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ABSTRACT: Currently, clinically available options for treating glioblastoma (GBM) are quite limited, and there is a clear need to develop novel treatment strategies that can more effectively manage tumors. Here, we present a combination treatment of temozolomide (TMZ), a blood-brain barrier penetrating DNA alkylating agent, and ZD6474 (vandetanib), a VEGFR2 and EGFR dual-targeting anti-angiogenic agent, as a novel treatment strategy for GBM. In a U-87MG orthotopic xenograft model, the combination treatment provided a marked 94% tumor volume reduction. This reduction was greater than that achieved by monotherapy of either agent, and was correlated with a statistically significant reduction in microvessel density (CD31+ cells) and proliferation (PCNA+ cells). These results confirm the necessity to target angiogenesis in addition to utilizing cytotoxic approaches, and provide the rationale for application of TMZ + ZD6474 combination therapy for treating GBM patients in the clinical setting.
Molecular Medicine Reports 04/2012; 6(1):88-92. · 0.42 Impact Factor
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ABSTRACT: Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic tool to treat multiple myeloma (MM). DC-based idiotype vaccination was recently suggested to induce idiotype-specific immune responses in MM patients. However, the clinical results so far have been largely disappointing, and the clinical effectiveness of such vaccinations in MM still needs to be demonstrated. DC-based therapies against MM may need to be boosted with other sources of tumor-associated antigens, and potent DCs should be recruited to increase the effectiveness of treatment. DCs with both high migratory capacity and high cytokine production are very important for effective DC-based cancer vaccination in order to induce high numbers of Th1-type CD4(+) T cells and CD8(+) cytotoxic T lymphocytes. The tumor microenvironment is also important in the regulation of tumor cell growth, proliferation, and the development of therapeutic resistance after treatment. In this review, we discuss how the efficacy of DC vaccination in MM can be improved. In addition, novel treatment strategies that target not only myeloma cells but also the tumor microenvironment are urgently needed to improve treatment outcomes.
The Korean journal of hematology 03/2012; 47(1):17-27.
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Yong Jung,
Kyeung Min Joo,
Dong Ho Seong,
Yoon-La Choi,
Doo-Sik Kong,
Yonghyun Kim, Mi Hyun Kim,
Juyoun Jin,
Yeon-Lim Suh,
Ho Jun Seol,
Chul Soo Shin,
Jung-Il Lee,
Jong-Hyun Kim,
Sang Yong Song,
Do-Hyun Nam
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ABSTRACT: A set of proteins reflecting the prognosis of patients have clinical significance since they could be utilized as predictive biomarkers and/or potential therapeutic targets. With the aim of finding novel diagnostic and prognostic markers for glioblastoma (GBM), a tissue microarray (TMA) library consisting of 62 GBMs and 28 GBM-associated normal spots was constructed. Immunohistochemistry against 78 GBM-associated proteins was performed. Expression levels of each protein for each patient were analyzed using an image analysis program and converted to H-score [summation of the intensity grade of staining (0-3) multiplied by the percentage of positive cells corresponding to each grade]. Based on H-score and hierarchical clustering methods, we divided the GBMs into two groups (n=19 and 37) that had significantly different survival lengths (p<0.05). In the two groups, expression of nine proteins (survivin, cyclin E, DCC, TGF-β, CDC25B, histone H1, p-EGFR, p-VEGFR2/3, p16) was significantly changed (q<0.05). Prognosis-predicting potential of these proteins were validated with another independent library of 82 GBM TMAs and a public GBM DNA microarray dataset. In addition, we determined 32 aberrant or mislocalized subcellular protein expression patterns in GBMs compared with relatively normal brain tissues, which could be useful for diagnostic biomarkers of GBM. We therefore suggest that these proteins can be used as predictive biomarkers and/or potential therapeutic targets for GBM.
International Journal of Oncology 12/2011; 40(4):1122-32. · 2.40 Impact Factor
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ABSTRACT: The tumor-tropic properties of neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to tumors in the brain. To apply this strategy to the treatment of brain metastases, we made a human NSC line expressing cytosine deaminase (F3.CD), which converts 5-fluorocytosine (5-FC) into 5-fluorouracil, an anticancer agent. In vitro, the F3.CD cells significantly inhibited the growth of tumor cell lines in the presence of the prodrug 5-FC. In vivo, MDA-MB-435 human breast cancer cells were implanted into the brain of immune-deficient mouse stereotactically, and F3.CD cells were injected into the contralateral hemisphere followed by systemic 5-FC administration. The F3.CD cells migrated selectively into the brain metastases located in the opposite hemisphere and resulted in significantly reduced volumes. The F3.CD and 5-FC treatment also decreased both tumor volume and number of tumor mass significantly, when immune-deficient mouse had MDA-MB-435 cells injected into the internal carotid artery and F3.CD cells were transplanted into the contralateral brain hemisphere stereotactically. Taken together, brain transplantation of human NSCs, encoding the suicide enzyme CD, combined with systemic administration of the prodrug 5-FC, is an effective treatment regimen for brain metastases of tumors.
