PURPOSE: The purpose of this study was to identify Radiosensitivity of proteins in tissues with different radiosensitivity. MATERIALS AND METHODS: C3H/HeJ mice were exposed to 10 Gy. The mice were sacrifiud 8 hrs after radiation. Their spleen and liver tissues were collected and analyzed histologicaly for apoptosis. The expressions of radiosusceptibility protein were analyzed by 2-dimensional electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. RESULTS: The peak of apoptosis levels were 35.3+/-1.7% in spleen and 0.6+/-0.2% in liver at 8 hrs after radiation. Liver, radioresistant tissues, showed that the levels of ROS metabolism related to proteins such as cytochromm c, glutathione S transferase, NADH dehydrogenase, riken cDNA and peroxiredoxin VI increased after radiation. The expression of cytochrome c increased significantly in spleen and liver tissues after radiation. In spleen, radiosensitivity tissue, the identified proteins showed a significantly quantitative alteration following radiation. It was categorized as signal transduction, apoptosis, cytokine, Ca signal related protein, stress-related protein, cytoskeletal regulation, ROS metabolism, and others. CONCLUSION: Differences of radiation-induced apoptosis by tissues specifted were coupled with the induction of related radiosensitivity and radioresistant proteins. The result suggests that apoptosis relate protein and redox proteins play important roles in this radiosusceptibility.
Animals ; Apoptosis ; Cytochromes c ; DNA, Complementary ; Electrophoresis ; Glutathione Transferase ; Liver ; Mass Spectrometry ; Metabolism ; Mice ; NADH Dehydrogenase ; Oxidation-Reduction ; Peroxiredoxin VI ; Proteomics* ; Radiation Tolerance* ; Signal Transduction ; Spleen

PURPOSE: To characterize strain-specific differences in radiation response in murine tissues with different radiosensitivity. MATERIALS AND METHODS: Six-week old male mice of 2 strains, C57Bl/6J and C3H/HeJ, were given whole body gamma-radiation with a single dose of 10 or 25 Gy. At different times after irradiation, mice were killed and tissues with different radiosensitivity, thymus and liver, were collected. Each tissue sample was stained with hematoxylin and eosin and apoptotic cells were scored. Expression of p53, Bcl-2, Bcl-x, and Bax was analysed by western blotting and densitometry. RESULTS: Radiation induced massive apoptosis in thymus with a peak level at 8 h after radiation. With 10 Gy irradiation, apoptotic indices in C57Bl/6J and C3H/HeJ were 81.0 2.5% and 59.4 4.0%, respectively (p<0.05). Radiation upregulated the expression of p53, Bcl-x, and Bax, but not Bcl-2; p53 with a peak level of 2.5 fold (C57Bl/6J) and 1.4 fold (C3H/HeJ) at 4 h, Bax with a peak level of 2.6 fold (C57Bl/6J) and 1.3 fold (C3H/HeJ) at 8 h, and Bcl-x with a peak level of 11.1 fold (C57Bl/6J) and 8.2 fold (C3H/HeJ) at 8 h after radiation. In liver, however, radiation-induced apoptosis was minimal (peak apoptotic index of 2.1% in C57Bl/6J and 1.7% in C3H/HeJ). None of p53, Bcl-2, Bcl-x, and Bax was significantly increased. CONCLUSIONS: Induction of apoptosis and regulation of related genes by radiation were tissue specific. Strain difference of radiation-induced apoptosis was well coupled with theinduction of related genes in thymus, a radiosensitive tissue. This study shows that quantitative difference of radiation induced apoptosis by strain is regulated at the gene level with the involvement of multiple genes.
Animals ; Apoptosis* ; Blotting, Western ; Densitometry ; Eosine Yellowish-(YS) ; Hematoxylin ; Humans ; Liver ; Male ; Mice ; Radiation Tolerance ; Thymus Gland

