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1.  Combination Chemotherapy with 5-Fluorouracil and Heptaplatin as First-line Treatment in Patients with Advanced Gastric Cancer 
Journal of Korean Medical Science  2004;19(3):369-373.
Heptaplatin is a recently developed platinum derivative. This agent has been reported to have a response rate of 17% as a single agent, and tolerable toxicity in the treatment of advanced gastric cancer. The aim of this study was to evaluate the efficacy and toxicity of a combination of 5-fluorouracil (5-FU) and heptaplatin in patients with advanced gastric cancer. Forty-seven chemotherapy-naive patients with advanced or recurred gastric cancer were recruited. 5-FU was administered over 120 hr by continuous intravenous infusion from day 1 to 5, at a daily dose of 1,000 mg/m2 and heptaplatin was administered over 1 hr by intravenous infusion on day 1 at 400 mg/m2, and this cycle was repeated every 4 weeks. The response rate was 21%, median progression-free survival was 1.9 months (95% CI, 1.6 to 2.2 months). Median overall survival was 6.2 months (95% CI, 4 to 8.4 months) and the 1-yr survival rate was 29% for all patients. The most frequent toxicity was proteinuria. Toxicities were generally mild and reversible. This study demonstrates that the combination of 5-FU/heptaplatin combination is less active but tolerated in patients with advance gastric cancer.
doi:10.3346/jkms.2004.19.3.369
PMCID: PMC2816837  PMID: 15201502
Drug Therapy; Fluorouracil; Stomach Neoplasms; Heptaplatin; Platinum Compounds
2.  Hemothorax caused by spontaneous rupture of a metastatic mediastinal lymph node in hepatocellular carcinoma: a case report 
doi:10.3904/kjim.2013.28.5.622
PMCID: PMC3759772  PMID: 24009462
Carcinoma, hepatocellular; Neoplasm metastasis; Hemothorax
3.  Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells 
Nucleic Acids Research  2013;41(11):5614-5625.
Tristetraprolin (TTP) and let-7 microRNA exhibit suppressive effects on cell growth through down-regulation of oncogenes. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. However, the precise mechanism of this repression is unknown. We here demonstrate that p53 stimulated by the DNA-damaging agent doxorubicin (DOX) induced the expression of TTP in cancer cells. TTP in turn increased let-7 levels through down-regulation of Lin28a. Correspondingly, cancer cells with mutations or inhibition of p53 failed to induce the expression of both TTP and let-7 on treatment with DOX. Down-regulation of TTP by small interfering RNAs attenuated the inhibitory effect of DOX on let-7 expression and cell growth. Therefore, TTP provides an important link between p53 activation induced by DNA damage and let-7 biogenesis. These novel findings provide a mechanism for the widespread decrease in TTP and let-7 and chemoresistance observed in human cancers.
doi:10.1093/nar/gkt222
PMCID: PMC3675463  PMID: 23595149
4.  Arsenic Trioxide as a Vascular Disrupting Agent: Synergistic Effect with Irinotecan on Tumor Growth Delay in a CT26 Allograft Model1 
Translational Oncology  2013;6(1):83-91.
The mechanism of action of arsenic trioxide (ATO) has been shown to be complex, influencing numerous signal transduction pathways and resulting in a vast range of cellular effects. Among these mechanisms of action, ATO has been shown to cause acute vascular shutdown and massive tumor necrosis in a murine solid tumor model like vascular disrupting agent (VDA). However, relatively little is understood about this VDA-like property and its potential utility in developing clinical regimens. We focused on this VDA-like action of ATO. On the basis of the endothelial cell cytotoxicity assay and tubulin polymerization assay, we observed that higher concentrations and longer treatment with ATO reduced the level of α- and β-tubulin and inhibited the polymerization of tubulin. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced murine CT26 colon carcinoma grown in female BALB/c mice. A single injection of ATO intraperitoneally displayed central necrosis of the tumor tissue by 24 hours. T1-weighted dynamic contrast-enhanced magnetic resonance image revealed a significant decrease in tumor enhancement in the ATO-treated group. Similar to other VDAs, ATO treatment alone did not delay the progression of tumor growth; however, ATO treatment after injection of other cytotoxic agent (irinotecan) showed significant additive antitumor effect compared to control and irinotecan alone therapy. In summary, our data demonstrated that ATO acts as a VDA by means of microtubule depolymerization. It exhibits significant vascular shutdown activity in CT26 allograft model and enhances antitumor activity when used in combination with another cytotoxic chemotherapeutic agent.
