• Journal of Korean Neurosurgical Society
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• 제61권5호
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• pp.592-599
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• 2018

Objective : Metastatic brain tumors (MBTs) often present with intracerebral hemorrhage. Although Gamma Knife surgery (GKS) is a valid treatment option for hemorrhagic MBTs, its efficacy is unclear. To achieve oncologic control and reduce radiation toxicity, we used a radiosurgical targeting technique that confines the tumor core within the hematoma when performing GKS in patients with such tumors. We reviewed our experience in this endeavor, focusing on local tumor control and treatment-associated morbidities. Methods : From 2007 to 2014, 13 patients with hemorrhagic MBTs were treated via GKS using our targeting technique. The median marginal dose prescribed was 23 Gy (range, 20-25). GKS was performed approximately 2 weeks after tumor bleeding to allow the patient's condition to stabilize. Results : The primary sites of the MBTs included the liver (n=7), lung (n=2), kidney (n=1), and stomach (n=1); in two cases, the primary tumor was a melanoma. The mean tumor volume was $4.00cm^3$ (range, 0.74-11.0). The mean overall survival duration after GKS was 12.5 months (range, 3-29), and three patients are still alive at the time of the review. The local tumor control rate was 92% (tumor disappearance 23%, tumor regression 46%, and stable disease 23%). There was one (8%) instance of local recurrence, which occurred 11 months after GKS in the solid portion of the tumor. No GKS-related complications were observed. Conclusion : Our experience shows that GKS performed in conjunction with our targeting technique safely and effectively treats hemorrhagic MBTs. The success of this technique may reflect the presence of scattered metastatic tumor cells in the hematoma that do not proliferate owing to the inadequate microenvironment of the hematoma. We suggest that GKS can be a useful treatment option for patients with hemorrhagic MBTs that are not amenable to surgery.

• 방사선산업학회지
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• 제9권4호
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• pp.187-192
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• 2015

CD44 is a particular adhesion molecule and facilitates both cell-cell and cell-matrix interactions. In particular, splice variants of CD44 are particularly overexpressed in a large number of malignancies and carcinomas. In this study, the $^{177}Lu$-labelled CD44 targeting antibody was prepared and bioevaluated in vitro and in vivo. Anti-CD44 was immunoconjugated with the equivalent molar ratio of cysteine-based DTPA-NCS and radioimmunoconjugated with $^{177}Lu$ at room temperature within 15 minutes. The stability was tested in human serum. An in vitro study was carried out in HT-29 human colon cancer cell lines. For the biodistribution study $^{177}Lu$-labelled anti-CD44 was injected in xenograft mice. Anti-CD44 was immunoconjugated with cysteine-based DTPA-NCS and purified by a centricon filter system having a molecular cut-off of 50 kDa. Radioimmunoconjugation with $^{177}Lu$ was reacted for 15 min at room temperature. The radiolabeling yield was >99%, and it was stable in human serum without any fragmentation or degradation. The radioimmunoconjugate showed a high binding affinity on HT-29 colon cancer cell surfaces. In a biodistribution study, the tumor-to-blood ratio of the radioimmunoconjugate was 43 : 1 at 1 day post injection (p.i) in human colon cancer bearing mice. The anti-CD44 monoclonal antibody for the targeting of colon cancer was effectively radioimmunoconjugated with $^{177}Lu$. The in vitro high immunoactivity of this radioimmunoconjugate was determined by a cell binding assay. In addition, the antibody's tumor targeting ability was demonstrated with very high uptake in tumors. This radioimmunoconjugate is applicable to therapy in human colon cancer with highly expressed CD44.

• BMB Reports
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• 제51권7호
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• pp.319-326
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• 2018

Increasing evidence suggests that cancer stem cell (CSC) theory represents an important mechanism underlying the observed failure of existing therapeutic modalities to fully eradicate cancers. In addition to their more established role in maintaining minimal residual disease after treatment and forming the new bulk of the tumor, CSCs might also critically contribute to tumor recurrence and metastasis. For this reason, specific elimination of CSCs may thus represent one of the most important treatment strategies. Emerging evidence has shown that CSCs have a different metabolic phenotype to that of differentiated bulk tumor cells, and these specific metabolic activities directly participate in the process of CSC transformation or support the biological processes that enable tumor progression. Exploring the role of CSC metabolism and the mechanism of the metabolic plasticity of CSCs has become a major focus in current cancer research. The targeting of CSC metabolism may provide new effective therapies to reduce the risk of recurrence and metastasis. In this review, we summarize the most significant discoveries regarding the metabolism of CSCs and highlight recent approaches in targeting CSC metabolism.

