• Radiation Oncology Journal
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• v.9 no.2
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• pp.205-213
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• 1991

In order to determine the value of induction chemotherapy (CT) for inoperable head and neck cancer, the authors conducted a retrospective study. Fifty-five patients were treated with CT and radiotherapy (R-T)(CT+RT group). This group was compared with a group of 54 patients treated RT alone (RT alone group). The CT regimen used were CF (cis-platine+5-FU), CVB (cyclophos-phamide+vincristine+bleomycin), CAP (cyclophosphamide+adriamycin+prednisolone) or PVBM(cis-platine+vincristine+bleomycin+methotrexate). Toxicity from induction chemo-therapy was minimal, and toxicity was limited primarily to nausea and vomiting, mucositis and myelosuppression. The complete response (CR) rate to CT was $14.5\%$ and the partial response (PR) rate was $47.3\%$ for an overall major response rate of $61.8\%$. The major response rate at the completion of loco-regional therapy was $87.3\%$(48/55) with 32 CR ($58.2\%$) and 16 PR ($29.1\%$) for CT-RT group and $81.5\%$(44/55) with 27 CR ($50.0\%$) and 17 PR ($31.5\%$) for RT alone group (p=0.57). Median follow-up of CT-RT group was 17 months and 11 months for RT alone group. Median survival was 30 months for CT-RT group and 24 months for RT alone group (p=0.3). The overall survival rate at 2 years, 3 years and 5 years, respectively was $60.9\%,\;48.6\%\;and\;42.5\%$, for CT-RT group, and $54.9\%,\;49.9\%\;and\;49.9\%$ for RT alone group (p=0.33). Comparision between patients in both groups, stratified by overall stage, T and N stage, site, and pathology, all failed to show any significant difference in survival rates. We conclude that this retrospective study failed to demonstrate an advantage for induction chemotherapy in inoperable head and neck cancer.

• Tuberculosis and Respiratory Diseases
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• v.82 no.1
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• pp.42-52
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• 2019

Background: Transforming growth factor ${\beta}$ (TGF-${\beta}$), retinoic acid (RA), p38 mitogen-activated protein kinase (MAPK), and MEK signaling play critical roles in cell differentiation, proliferation, and apoptosis. We investigated the effect of RA and the role of these signaling molecules on the phosphorylation of Smad2/3 (p-Smad2/3) induced by TGF-${\beta}1$. Methods: A549 epithelial cells and CCD-11Lu fibroblasts were incubated and stimulated with or without all-trans RA (ATRA) and TGF-${\beta}1$ and with MAPK or MEK inhibitors. The levels of p-Smad2/3 were analyzed by western blotting. For animal models, we studied three experimental mouse groups: control, bleomycin, and bleomycin+ATRA group. Changes in histopathology, lung injury score, and levels of TGF-${\beta}1$ and Smad3 were evaluated at 1 and 3 weeks. Results: When A549 cells were pre-stimulated with TGF-${\beta}1$ prior to RA treatment, RA completely inhibited the p-Smad2/3. However, when A549 cells were pre-treated with RA prior to TGF-${\beta}1$ stimulation, RA did not completely suppress the p-Smad2/3. When A549 cells were pre-treated with MAPK inhibitor, TGF-${\beta}1$ failed to phosphorylate Smad2/3. In fibroblasts, p38 MAPK inhibitor suppressed TGF-${\beta}1$-induced p-Smad2. In a bleomycin-induced lung injury mouse model, RA decreased the expression of TGF-${\beta}1$ and Smad3 at 1 and 3 weeks. Conclusion: RA had inhibitory effects on the phosphorylation of Smad induced by TGF-${\beta}1$ in vitro, and RA also decreased the expression of TGF-${\beta}1$ at 1 and 3 weeks in vivo. Furthermore, pre-treatment with a MAPK inhibitor showed a preventative effect on TGF-${\beta}1$/Smad phosphorylation in epithelial cells. As a result, a combination of RA and MAPK inhibitors may suppress the TGF-${\beta}1$-induced lung injury and fibrosis.