Molecular Therapy 02/2009; 17(3):570-5. · 6.87 Impact Factor
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ABSTRACT: P-glycoprotein (P-gp), a factor responsible for the multidrug resistance of tumors, is specifically expressed in brain microenvironment. To test its roles in brain metastatic tumor chemoresistance, we implanted the paclitaxel-sensitive melanoma cell line, K1735, into the skin or brain of mice and examined its paclitaxel resistances. When implanted into the skin, paclitaxel inhibited tumor growth, however, it had no inhibitory effect on cells implanted into the brain. The paclitaxel resistance of the brain K1735 tumors was eliminated by combined treatment with a P-gp inhibitor, HM30181A, and paclitaxel. Previously we found that there is a defined therapeutic window for combined treatment of brain tumors with HM30181A and paclitaxel. To determine whether it is due to responses of the brain microenvironment we measured changes in P-gp expression and function of brain endothelial cells in response to HM30181A treatment in vitro and in vivo. They were significantly increased by high-dose HM30181A treatment and it was related with the therapeutic effect loss of high-dose HM30181A treatment. Therefore, P-gp in the brain microenvironment has crucial roles in the brain metastatic tumor chemoresistance and brain microenvironment responses to P-gp inhibitor treatment should be considered in the development of brain endothelial cell-targeted chemotherapy using P-gp inhibitor.
International Journal of Oncology 11/2008; 33(4):705-12. · 2.40 Impact Factor
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Do-Hyun Nam,
Hye-Min Jeon,
Shiyeon Kim, Mi Hyun Kim,
Young-Ju Lee,
Min Su Lee,
Hyunggee Kim,
Kyeung Min Joo,
Dong-Sup Lee,
Janet E Price,
Sa Ik Bang,
Woong-Yang Park
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ABSTRACT: The potential of metastasis can be predicted from clinical features like tumor size, histologic grade, and gene expression patterns. We examined the whole-genome transcriptomic profile of a xenograft model of breast cancer to understand the characteristics of brain metastasis.
Variants of the MDA-MB-435 cell were established from experimental brain metastases. The LvBr2 variant was isolated from lesions in a mouse injected in the left ventricle of the heart, and these cells were used for two cycles of injection into the internal carotid artery and selection of brain lesions, resulting in the Br4 variant. To characterize the different metastatic variants, we examined the gene expression profile of MDA-MB-435, LvBr2, and Br4 cells using microarrays.
We could identify 2,016 differentially expressed genes in Br4 by using the F test. Various metastasis-related genes and a number of genes related to angiogenesis, migration, tumorigenesis, and cell cycle were differentially expressed by the Br4 cells. Notably, the Notch signaling pathway was activated in Br4, with increased Jag2 mRNA, activated Notch intracellular domain, and Notch intracellular domain/CLS promoter-luciferase activity. Br4 cells were more migratory and invasive than MDA-MB-435 cells in collagen and Matrigel Transwell assays, and the migration and invasion of Br4 cells were significantly inhibited by inactivation of Notch signaling using DAPT, a gamma-secretase inhibitor, and RNA interference-mediated knockdown of Jagged 2 and Notch1.
Taken together, these results suggest that we have isolated variants of a human cancer cell line with enhanced brain metastatic properties, and the activation of Notch signaling might play a crucial role in brain metastasis.
Clinical Cancer Research 08/2008; 14(13):4059-66. · 7.74 Impact Factor
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ABSTRACT: Since cancer stem cells in brain tumors were introduced, there have been few explanations regarding the role of cancer stem cells in the progression of glioma. Here, we investigated their major molecular changes in tumor progression in relation to the stem cell subpopulation. Using 12 surgical specimens of gliomatosis cerebri (GC) in the early and advanced stages, we measured the expression of a panel of cell proliferation, microvessel density, microvessel areas, angiogenic factors and their associated receptors. In addition, expression of neural stem cell markers and associated cytokines were examined in tumor tissues by quantitative real-time RT-PCR. Comparing the biological characteristics between the initial infiltrating lesions (n=7) and progressed lesions (n=5), Sox2 and Musashi-1 were expressed in the tumor tissue at an early and a progressed state. Contrary to the early infiltrative phase representing angiogenesis-independent growth, GC with progression showed that nestin (+), PCNA (+) cells and total vessel area (angioectasia) were markedly increased with a higher expression of proangiogenic molecules and their receptors. These results suggest that tumor progression is mediated by cancer stem cells and cross-talk of cancer stem cells along with their environment and are closely associated with angiogenesis-dependent progression and -independent growth.