• Asian Pacific Journal of Cancer Prevention
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• 제16권11호
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• pp.4509-4513
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• 2015

Osteosarcoma is the most common primary bone tumor in humans, especially in childhood. However, the genetic etiology for its pathogenesis remains elusive. It is known that microRNAs (miRNAs) are involved in the development of tumor progression. Here we show that microRNA-9 (miR-9) is a potential oncogene upregulated in osteosarcoma cells. Knockdown of miR-9 in osteosarcoma resulted in suppressed colony formation and cell proliferation. Further study identified GCIP, a Grap2 and cyclin D interacting protein, as a direct target of miR-9. In addition, GCIP overexpression activated retinoblastoma 1 (Rb) and suppressed E2F transcriptional target expression in osteosarcoma cells. Moreover, GCIP depletion reversed miR-9 knockdown induced colony formation and cell proliferation suppression. In sum, these results highlight the importance of miR-9 as an oncogene in regulating the proliferation of osteosarcoma by directly targeting GCIP and may provide new insights into the pathogenesis of osteosarcoma.

• Asian Pacific Journal of Cancer Prevention
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• 제15권15호
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• pp.6243-6246
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• 2014

To investigate the role of miR-1297 and the tumor suppressor gene PTEN in cell proliferation of testicular germ cell tumors (TGCT). MTT assays were used to test the effect of miR-1297 on proliferation of the NCCIT testicular germ cell tumor cell line. In NCCIT cells, the expression of PTEN was assessed by Western blotting further. In order to confirm target association between miR-1297 and 3'-UTR of PTEN, a luciferase reporter activity assay was employed. Moreover, roles of PTEN in proliferation of NCCIT cells were evaluated by transfection of PTEN siRNA. Proliferation of NCCIT cells was promoted by miR-1297 in a concentration-dependent manner. In addition, miR-1297 could bind to the 3'-UTR of PTEN based on luciferase reporter activity assay, and reduced expression of PTEN at protein level was found. Proliferation of NCCIT cells was significantly enhanced after knockdown of PTEN by siRNA. miR-1297 as a potential oncogene could induce cell proliferation by targeting PTEN in NCCIT cells.

• Radiation Oncology Journal
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• 제36권3호
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• pp.172-181
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• 2018

Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation-induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio.

• Macromolecular Research
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• 제13권4호
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• pp.293-296
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• 2005

Transferrin ($T_{f}$) has been used as a targeting ligand for delivering liposome/interleukin-12 (IL-12) pDNA complexes to cancer cells mostly due to the greater number of transferrin receptors ($T_{f}R$) found on tumor cells than on normal cells. $T_{f}$ was conjugated to liposomes via the reaction of MPB-PE with thiol groups of $T_{f}$ introduced by a heterobifunctional cross-linking agent, N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP). Four days after C26 inoculation when the tumor volume reached ${\sim}100mm^{3}$, tumor-bearing Balb/c mice were injected intravenously with $T_{f}-liposome/IL-12 pDNA$complexes twice a week for 3 weeks. Significant suppression of tumor growth was achieved in the group treated with the $T_{f}-liposome/IL-12 pDNA$ complexes, with a dose of $10{\mu}g$ of IL-12 pDNA showing the highest suppression effect among the tested doses. Similar results were obtained when the therapy was initiated one day after tumor inoculation, although in this case $30{\mu}g$ IL-12 pDNA/$T_{f}-liposome$ complexes showed a significant suppression of tumor growth between 19 and 23 days after tumor inoculation. This result indicates that the transferrin receptor-targeted liposomal system is an efficient delivery agent of therapeutic genes, such as IL-12, in mice and that its potential clinical use warrants further research investigation.

