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Chan P.-C.,National Yang Ming University | Wu C.-Y.,China Medical University at Taichung | Chou L.-S.,National Yang Ming University | Ho C.-H.,National Yang Ming University | And 10 more authors.
Molecular Imaging and Biology | Year: 2015

Purpose: This study employed 3′-deoxy-3′-[18F]-fluorothymidine ([18F]FLT) microPET scanning to assess the treatment response of histone deacetylase inhibitors (HDACi), e.g., N1-hydroxy-N8-phenyloctanediamide (SAHA) and its iodinated derivative ISAHA, in a hepatoma mouse model.Procedures: The in vitro cytotoxicity of HDACi in various hepatoma cell lines was determined by MTT assay and flow cytometry. ISAHA and SAHA were used to treat HepG2 hepatoma xenograft-bearing mice. The treatment responses were characterized in terms of tumor burden, microPET imaging, and immunohistochemical staining of tumor sections.Results: ISAHA effectively inhibited HepG2 hepatoma cell survival and tumor growth. A significantly reduced tumor uptake during HDACi treatment was noticed in [18F]FLT microPET imaging, which was consistent with the findings in immunohistochemical staining.Conclusions: ISAHA can suppress tumor cell proliferation both in vitro and in vivo. [18F]FLT PET is a promising modality for evaluating the in vivo therapeutic efficacy of HDACi at the early stage of treatment. © 2014, Academy of Molecular Imaging and Society for Molecular Imaging.


Hsieh Y.-J.,Kaohsiung Medical University | Hwu L.,National Comprehensive Mouse Phenotyping and Drug Testing Center | Hwu L.,National Yang Ming University | Ke C.-C.,National Yang Ming University | And 9 more authors.
Molecular Imaging and Biology | Year: 2015

Purpose: Promoters developed for radiogene therapy always show non-negligible transcriptional activities, even when cells are not irradiated. This study developed a tightly radiation-controlled molecular switch based on radiation responsive element (CArG) repeats for in vivo molecular imaging using the Cre/loxP system. Procedures: Different numbers of CArG repeats were cloned as a basal promoter directly, and its pre- and postirradiation transcriptional activities were analyzed by luciferase assay. Nine CArG repeats (E9) were chosen for use as a radiation-controlled molecular switch for the Cre/loxP system, and the feasibility of the switch in vitro and in vivo was demonstrated by luciferase assay and bioluminescence imaging, respectively. Results: The E9 promoter, which exhibits extremely low transcriptional activity, showed a 1.8-fold enhancement after irradiation with a clinical dose of 2 Gy. Both in vitro and in vivo results indicated that E9 is relatively inert but sufficient to trigger the Cre/loxP system. The luciferase activity of stable H1299/pSTOP-FLuc cells transfected with pE9-NLSCre and exposed to 2-Gy radiation can reach 44 % of that of the same cells transfected with pCMV-NLSCre and not subjected to irradiation. By contrast, no appreciable difference was observed in reporter gene expression in both H1299/pSTOPFluc cells and tumors transfected with pE4Pcmv-NLSCre before and after irradiation, because the strong basal transcriptional activity of the CMV promoter, which acts as a copartner of E4, masked the response of E4 to radiation. Conclusions: Our results provide detailed insight into CArG elements as a radiation-controlled molecular switch that can facilitate the development of radiogene therapy. © 2015, World Molecular Imaging Society.


Wu C.-Y.,China Medical University at Taichung | Tang J.-H.,National Yang Ming University | Chan P.-C.,National Yang Ming University | Li J.-J.,National Yang Ming University | And 6 more authors.
Molecular Imaging and Biology | Year: 2016