PMCID: PMC3573657  PMID: 23418620
5.  Arsenic trioxide induces depolymerization of microtubules in an acute promyelocytic leukemia cell line 
The Korean Journal of Hematology  2012;47(2):105-112.
Background
Arsenic trioxide (As2O3) is a well-known and effective treatment that can result in clinical remission for patients diagnosed with acute promyelocytic leukemia (APL). The biologic efficacy of As2O3 in APL and solid tumor cells has been explained through its actions on anti-proliferation, anti-angiogenesis, and apoptotic signaling pathways. We theorize that As2O3 activates a pathway that disrupts microtubule dynamics forming abnormal, nonfunctioning mitotic spindles, thus preventing cellular division. In this study, we investigated how As2O3 induces apoptosis by causing microtubule dysfunction.
Methods
Cultured NB4 cells were treated with As2O3, paclitaxel, and vincristine. Flow cytometric analysis was then performed. An MTT assay was used to determine drug-mediated cytotoxicity. For tubulin polymerization assay, each polymerized or soluble tubulin was measured. Microtubule assembly-disassembly was measured using a tubulin polymerization kit. Cellular microtubules were also observed with fluorescence microscopy.
Results
As2O3 treatment disrupted tubulin assembly resulting in dysfunctional microtubules that cause death in APL cells. As2O3 markedly enhanced the amount of depolymerized microtubules. The number of microtubule posttranslational modifications on an individual tubulin decreased with As2O3 concentration. Immunocytochemistry revealed changes in the cellular microtubule network and formation of polymerized microtubules in As2O3-treated cells.
Conclusion
The microtubules alterations found with As2O3 treatment suggest that As2O3 increases the depolymerized forms of tubulin in cells and that this is potentially due to arsenite's negative effects on spindle dynamics.
doi:10.5045/kjh.2012.47.2.105
PMCID: PMC3389058  PMID: 22783356
Acute promyelocytic leukemia; Arsenic trioxide; Tubulin; Apoptosis; Antimitotic agents
6.  The presence of high level soluble herpes virus entry mediator in sera of gastric cancer patients 
Experimental & Molecular Medicine  2011;44(2):149-158.
The development of gastric cancer (GC) is closely related to chronic inflammation caused by Helicobacter pylori infection, and herpes virus entry mediator (HVEM) is a receptor expressed on the surface of leukocytes that mediates potent inflammatory responses in animal models. However, the role of HVEM in human GC has not been studied. Previously, we showed that the interaction of HVEM on human leukocytes with its ligand LIGHT induces intracellular calcium mobilization, which results in inflammatory responses including induction of proinflammatory cytokine production and anti-bacterial activities. In this study, we report that leukocytes from GC patients express lower levels of membrane HVEM (mHVEM) and have lower LIGHT-induced bactericidal activities than those from healthy controls (HC). In contrast, levels of soluble HVEM (sHVEM) in the sera of GC patients were significantly higher than in those of HC. We found that monocyte membrane-bound HVEM is released into the medium when cells are activated by proinflammatory cytokines such as TNF-α and IL-8, which are elevated in the sera of GC patients. mHVEM level dropped in parallel with the release of sHVEM, and release was completely blocked by the metalloprotease inhibitor, GM6001. We also found that the low level of mHVEM on GC patient leukocytes was correlated with low LIGHT-induced bactericidal activities against H. pylori and S. aureus and production of reactive oxygen species. Our results indicate that mHVEM on leukocytes and sHVEM in sera may contribute to the development and/or progression of GC.
doi:10.3858/emm.2012.44.2.010
PMCID: PMC3296811  PMID: 22113134
cytokines; inflammation; monocytes; receptors, tumor necrosis factor, member 14; stomach neoplasms; TNFSF14 protein, human
7.  Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28 
Nucleic Acids Research  2011;40(9):3856-3869.
Tristetraprolin (TTP) is a AU-rich element (ARE) binding protein and exhibits suppressive effects on cell growth through down-regulation of ARE-containing oncogenes. The let-7 microRNA has emerged as a significant factor in tumor suppression. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. In this work, an unexpected link between TTP and let-7 has been found in human cancer cells. TTP promotes an increase in expression of mature let-7, which leads to the inhibition of let-7 target gene CDC34 expression and suppresses cell growth. This event is associated with TTP-mediated inhibition of Lin28, which has emerged as a negative modulator of let-7. Lin28 mRNA contains ARE within its 3′-UTR and TTP enhances the decay of Lin28 mRNA through binding to its 3′-UTR. This suggests that the TTP-mediated down-regulation of Lin28 plays a key role in let-7 miRNA biogenesis in cancer cells.