PURPOSE: This study evaluated the treatment effectiveness and proper radiation dose of helical tomotherapy (HT) in spine oligometastases from gastrointestinal cancers. MATERIALS AND METHODS: From 2006 to 2010, 20 gastrointestinal cancer patients were treated with HT for spine oligometastases (31 spine lesions). The gross tumor volume (GTV) was the tumor evident from magnetic resonance imaging images fused with simulation computed tomography images. Clinical target volume (CTV) encompassed involved vertebral bodies or dorsal elements. We assumed that the planning target volume was equal to the CTV. We assessed local control rate after HT for 31 spine metastases. Pain response was scored by using a numeric pain intensity scale (NPIS, from 0 to 10). RESULTS: Spine metastatic lesions were treated with median dose of 40 Gy (range, 24 to 51 Gy) and median 5 Gy per fraction (range, 2.5 to 8 Gy) to GTV with median 8 fractions (range, 3 to 20 fraction). Median biologically equivalent dose (BED, alpha/beta = 10 Gy) was 52 Gy10 (range, 37.5 to 76.8 Gy10) to GTV. Six month local control rate for spine metastasis was 90.3%. Overall infield failure rate was 15% and outfield failure rate was 75%. Most patients showed pain relief after HT (93.8%). Median local recurrence free survival was 3 months. BED over 57 Gy10 and oligometastases were identified as prognostic factors associated with improved local progression free survival (p = 0.012, p = 0.041). CONCLUSION: HT was capable of delivering higher BED to metastatic lesions in close proximity of the spinal cord. Spine metastases from gastrointestinal tumors were sensitive to high dose radiation, and BED (alpha/beta = 10 Gy) higher than 57 Gy10 could improve local control.
Disease-Free Survival ; Gastrointestinal Neoplasms ; Humans ; Magnetic Resonance Imaging ; Neoplasm Metastasis ; Radiotherapy, Intensity-Modulated ; Recurrence ; Spinal Cord ; Spine ; Treatment Outcome ; Tumor Burden

No abstract available.
Apoptosis* ; Fas Ligand Protein

PURPOSE: Extracellular signal-regulated kinase (ERK), which is part of the mitogen-activated protin kinase cascade, opposes initiation of the apoptotic cell death which is programmed by diverse cytotoxic stimuli. In this regard, the inhibition of ERK may be useful in improving the therapeutic efficacy of established anticancer agents. MATERIALS AND METHODS: Murine hepatocarcinoma, HCa-I is known to be highly radioresistant with a TCD50 (radiation dose yield in 50% cure) of more than 80 Gy. Various anticancer drugs have been found to enhance the radioresponse of this particular tumor but none were successful. The objective of this study was to explore whether the selective inhibition of MEK could potentiate the antitumor efficacy of radiation in vivo, particularly in the case of radioresistant tumor. C3H/HeJ mice bearing 7.5~8 mm HCa-I, were treated with PD98059 (intratumoral injection of 0.16 microgram in 50 microliter). RESULTS: Downregulation of ERK by PD98059 was most prominent 1h after the treatment. In the tumor growth delay assay, the drug was found to increase the effect of the tumor radioresponse with an enhancement factor (EF) of 1.6 and 1.87. Combined treatment of 25 Gy radiation with PD98059 significantly increased radiation induced apoptosis. The peak apoptotic index (number of apoptotic nuclei in 1000 nuclei X100) was 1.2% in the case of radiation treatment alone, 0.9% in the case of drug treatment alone and 4.9%, 5.3% in the combination treatment group. An analysis of apoptosis regulating molecules with Western blotting showed upregulation of p53, p21WAF1/CIP1 and Bcl-XS in the combination treatment group as compared to their levels in either the radiation alone or drug alone treatment groups. The level of other molecules such as Bcl-XL, Bax and Bcl-2 were changed to a lesser extent. CONCLUSION: The selective inhibition of MEK in combination with radiation therapy may have potential benefit in cancer treatment.
Animals ; Antineoplastic Agents ; Apoptosis ; Blotting, Western ; Cell Death ; Down-Regulation ; Mice ; Phosphotransferases ; Radiation Dosage ; Radiation, Ionizing ; Up-Regulation