Purpose: Surgical resection is the standard treatment for localized colorectal cancer, which is the most common type of gastrointestinal cancer. However, over 40 % cases are diagnosed metastasized and apparently inoperable. Systemic chemotherapy provides an alternative to these patients. This study aims to evaluate the therapeutic potential of liposomal doxorubicin (lipoDox) in combination with liposomal vinorelbine (lipoVNB) in a CT-26 colon carcinoma-bearing mouse model. Procedures: The in vitro cytotoxicity of Dox and VNB on CT-26 cancer cells was determined by MTT and colony formation assays. Mice were subcutaneously inoculated with 2 × 105 of CT-26 cells in the right hind flank. When tumor size reached 200 ± 50 mm3, mice were assigned to receive different treatment protocols. The pharmacokinetics, micro single-photon emission computed tomography/x-ray computed tomography imaging, biodistribution, and immunohistochemical staining studies were performed to survey the therapeutic efficacy of each regimen. Results: Based on the results of pharmacokinetic study, co-administration of lipoDox and lipoVNB did not affect their individual systemic distribution, while lipoDox retained longer in blood than lipoVNB did. Superior tumor growth retardation was observed in the group received lipoDox plus lipoVNB administration (1 mg/kg each, namely D1V1) than those injected with lipoDox plus VNB (1 mg/kg each, namely D1fV1). No severe side effects were detected in each group. The tumor-to-muscle ratio (T/M) derived from 3′-dexoy-3′-[18F]fluorothymidine ([18F]FLT) micro positron emission tomography (PET) images of D1V1- and D1fV1-treated mice and the controls on day 7 was 6.88 ± 0.54, 7.50 ± 0.84, and 9.87 ± 0.73, respectively, suggesting that D1V1 is a more efficacious regimen against CT-26 xenografts. The results of proliferating cell nuclear antigen (PCNA) immunohistochemical staining were consistent with those findings obtained from [18F]FLT microPET imaging. Conclusion: This study demonstrated that lipoDox in combination with lipoVNB was more efficacious than clinically used regimen, lipoDox plus VNB, in the treatment of colon carcinoma and [18F]FLT-PET is a promising approach in monitoring the treatment outcome at early stage. © 2016 World Molecular Imaging Society


Chang C.-C.,National Yang Ming University | Chang C.-H.,National Yang Ming University | Chang C.-H.,Institute of Nuclear Energy Research of Taiwan | Lo Y.-H.,National Yang Ming University | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. Previous studies have demonstrated the specific binding ability of benzamide moiety to melanin. In this study, we developed a novel 18F-labeled NOTA–benzamide conjugate, Al18F–NOTA–BZA, which can be synthesized in 30 min with a radiochemical yield of 20–35% and a radiochemical purity of >95%. Al18F–NOTA–BZA is highly hydrophilic (log P = −1.96) and shows good in vitro stability. Intravenous administration of Al18F–NOTA–BZA in two melanoma-bearing mouse models revealed highly specific uptake in B16F0 melanotic melanoma (6.67 ± 0.91 and 1.50 ± 0.26% ID/g at 15 and 120 min p.i., respectively), but not in A375 amelanotic melanoma (0.87 ± 0.21 and 0.24 ± 0.09% ID/g at 15 and 120 min p.i., respectively). The clearance from most normal tissues was fast. A microPET scan of Al18F–NOTA–BZA-injected mice also displayed high-contrast tumor images as compared with normal organs. Owing to the favorable in vivo distribution of Al18F–NOTA–BZA after intravenous administration, the estimated absorption dose was low in all normal organs and tissues. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and the low projected human dosimetry supported that Al18F–NOTA–BZA is a very promising melanin-specific PET probe for melanin-positive melanoma. © 2016 Elsevier Ltd


Ke C.-C.,Anticancer, Inc. | Ke C.-C.,National Yang Ming University | Liu R.-S.,National Yang Ming University | Liu R.-S.,Taipei Veterans General Hospital | And 8 more authors.
PLoS ONE | Year: 2013

Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which are recruited to the tumor microenvironment (TME) and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs. © 2013 Ke et al.


Kuo W.-Y.,National Yang Ming University | Wu C.-Y.,China Medical University at Taichung | Hwu L.,National Comprehensive Mouse Phenotyping and Drug Testing Center | Lee J.-S.,National Yang Ming University | And 9 more authors.
Oncotarget | Year: 2015

Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-FluctTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDHbr lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs.