Oncology Reports 04/2008; 19(3):639-43. · 1.84 Impact Factor
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ABSTRACT: Oral chemotherapy has many advantages over parenteral chemotherapeutics administration. To use the advantages of the oral chemotherapy and maximize anti-tumor effects of the chemotherapeutic agent, we designed HM30181A (a P-glycoprotein inhibitor) and a paclitaxel oral co-administration chemotherapeutic method. HM30181A is used to aid paclitaxel absorption from gut lumen into blood and to inhibit paclitaxel exclusion out of the brain tumor mass by endothelial cells, which inhibits paclitaxel access to tumor cells in the brain parenchyma. We applied HM30181A and paclitaxel oral co-administration methods to the treatment of tumors in the brain using the K1735 melanoma brain metastasis animal model and the U-87 MG glioblastoma animal model. Administrations were performed twice per week for 28 days and the therapeutic effect was examined using tumor volume change. We observed that 32 mg/kg HM30181A and 16 mg/kg of paclitaxel (dose ratio 2:1) oral co-administration showed significant therapeutic effects in both animal models, but when the doses or dose ratio was changed, the effects could not be observed. Therefore, adjustments of doses and dose ratio of the agents seems to be essential in realizing oral HM30181A and paclitaxel treatment in brain tumors. These results suggest that if the doses and dose ratio can be successfully adjusted, the oral co-administration of HM30181A and paclitaxel can be used to treat tumors in the brain.
Oncology Reports 02/2008; 19(1):17-23. · 1.84 Impact Factor
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ABSTRACT: Metastatic breast cancer is still defined as an incurable disease, with the lungs being the most common metastatic sites in breast cancer patients. Epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase family, is known to be involved in survival, migration, angiogenesis and metastasis of cancer. The spontaneous pulmonary metastasis mouse model was applied to evaluate the effects of the EGFR tyrosine kinase inhibitor, erlotinib, on the prevention of pulmonary metastasis in curatively resected breast carcinoma. The expression of EGF and EGFR was significantly strong in pulmonary metastatic nodules compared to those in primary breast carcinoma tissue. A treatment of erlotinib (oral gavage, 50 mg/kg/day, every day for 6 weeks) given to mastectomized mice inhibited the incidence of pulmonary metastasis. The number of metastatic pulmonary nodules was significantly reduced in the erlotinib-treated group compared with the control. Therefore, erlotinib may play a role in preventing pulmonary metastasis, which shows the strong expression of EGF and EGFR after curative resection of primary breast cancer.
Oncology Reports 08/2006; 16(1):119-22. · 1.84 Impact Factor
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Ji Tae Kim,
Jong-Soo Kim,
Kwang Won Ko,
Doo-Sik Kong,
Chang-Mo Kang, Mi Hyun Kim,
Myung Jin Son,
Hyun Seok Song,
Hyung-Jin Shin,
Dong-Sup Lee,
Whan Eoh,
Do-Hyun Nam
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ABSTRACT: Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy.
Oncology Reports 08/2006; 16(1):33-9. · 1.84 Impact Factor
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Myung Jin Son,
Hyun Seok Song, Mi Hyun Kim,
Ji Tae Kim,
Chang-Mo Kang,
Ji Won Jeon,
Shi-Young Park,
Yung-Jin Kim,
Morris D Groves,
Kwan Park,
Jong-Hyun Kim,
Do-Hyun Nam
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ABSTRACT: Glioblastomas are highly vascularized tumors and anti-angiogenic strategy is one of the most promising therapeutic approaches to treat brain tumors. Interferon alpha (IFN-alpha) as a single agent or combined with standard chemo-therapy has been shown to inhibit various tumors, but the effect of combination anti-angiogenic therapy on brain tumors has not been well studied. We determined the optimal dose and schedule of pegylated IFN-alpha (PEG-IFN-alpha) against U-87MG human glioblastoma cells growing orthotopically in nude mice, since several clinical trials reported that PEG-IFN-alpha administered at higher or lower doses was less effective. The group treated two times per week with injections of 10 KU of PEG-IFN-alpha for 4 weeks showed significant decreases in cell proliferation and angiogenesis. Moreover, the optimal dose and schedule of PEG-IFN-alpha determined in this study and combined with paclitaxel treatment potently inhibited tumor growth in vivo. The mechanisms of the significant therapeutic effects were most likely caused by directly inhibiting cell proliferation and angiogenesis, and rendering apoptosis increased. Specifically PEG-IFN-alpha/paclitaxel combination induced apoptosis of tumor-associated endothelial cells more than that of tumor cells. These results suggest that optimal biological dosage and scheduling of PEG-IFN-alpha and paclitaxel combination is a potent strategy for glioblastoma patients as a new synergistic anti-endothelial treatment.