Objectives: ：Somatic symptom disorder (SSD) is characterized by the manifestation of a variety of physical symptoms, but little is known about differences in autonomic nervous system activity according to symptom severity, especially within patient groups. In this study, we examined differences in heart rate variability (HRV) across symptom severity in a group of SSD patients to analyze a representative marker of autonomic nervous system changes by symptoms severity. Methods: ：Medical records were retrospectively reviewed for patients who were diagnosed with SSD based on DSM-5 from September 18, 2020 to October 29, 2021. We applied inverse probability of treatment weighting (IPTW) methods to generate more homogeneous comparisons in HRV parameters by correcting for selection biases due to sociodemographic and clinical characteristic differences between groups. Results: ：There were statistically significant correlations between the somatic symptom severity and LF (nu), HF (nu), LF/HF, as well as SD1/SD2 and Alpha1/Alpha2. After IPTW estimation, the mild to moderate group was corrected to 27 (53.0%) and the severe group to 24 (47.0%), and homogeneity was achieved as the differences in demographic and clinical characteristics were not significant. The analysis of inverse probability weighted regression adjustment model showed that the severe group was associated with significantly lower RMSSD (β=-0.70, p=0.003) and pNN20 (β=-1.04, p=0.019) in the time domain and higher LF (nu) (β=0.29, p<0.001), lower HF (nu) (β=-0.29, p<0.001), higher LF/HF (β=1.41, p=0.001), and in the nonlinear domain, significant differences were tested for SampEn15 (β=-0.35, p=0.014), SD1/SD2 (β=-0.68, p<0.001), and Alpha1/Alpha2 (ß=0.43,p=0.001). Conclusions ：These results suggest that differences in HRV parameters by SSD severity were showed in the time, frequency and nonlinear domains, specific parameters demonstrating significantly higher sympathetic nerve activity and reduced ability of the parasympathetic nervous system in SSD patients with severe symptoms.

PURPOSE: Unresectabel rectal cancer has a grave prognosis, regardless of the therapy used and median survival is less than 1 year. Also, it is reported by many authors that 50-80% of unresectable lesions were rendered respectable by radiation therapy and the median survival time for the completely resected patients were better than that of the unresected patients. So we analyzed retrospectively our data for the better treatment outcome in these patients. MATERIALS AND METHODS: From 1980 to 1992, 45 patients with initially unresectable tumors in the rectum were treated with radiation therapy with/without surgery in Department of Radiation Oncology, Yonsei Cancer Center. 10 MV radiation and multiple field technique( box or AP/PA) were used. The total dose was 8-70 Gy and median dose was 48 Gy. We evaluated the lesion status at 45-50 Gy for operability. If the lesions appeared to be respectable, the patients were operated on 4-6 weeks after radiation therapy. But if the lesions were still fixed, the radiation dose was increased to 60-65 Gy. RESULTS: For all patients, the 2-year actuarial survival was 13.3% and median survival was 9.5 months. Of 6 patients who had received less than 45 Gy, only 17% of patients responded, but in the patients who had received more than 45 Gy, 60% of response rate was achieved. Six of the 24 patinets(25%) underwent surgical resections following RT. For patients undergoing curative resection, the two-year survival was 50%, but that of the patients without resection was 9.5% (p<0.01). Survival of patients with complete response following RT was 50% at 2 years. Survival of patients with partial response, stable disease and progressive disease after RT was 13.4%, 15.4%, 0% respectively (p<0.05). Conclusion: Our data suggests that the efforts which can increase the response rate and aggressive surgical approach are needed to achieve the better local control and survival in unresectable rectal cancers.
Humans ; Prognosis ; Radiation Oncology ; Rectal Neoplasms* ; Rectum ; Retrospective Studies ; Treatment Outcome

BACKGROUNDS: The purpose of this study was to identify drugs that can enhance radioresponse of murine hepatocarcinoma. METHODS: C3H/HeJ mice bearing 8 mm tumors of murine hepatocarcinoma, HCa-I, were treated with 25 Gy radiation and one of the following drugs: 5-Fu, 150 mg/kg; adriamycin, 8 mg/kg; cisplatin, 6 mg/kg; paclitaxel, 40 mg/kg; and gemcitabine, 50 mg/kg. Tumor response to the treatment was determined by tumor growth delay assay and by enhancement factor. Apoptotic level was assessed in tissue sections. Expression of regulating molecules was analyzed by western blotting for p53, Bcl-2, Bax, Bcl-XL, Bcl-XS, and p21WAF1/CIP1. RESULTS: Among the drugs tested, only gemcitabine enhanced the antitumor effect of radiation, with enhancement factor of 1.6. Induction of apoptosis by a combination of gemcitabine and radiation was shown as only additive level. In analysis of radiation-induced expression of regulating molecules, the most significant change by combining gemcitabine was activation of p21WAF1/CIP1. CONCLUSION: Gemcitabine is the first drug showing an enhancement of radioresponse in murine hepatocarcinoma, when combined with radiation. The key element of enhancement is thought to be p21WAF1/CIP1.
Animals ; Apoptosis ; Blotting, Western ; Cisplatin ; Doxorubicin ; Drug Therapy* ; Fluorouracil ; Mice ; Paclitaxel ; Radiation Dosage