Chan P.-C.,National Yang Ming University | Wu C.-Y.,National Yang Ming University | Chang W.-T.,National Yang Ming University | Lin C.-Y.,National Yang Ming University | And 7 more authors.
Nuclear Medicine and Biology | Year: 2013

Objective: Previous studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2'-deoxy-2'-[18F]fluoro-β-d-arabinofuranosyluracil ([18F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model. Methods: Female syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150±50mm3 (day 0), lipo-VNB (5mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [18F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [18F]FDG/[18F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining. Results: A significant inhibition (p<0.001) in tumor growth was observed on day 3 after a single dose treatment. The tumor-to-muscle ratio (T/M) derived from [18F]FMAU-PET images of lipo-VNB-treated group declined from 2.33±0.16 to 1.26±0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [18F]FDG and [18F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period. Conclusion: Lipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [18F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB. © 2013 Elsevier Inc.


Wu C.-Y.,National Yang Ming University | Chan P.-C.,National Yang Ming University | Chou L.-S.,National Yang Ming University | Chang C.-W.,Taipei Veterans General Hospital | And 8 more authors.
Molecular Imaging and Biology | Year: 2014

Purpose: This study aims to demonstrate that pulsed high-intensity focused ultrasound (pulsed-HIFU) may enhance the fructose-conjugated 4-borono-L-phenylalanine (BPA-Fr) accumulation in tumor lesion using 18F-FBPA-Fr microPET scans. Procedures: To the mice bearing orthotopic SASC03 human tongue squamous carcinoma xenograft, a 2-min pulsed-HIFU was applied to tumor. Immediately after pulsed-HIFU treatment, 18F-FBPA-Fr was intravenously injected, and biological characterizations including microPET imaging and biodistribution were conducted. Results: Both biodistribution studies and microPET imaging performed after intravenous injection of 18F-FBPA-Fr revealed higher tumor uptake in HIFU-treated mice than that of the control. CD31 and Ki-67 histochemical staining of tumor sections and H&E staining of nearby normal tissues revealed no significant difference between the pulsed-HIFU-treated mice and the control. Conclusion: This study demonstrated that pulsed-HIFU was beneficial to the accumulation of boron drug in the head and neck tumor lesion and may enhance the therapeutic efficacy of clinical BNCT. © 2013 World Molecular Imaging Society.


Hsieh T.-H.,National Yang Ming University | Chien C.-L.,Cheng Hsin General Hospital | Chien C.-L.,Taipei Veterans General Hospital | Lee Y.-H.,National Yang Ming University | And 21 more authors.
Carcinogenesis | Year: 2014

Embryonal tumors of the central nervous system represent a highly malignant tumor group of medulloblastoma (MB), atypical teratoid/rhabdoid tumor (AT/RT) and primitive neuroectodermal tumor that frequently afflict children. AT/RT is often misdiagnosed as MB/primitive neuroectodermal tumor but with higher recurrence and lower survival rates. Pathogenesis of AT/RT is largely unknown. In this study, we report both the miRNome and transcriptome traits in AT/RT and MB by using small RNA sequencing and gene expression microarray analyses. Our findings demonstrate that the miR-221/222-encoded micro RNAs are abundantly expressed in AT/RT but not in MB, which contribute substantially to the malignancy of embryonal tumors. miR-221/222 targeted SUN2, a newly discovered tumor suppressor, directly to increase cell proliferation and tumor malignancy in vitro and in vivo. Immunohistochemistry against SUN2 in a tissue microarray of 33 AT/RT and 154 MB tumor specimens also detected less SUN2 protein in AT/RT. Collectively, this study uncovers a novel tumor suppressor, SUN2, plays a critical role in miR-221/222-mediated AT/RT malignancy as well as supports miR-221/222 and SUN2 represent new promising targets for more active therapies in AT/RT. In addition, our miRNome and transcriptome data also provide a roadmap for further embryonal tumor research. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


PubMed | China Medical University at Taichung, Chung Yuan Christian University, National Comprehensive Mouse Phenotyping and Drug Testing Center, National Yang Ming University and Barbara Ann Karmanos Cancer Institute
Type: Journal Article | Journal: Oncotarget | Year: 2015

Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-Fluc-tTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDHbr lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs.

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