doi:10.1093/nar/gkr1302
PMCID: PMC3351177  PMID: 22210895
8.  Anorectal and gastric peripheral T-cell lymphoma, unspecified in a non-AIDS patient 
Anorectum is a rare location for malignant lymphoma. Involvement of is rare even for the lymphoma associated with acquired immune deficiency syndrome (AIDS), and AIDS has a relatively increased frequency of anorectal lymphoma. Most lymphomas in AIDS patients are of a B-cell origin, and T-cell lymphoma of the gastrointestinal tract is extremely rare. We report here on a case of anorectal and gastric peripheral T-cell lymphoma, unspecified (PTCLu) in a non-AIDS patient. A previously healthy 29-year-old man presented with hematochezia and tenesmus that he had suffered with for the previous 2 months. Sigmoidoscopy showed anal and rectal submucosal tumor. Multiple round-shaped, flat and elevated lesions were noted on the gastric antrum and body as well. He underwent excisional biopsy for the anal mass and the diagnosis was PTCLu. Biopsies of the gastric lesions gave the same diagnosis. There was no lymphoma involved in the bone marrow. At admission, no antibodies against human immunodeficiency virus were detected. He underwent systemic chemotherapy and upfront autologous stem cell transplantation.
doi:10.3904/kjim.2006.21.4.262
PMCID: PMC3891034  PMID: 17249511
Rectum; Peripheral T-cell lymphoma unspecified; Non-AIDS
9.  Active immunization using dendritic cells mixed with tumor cells inhibits the growth of lymphomas. 
Journal of Korean Medical Science  2003;18(3):372-380.
Dendritic cells (DCs) are potent antigen-presenting cells for the induction and activation of cytotoxic T lymphocytes. We tested whether bone marrow-derived DCs are capable of inducing protective immunity against a murine lymphoma (A20). DCs were grown from tumor-bearing BALB/c mice by culturing bone marrow cells. BALB/c mice were injected (sc) with A20 cells on day 0. Intraperitoneal immunization with DCs mixed with lethally irradiated A20 cells were started when the tumor reached ca. 4-5 mm in diameter (Group A) or on day -7 (Group B). Booster immunizations were given every 3-4 days for four weeks. By 31 days in group A, there was a significant reduction in tumor growth in the mice immunized with DCs mixed with irradiated A20 cells as compared with the control groups (p=0.016). In group B, tumor growth was completely inhibited and there was no tumor growth following extended observations after completion of immunization. Thus, DCs mixed with irradiated tumor cells can induce an antitumor effect. This provides a rationale for the use of DCs mixed with irradiated tumor cells in immunotherapy for minimal residual disease of lymphomas.
PMCID: PMC3055039  PMID: 12808324
10.  KML001 Displays Vascular Disrupting Properties and Irinotecan Combined Antitumor Activities in a Murine Tumor Model 
PLoS ONE  2013;8(1):e53900.
KML001 is sodium metaarsenite, and has shown cytotoxic activity in human tumor cell lines. The anti-cancer mechanism of KML001 involves cancer cell destruction due to DNA damage at the telomeres of cancer cell chromosomes. In this study, we assessed the vascular disrupting properties of KML001 and investigated whether KML001 as VDA is able to increase anti-tumor activity in irinotecan combined treatment. We used a murine model of the CT26 colon carcinoma cell line. CT26 isograft mice treated intraperitoneally with 10 mg/kg KML001 displayed extensive central necrosis of tumor by 24 h. The vascular disrupting effects of KML001 were assessed by dynamic contrast enhanced magnetic resonance imaging. Gadopentetic acid-diethylene triaminepentaacetic acid contrast enhancement was markedly decreased in KML001-treated mice one day after treatment, whereas persistently high signal enhancement was observed in mice injected with saline. Rate constant Kep value representing capillary permeability was significantly decreased (p<0.05) in mice treated with KML001. Cytoskeletal changes of human umbilical vein endothelial cells (HUVECs) treated with 10 uM KML001 were assessed by immune blotting and confocal imaging. KML001 degraded tubulin protein in HUVECs, which may be related to vascular disrupting properties of KML001. Finally, in the mouse CT26 isograft model, KML001 combined with irinotecan significantly delayed tumor growth as compared to control and irinotecan alone. These results suggest that KML001 is a novel vascular disrupting agent, which exhibits significant vascular shut-down activity and enhances anti-tumor activity in combination with chemotherapy. These data further suggest an avenue for effective combination therapy in treating solid tumors.
doi:10.1371/journal.pone.0053900
PMCID: PMC3543270  PMID: 23326531

Results 1-10 (10)