PURPOSE: To determine whether TNF-alpha increases the antitumor effect of radiotherapy in murine syngeneic tumor system. MATERIALS AND METHODS: Syngeneic murine tumors of MCa-K or MCa-4 (mammary carcinoma), OCa-I (ovarian carcinoma), or HCa-I (hepatocarcinoma were grown in hind legs of C3Hf/HeJ mice. When tumors were grown to 6 mm in mean diameter, mice were treated with TNF-alpha, radiation, or combination of the both. Gamma-radiation was given as a single dose of 30 Gy for HCa-I and 15 Gy for other tumors using Cobalt-60 teletherapy unit. A novel TNF-alpha mutein developed in Korea, was intraperitoneally administered daily at a dose of 10 microgram per mouse for 7 days. In combination of radiation and TNF-alpha, the drug was started 1 hour after radiation. Tumor growth delay assay was used to measure the tumor response to the treatment. RESULTS: Among 4 tested tumors, TNF-alpha alone showed significant antitumor activity in MCa-K and OCa-I tumors, which showed absolute growth delay (AGD) of 5.0 days and 6.5 days, respectively. In combination with radiation, TNF-alpha showed significant delay of AGD (41.1 days) in OCA-I compared to AGDs of TNF-alpha alone and radiation, i.e., 6.5 days and 26.9 days, respectively (p<0.05). Enhancement factor was 1.29 in OCa-I, which showed supraadditive effect. TNF-alpha did not show significant delay of AGDs in the remaining 3 tumors compared to AGDs of TNF-alpha alone and radiation. CONCLUSIONS: TNF-alpha alone showed antitumor effects in MCa-K and OCa-I. In combination with radiation, TNF-alpha acted in supraadditive way in OCa-I only. The results of this study imply that the combination of TNF-alpha and radiation has different therapeutic potential depending on tumor model and further study is advocated.
Animals ; Korea ; Leg ; Mice ; Radiotherapy* ; Tumor Necrosis Factor-alpha*

PURPOSE: It has been recognized that interaction of the Fas : Fas ligand plays an important role in radiation-induced apoptosis. The purpose of this study was to investigate the role of Fas mutation in radiation-induced apoptosis in vivo. MATERIALS AND METHODS: Mice with mutations in Fas, MRL/Mpj-Fas(lpr), and its normal control, MRL/Mpj, were used in this study. Eight-week old male mice were given whole body radiation. After irradiation, the mice were killed and their spleens were collected at different time intervals. Tissue samples were stained with hematoxylin-eosin and the numbers of apoptotic cells were scored. Regulating molecules of apoptosis including p53, Bcl-2, Bax, Bcl-XL, and Bcl-XS were also analyzed by Western blotting. RESULTS: At 25 Gy irradiation, the level of apoptosis reached the peak value at 8 hr after radiation and recovered to the normal value at 24 hr after radiation in MRL/Mpj mice. In contrast, the peak apoptosis level appeared at 4 hr after radiation in MRL/Mpj-Fas(lpr) mice. At 8 hr after radiation, the levels of apoptosis in MRL/Mpj mice and MRL/Mpj-Fas(lpr) mice were 52.3+/-7.8% and 8.0+/-8.6%, respectively (p<0.05). The expression of apoptosis regulating molecules, p53, Bcl-XL and Bcl-XS, increased in MRL/Mpj mice in response to radiation; p53 with a peak level of 3-fold at 8 h, Bcl-XL with a peak level of 3.3-fold at 12 h, and Bcl-XS with a peak level of 3-fold at 12 h after 25 Gy radiation. Bcl-2 and Bax did not show significant change in MRL/Mpj mice. However in MRL/Mpj-Fas(lpr) mice, the expression levels of p53, Bcl-2, Bax, Bcl-XL and Bcl-XS showed no significant change. CONCLUSION: The level of radiation-induced apoptosis was lower in Fas mutated mice, lpr, than in control mice. This seemed to be related to the lack of radiation-induced p53 activation in the lpr mice. This result suggests that Fas plays an important role in radiation-induced apoptosis in vivo.
Animals ; Apoptosis* ; Blotting, Western ; Fas Ligand Protein ; Humans ; Male ; Mice ; Radiation Dosage ; Reference Values ; Spleen ; Whole-Body Irradiation