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Radiation Oncology Journal ; : 265-275, 2015.
Article in English | WPRIM | ID: wpr-70167


Despite the increasing use of stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS) in recent years, the biological base of these high-dose hypo-fractionated radiotherapy modalities has been elusive. Given that most human tumors contain radioresistant hypoxic tumor cells, the radiobiological principles for the conventional multiple-fractionated radiotherapy cannot account for the high efficacy of SBRT and SRS. Recent emerging evidence strongly indicates that SBRT and SRS not only directly kill tumor cells, but also destroy the tumor vascular beds, thereby deteriorating intratumor microenvironment leading to indirect tumor cell death. Furthermore, indications are that the massive release of tumor antigens from the tumor cells directly and indirectly killed by SBRT and SRS stimulate anti-tumor immunity, thereby suppressing recurrence and metastatic tumor growth. The reoxygenation, repair, repopulation, and redistribution, which are important components in the response of tumors to conventional fractionated radiotherapy, play relatively little role in SBRT and SRS. The linear-quadratic model, which accounts for only direct cell death has been suggested to overestimate the cell death by high dose per fraction irradiation. However, the model may in some clinical cases incidentally do not overestimate total cell death because high-dose irradiation causes additional cell death through indirect mechanisms. For the improvement of the efficacy of SBRT and SRS, further investigation is warranted to gain detailed insights into the mechanisms underlying the SBRT and SRS.

Humans , Antigens, Neoplasm , Cell Death , Radiobiology , Radiotherapy , Recurrence
Experimental Neurobiology ; : 55-70, 2015.
Article in English | WPRIM | ID: wpr-190710


Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins alphanubeta3, alpha4, beta1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1alpha to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

Animals , Humans , Rats , Angiogenesis Inducing Agents , Blood Vessels , Brain , Brain Injuries , Brain Ischemia , Capillaries , Cartilage Oligomeric Matrix Protein , Cell Membrane , Cell- and Tissue-Based Therapy , Fetal Blood , Human Umbilical Vein Endothelial Cells , Integrins , Ischemia , Morphogenesis , Salvage Therapy , Stem Cells , Wounds and Injuries
Cancer Research and Treatment ; : 183-190, 2005.
Article in English | WPRIM | ID: wpr-115164


PURPOSE: To reveal the interaction between beta-Lapachone (beta-lap) and ionizing radiation in causing cell death in RKO human colon adenocarcinoma cells, and to elucidate the potential usefulness of combined beta-lap treatment and radiotherapy for cancer treatment. MATERIALS AND METHODS: The cytotoxicities of various treatments were determined in vitro using clonogenic and apoptotic cell death. The changes in cell cycle distribution were studied using flow cytometry and an in vitro kinase assay. The tumor growth was studied using RKO tumors grown s.c. in the hind leg BALB/c- nuslc nude mice. RESULTS: beta-lap caused clonogenic cell death and rapid apoptosis in RKO cells in vitro, in a dose dependent manner. The repair of sublethal radiation damage was almost completely inhibited when cells were maintained in beta-lap during the interval between the two-dose irradiation. Flow cytometry study demonstrated that beta-lap induced apoptosis, independent of the cell cycle phase, and completely prohibited the induction of radiation- induced G2 arrest in irradiated cells. The prohibition of radiation-induced G2 arrest is unclear, but may be related to the profound suppression of the p53, p21 and cyclin B1-Cdc2 kinase activities observed in cells treated with beta-lap. The combination of beta-lap and radiation markedly enhanced the radiation-induced growth suppression of tumors. CONCLUSION: beta-lap is cytotoxic against RKO cells, both in vitro and in vivo, and also sensitized cells to ionizing radiation by inhibiting sublethal radiation damage repair. beta-lap is potentially useful as a potent anti-cancer chemotherapy drug and potent radiosensitizer against caner cells.

Animals , Humans , Mice , Adenocarcinoma , Apoptosis , Cell Cycle , Cell Death , Colon , Cyclins , Drug Therapy , Flow Cytometry , Leg , Mice, Nude , Phosphotransferases , Radiation, Ionizing , Radiotherapy
Experimental & Molecular Medicine ; : 181-188, 2003.
Article in English | WPRIM | ID: wpr-10313


The role of sphingomyelinase (SMase) activation and mitogen activated protein kinases (MAPKs) activation in cellular apoptosis was investigated during the hyperthermic treatment of HL-60 human leukemia cells. Treating the cells for 1 h at 43oC caused more than 50% of cellular apoptosis within several hours. The neutral-SMase activity in the cells treated for 1 h at 42degrees C was slightly increased but decreased in the cells treated at 43degrees C or 44degrees C for the same period whereas the acid SMase activity was slightly increased after heating the cells at 42degrees C and 43degrees C and markedly increased at 44degrees C for 1 h. Treatment of cells with inhibitors of SMase activation and ceramide formation significantly reduced the heat-induced apoptosis. Three major families of mitogen-activated protein kinases (MAPKs) i.e. ERK1/2, p38 and JNK, were activated by the hyperthermic treatment of cells. Inhibition of ERK1/2 with PD98059 exerted little effect on the heat-induced apoptosis and p38 inhibition with SB203580 slightly lessened apoptosis whereas, inhibition of JNK with SP600125 markedly suppressed the heat-induced apoptosis. These results indicate that heat-shock induced the activation of SMase, particularly acid-SMase, thereby causing apoptosis and that JNK played a pivotal role in heat-induced apoptosis in HL-60 leukemia cells.

Humans , Apoptosis/physiology , Enzyme Activation , HL-60 Cells , Hot Temperature , Mitogen-Activated Protein Kinase Kinases/metabolism , Sphingomyelin Phosphodiesterase/metabolism
Journal of the Korean Society for Therapeutic Radiology ; : 1-6, 1990.
Article in English | WPRIM | ID: wpr-152960


In the present study, a perfluorochemical emulsion (Fluosol-DA 20%) did not alter Do and and Dq values on cell survival curve, indicating that the lack of a direct effect of Fluosol-DA 20% on cellular radiosensitivity in vitro. The effect of Fluosol-DA 20% injection in combination with carbogen breathing was determined on the hupoxic cell fraction in SCK tumors. The hypoxic cell fraction in control SCK tumors was 0.39. This value decreased to 0.05 when the mice were i.v. injected with 12 ml/kg of Fluosol-DA 20% in a carbogen atomosphere. The measured mean and median PO2 values with a microelectorde in the control tumors was 9 mmHg and 4 mmHg, respectively. The treatment of the SCK tumors in the host mice with injected Fluosol-DA 20% in combination with carbogen breathing increased the mean and median PO2 values to 67 mmHg and 62 mmHg, respectively. Using carbogen breathing alone caused a moderate increase of tumor PO2. But Fluosol-DA 20% injection alone caused little change PO2 in the tumor. It was concluded that the combination of Fluosol-DA injection and carbogen breathing is an effective means to improve oxygenation of tumors.

Animals , Mice , Cell Survival , Oxygen , Radiation Tolerance , Respiration