• 한국환경성돌연변이발암원학회지
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• 제22권2호
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• pp.65-69
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• 2002

To elucidate the effect of microsphere coinjection on the administration of oligodeoxynucleotides (ODN), we have investigated biodistribution of ［S-35］-labeled antisense ODN targeted to cAMP-dependent protein kinase (PKA) RI-$\alpha$ subunit in nude mice xenografted with WiDr (human colon cancer, ATCC CCL218). The strategy of using microsphere has been proposed for cancer treatment as a carrier of therapeutic ODN so that it could offer an advantage with respect to maintaining constant ODN levels in blood and obtaining higher therapeutic ODN concentration at tumor sites. Comparative biodistribution studies were performed in nude mice (female, 20 g of body weight, n = 4-6) xenografted with WiDr cancer cells, when 0.1 $\mu$Ci (specific activity, 2.94 mCi/$\mu$mole) of ［S-35］-labeled RI-$\alpha$ antisense ODN was injected alone or with microsphere (PLG-18, polylactic copolymer with cationic surfactant DDAB18). Peak tumor uptake of ［S-35］-labeled ODN was significantly increased from 17.7% (at 6 h) of injected dose per gram of tissue (ID/g) to 42.5% (at 24 h) ID/g when microsphere was coinjected with ODN. The different biodistribution in the kidney accumulation (e.g., 100.2% ID/g for ODN alone and 54.9%/ID/g for microshpere coinjection) may contribute to higher blood concentration (e.g., 21.5%ID/$m\ell$ for ODN alone and 37.5%ID/$m\ell$ for microsphere coinjection) of radiolabeled ODN. Of importance is the fact that the whole body retention of radioactivity increased with microsphere coinjection from 50.8%ID/g to 68.0%ID/g after 24-h of injection. This decreased kidney accumulation and increased whole body retention of ［S-35］-labeled ODN resulted in a significant improvement of ODN targeting to the tumor site. In conclusion, the coinjection of microsphere appears to be an important carrier system in vehiculation of antisense oligonucleotide to the tumor tissue in vivo.

• 핵의학기술
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• 제28권1호
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• pp.1-11
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• 2024

Hypoxia, defined as the deficiency of oxygen, is a significant hallmark of cancers presenting in the majority of solid tumors. Detection of tumor hypoxia is essential in cancer diagnosis to prevent cancer progression, metastasis, and resistance to cancer therapies in clinical practices. Single-photon emission computed tomography (SPECT) is one of the methods studied and applied for hypoxia detection with the use of radiolabeled imaging agents in which ^99mTc is the common radioisotope used for radiolabeling. Nitroimidazoles are the hypoxia-targeting moieties presenting in numerous ^99mTc-radiolabeled imaging agents due to their bio-reducible ability in hypoxic environments. Recently, in addition to ^99mTc-labeled radiopharmaceuticals containing one nitroimidazole unit, there has been considerable attention given to ^99mTc-radiopharmaceuticals bearing two or more nitroimidazole units. This review summarizes the synthesis of hypoxia-targeting chelators and radiolabeling processes to produce these ^99mTc-radiopharmaceuticals for SPECT imaging.

• Journal of Pharmaceutical Investigation
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• 제33권4호
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• pp.287-292
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• 2003

A novel antitumor agent, antibody-endostatin fusion protein $(anti-HER2/neu\;IgG3C_H3-Endostatin,\;AEFP)$ formed by genetic engineering procedure from antibody (Ab) which specifically targets to tumor cells ad angiogenesis inhibitor, endostatin (Endo) that has excellent antitumor effect, minimizes the toxicity of normal cells and selectively kills only tumor cells. The purpose of this study is to evaluate the phamacokinetic parameters and to analyze the localization of AEFP. After an intravenous injection of $150\;{\mu}l\;(5\;{\mu}Ci)\;[^{125}I]Ab,\;[^{125}I]AEFP$ to mice, blood was collected though retroorbital plexus from 15 min to 2880 min. Following the jugular vein injetion of $150\;{\mu}l\;(10\;{\mu}Ci)\;[^{125}I]Endo$, blood was collected by the use of carotid artery cannulation from 0.25 min to 30 min. Consequently, Endo was very rapidly removed from plasma compartment within 30 min. On the other hand, AEFP similar to Ab was slowly cleared from plasma. Also, Endo was metabolized about 40% within 30 min. However, AEFP was shown to metabolize less than 10% within 2880 min. The organ distribution of Endo was in order kidney, lung, spleen. Both Ab and AEFP were localized in order spleen, kidney, liver. Futhermore the tumor/blood distribution ratio of AEFP at 96 hours after injection is about 20 times higher than it of Endo at one hour after injection. In conclusion, these studies demonstrate that the anti-cancer or suppression of angiogenesis effect of Endo may be improved by the use of AEFP because the longer half life and stability of AEFP is able to selectively target antigens expressed on tumors.