakes of metabolic radiotracers and beta-radiation pretreatment using a dominant mutant p53 (p53mt) cell line to evaluate the effects of p53 genes on (18)F labeled positron emission tomography (PET) radiotracer uptakes.

Cellular metabolic responses of PET radiotracers to (188)Re radiation in an MCF7 cell line containing dominant-negative mutant p53.

The tumor suppressor gene, p53, plays a pivotal role for cell survival and apoptosis, which could cause different responses to therapeutic agents. Rhenium-188 ((188)Re) decays with the emission of a beta-particle with high energy and is expected to be an important candidate of radiotherapy. We investigated the cellular response of (18)F-fluorodeoxyglucose ((18)F-FDG) uptake and the effect of p53 according to beta-irradiation by (188)Re.

Comparison of cellular metabolic responses of (18)F-FDG according to the effect of beta-irradiation in p53 wild and deleted cell lines.

Despite the increasing lung cancer-associated death rate, its therapy has been constrained by impasse of early diagnosis. To apply non-invasive imaging for potential cancer diagnosis system, we screened human lung adenocarcinoma-specific peptides using the phage display technique. For in vivo phage-displayed peptide screening, M13 phage library displaying 2.9 × 10(9) random peptides was injected through tail vein to lung adenocarcinoma cell-derived xenograft mouse model. Through four rounds of biopanning, a specific peptide sequence (CAKATCPAC) was screened out with the highest frequency and was named as Pep-1, and it was analyzed for its targeting ability as an imaging probe by in vitro competitive assay to test its cell-binding ability, immunohistochemical detection in the tumor tissue, and in vivo NIR fluorescent optical imaging. The specificity of Pep-1 toward lung cancer was ensured by in vivo imaging using xenograft animals of various cancer types. The results suggest that Pep-1 is a promising diagnostic lead molecule for rapid and accurate detection of human lung adenocarcinoma. In addition, it was found that the targeting ability was much enhanced by ionizing radiation in both cell-derived and patient-derived lung adenocarcinoma xenografts, suggesting the possibility of applying Pep-1 for prognostic diagnosis after radiotherapy. Taken together, this study suggests that Pep-1 possesses a specific-targeting ability for human lung adenocarcinoma and that this peptide could be directly used as a clinically applicable imaging probe.

Application of peptide displaying phage as a novel diagnostic probe for human lung adenocarcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene's expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment. 

Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma.

We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP-DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m2 escalated to 35 mg/m2, 45 mg/m2, 60 mg/m2 and 75 mg/m2. Pharmacokinetics, tumor response, toxicities were evaluated. Preclinical result revealed the more potent cytotoxic effect of PNP-DTX than docetaxel (DTX). However, there was no difference between PNP-DTX and DTX in subcutaneous model. Tubulin polymerization assay showed that PNP-DTX preserved original mode of action of DTX. For phase I clinical trial, 18 patients were analyzed. The dose of 75 mg/m2 was tentatively determined as the MTD and the most common toxicity was grade 4 neutropenia not lasting over 7days. The Cmax of 60 mg/m2 PNP-DTX and AUClast of 45 mg/m2 PNP-DTX were measured to be comparable to those of 75 mg/m2 DTX. Partial remission (PR) was achieved in 4 (22%) patients. The potency of PNP-DTX was revealed especially in orthotopic mouse model. The MTD of PNP-DTX could not be confirmed, but 75 mg/m2 was tentatively determined. The PNP-DTX of 45 mg/m2 had the same pharmacokinetic profile with that of 75 mg/m2 DTX.

Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model.

O-2-F-fluoroethyl-l-tyrosine ([F]FET) has been widely used for glioblastomas (GBM) in clinical practice, although evaluation of its applicability in non-clinical research is still lacking. The objective of this study was to examine the value of [F]FET for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic mouse model of GBM. Human U87MG cells were implanted into nude mice and then bevacizumab, a representative anti-angiogenic drug, was administered. We monitored the effect of anti-angiogenic agents using multiple imaging modalities, including bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT). Among these imaging methods analyzed, only [F]FET uptake showed a statistically significant decrease in the treatment group compared to the control group (=0.02 and =0.03 at 5 and 20 mg/kg, respectively). This indicates that [F]FET PET is a sensitive method to monitor the response of GBM bearing mice to anti-angiogenic drug. Moreover, [F]FET uptake was confirmed to be a significant parameter for predicting the prognosis of anti-angiogenic drug (=0.041 and =0.007, on Days 7 and 12, respectively, on Pearson's correlation; =0.048 and =0.030, on Days 7 and 12, respectively, on Cox regression analysis). However, results of BLI or MRI were not significantly associated with survival time. In conclusion, this study suggests that [F]FET PET imaging is a pertinent imaging modality for sensitive monitoring and accurate prediction of treatment response to anti-angiogenic agents in an orthotopic model of GBM.

Article	Year
Cellular metabolic responses of PET radiotracers to (188)Re radiation in an MCF7 cell line containing dominant-negative mutant p53. Nuclear medicine and biology\| PubMed ID: 17499732	2007
Comparison of cellular metabolic responses of (18)F-FDG according to the effect of beta-irradiation in p53 wild and deleted cell lines. Cancer biotherapy & radiopharmaceuticals\| PubMed ID: 17979566	2007
Application of peptide displaying phage as a novel diagnostic probe for human lung adenocarcinoma. Amino acids\| PubMed ID: 26759016	2016
Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma. World journal of gastroenterology\| PubMed ID: 27468205	2016
Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model. Oncotarget\| PubMed ID: 27764799	2016
[F]FET PET is a useful tool for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic glioblastoma mouse model. Laboratory animal research\| PubMed ID: 30671112	2018

Hye Kyung Chung

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