International Journal of Oncology 07/2006; 28(6):1385-92. · 2.40 Impact Factor
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Myung Jin Son,
Jong-Soo Kim, Mi Hyun Kim,
Hyun Seok Song,
Ji Tae Kim,
Heechul Kim,
Taekyun Shin,
Hyun Jung Jeon,
Dong-Sup Lee,
Shi-Young Park,
Yung-Jin Kim,
Jong-Hyun Kim,
Do-Hyun Nam
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ABSTRACT: The chemotherapeutic agent temozolomide (TMZ) and the anti-angiogenic agent thalidomide (THD) have both demonstrated anti-tumor activity in patients with recurrent malignant glioma. Combination treatment with TMZ and THD in patients with glioblastoma multiforme (GBM) appears to be more effective than treatment with either drug alone. To investigate the mechanism of this anti-tumor effect, we examined the combined effects of TMZ and THD in a rat glioma xenograft model. We found that combination treatment markedly inhibited the growth of tumors that were orthotopically implanted into rat brains. Using proliferating cell nuclear antigen (PCNA) staining, we observed a significant decrease in cell proliferation in these tumors. CD31 staining of the microvasculature revealed a significant decrease in angiogenesis. We also found increased apoptosis in treated tumors by terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. We further demonstrated that the expression of angiogenic factors, such as vascular endothelial cell growth factor (VEGF) and basic fibroblastic growth factor (bFGF), were inhibited by THD. THD also decreased the number of ED1-positive, activated macrophages or microglial cells, which produce pro-angiogenic molecules around the glioma. Taken together, these results suggest that combination treatment with TMZ and THD inhibits tumor growth via the induction of apoptosis and the inhibition of angiogenesis in a rat model and may be a promising therapy for malignant gliomas.
International Journal of Oncology 02/2006; 28(1):53-9. · 2.40 Impact Factor
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Do-Hyun Nam,
Kwan Park,
Chaehwa Park,
Young-Hyuck Im, Mi-Hyun Kim,
Sangjun Lee,
Seung-Chyul Hong,
Hyung-Jin Shin,
Jong-Hyun Kim,
Whan Eoh,
Timothy J McDonnell
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ABSTRACT: Higher cyclooxygenase-2 (COX-2) expression is clinically associated with more aggressive gliomas and is a strong predictor of poor survival. To determine whether oral administration of a COX-2-specific inhibitor can inhibit glial tumors, we analyzed the effect of celecoxib on the growth of 9L rat gliosarcoma cells that were orthotopically transplanted into rat brains. Oral administration of celecoxib beginning 1 day after implantation of 5 x 10(4) 9L rat gliosarcoma cells into rat brain reduced the incidence and size of tumors significantly. Immunohistochemical analysis of implanted gliosarcoma cells from rats treated with celecoxib showed lower levels of phospho-Akt, phospho-EGFR, Bcl-2, and Bcl-XL expression compared with untreated tumor cells. Gliosarcoma cells from treated rats had significantly more TUNEL- and caspase-3-positive cells and fewer PCNA-positive cells. These results demonstrate that selective COX-2 inhibitors may be useful as adjuvants and/or therapeutic agents to treat gliomas overexpressing COX-2.
Oncology Reports 03/2004; 11(2):263-8. · 1.84 Impact Factor
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ABSTRACT: The objective of this study was to examine the antitumor effect of ZD6474, an orally available inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) and the epidermal growth factor receptor (EGFR), on tumor growth in an orthotopic metastatic brain tumor model. In order to determine the antitumor mechanism of ZD6474 treatment, in vitro and in vivo studies were performed. Human breast carcinoma cells (MDA-MB-435) were injected using direct intracranial (IC) inoculation (5x105 cells/100 µl) and internal carotid artery (ICA) injection (5x104 cells/100 µl) in Balb/c-nu female mice. Daily oral treatment with ZD6474 (50 mg/kg) was initiated on day 14 after the establishment of micrometastasis. Mice (n=12 per group) were sacrificed on day 28. Western blot analysis revealed that the autophosphorylation of EGFR and Akt was increasingly decreased with ZD6474 treatment in lung and brain endothelial cells and the MDA-MB-435 cell line. MTT assay also showed that the in vitro antitumor activity of ZD6474 was dependent on EGFR tyrosine kinase inhibition at a higher dose. Daily oral treatment with ZD6474 led to marked inhibition of metastatic tumor growth in the ICA injection and the direct IC inoculation models (median size 3.5 mm3, range 1.6-13.9 mm3) as compared to the control group (median size 62.4 mm3, range 11.5-206.9 mm3). These results suggest that simultaneous inhibition of both the EGFR and VEGFR-2 signaling pathways has a valuable therapeutic effect through its inhibition of the growth of metastatic brain tumors.
Molecular Medicine Reports 1(3):343-6. · 0.42 Impact Factor