• Environmental Mutagens and Carcinogens
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• v.18 no.2
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• pp.116-122
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• 1998

The present investigation has been performed to elucidate the effect of pretreatment with low dose of ultraviolet radiation (UV), ethyl methansulfonate (EMS), and bleomycin (BLM) on cell survival and lectin-binding glycoconjugates of plasma membrane in HeLa cells treated with mutagen. The percentage of survival of cells pretreated with 1 mM EMS following treatment with 10 mM EMS was higher than that of cells treated with 10 mM EMS alone. Wheat germ agglutinin (WGA) staining intensity of cells pretreated with 1 mM EMS and subsequently treated with 10 mM EMS was stronger than that of cells treated with 10 mM EMS alone. But, succinylated wheat germ agglutinin (sWGA) staining intensity of cells pretreated with 1 mM EMS and subsequently treated with 10 mM EMS was similar to that of cells treated with 10 mM EMS alone. These results suggest that the acquired resistance to EMS is related to the glycoconjugates containing sialic acid of plasma membrane involved in multidrug resistance or adaptive response in HeLa cells.

• Radiation Oncology Journal
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• v.9 no.1
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• pp.59-63
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• 1991

Thirty-one patients with previously untreated and locally advanced nasopharyngeal cancer were retrospectively reviewed for comparing the effects of radical radiotherapy alone with that of combining chemotherapy and radiotherapy from 1983 to 1989 at Kangnam 51. Mavy's hospital.23/31 were evaluable for recurrence and suwival. There were 8 patients for stage III, and 15 patients for stage IV. Eleven patients were treated with radical radiation therapy done (arm I). Twelve patients were given 1~3 courses of cisplatin-5FU or cisplatin-bleomycin-vincristine prior to radiation therapy (arm II). The two arms were comparable in patient characteristics Of 11 radiotherapy Patients, complete response was 55%(6/11) and Partial response 45%(5/11). Among 12 patients after induction chemotherapy, complete response was 25%(3/12) and partial response 75%(9/12). After subsequent radiotherapy, complete response was increased to 83%(10/12) and partial response was 17%(2/12). Treatment failure was 30%(local recurrence; 3/11, and regional recurrence; 1/11) in arm 1 and 33% (local recurrence; 1/12, regional recurrence; 2/12 and distant metastasis; 1/12) in arm ll . There was no significant difference in survival between arm I and arm II (p> 0.05). The toxicities of treatment were acceptable. More controlled clinical trials must be completed before acceptance of chemotherapy as part of a standard radical treatment for locally advanced nasopharyngeal cancer.

• Environmental Mutagens and Carcinogens
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• v.8 no.1
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• pp.1-12
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• 1988

The effects of aphidicolin (APC), an inhibitor of DNA polymerase alpha, or 2', 3'-dideoxythymidine 5'-triphosphate (ddTTP), an inhibitor of DNA polymerase beta, on the repair of DNA damage induced by ethyl methanesulfonate (EMS) or bleomycin (BLM) were investigated in Chinese hamster ovary (CHO)-K1 cells. Three assays were employed in this study: unscheduled DNA synthesis, alkaline elution and alkaline sucrose gradient sedimentation. It was shown that APC or ddTTP inhibited DNA induced by EMS, and thus, the post-treatment with APC or ddTTP following EMS treatment was resulted in the more amount of unscheduled DNA synthesis, and the more accumulation of DNA single-stand breaks than the cells post-incubated without APC or ddTTP. While, in the BLM induced DNA repair, only ddTTP inhibited DNA repair induced by BLM. And thus, the groups post-incubated with or without APC after BLM treatment had the same value in the amount of unscheduled DNA synthesis and of DNA single-strand breaks, while post-treatment with ddTTP was resulted in the increased amount of unscheduled DNA synthesis and the increased DNA sin -strand breaks than the group without ddTTP. These results suggested that both of DNA polymerase $\alpha$ and $\beta$ participated in the repair of DNA damage induced by EMS, but in BLM-induced DNA repair, polymerase $\beta$ participated.ipated.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.1
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• pp.101-104
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• 2016

Background: With advances in diagnostics and treatment approaches, patients with Hodgkin's lymphoma (HL) in developed countries can nowadays expect to have excellent outcomes. However, information about the characteristics and outcomes in the developing world is very scarce, and this is important given the fact that there are several reports about differences of disease characteristics depending on geographic location and the development level of the country. Materials and Methods: In this retrospective study we assessed the features of 36 adult (${\geq}18$ years old) patients with HL and their diagnosis and treatment and outcomes in the Clinic of Chemotherapy of Muratsan University Hospital of Yerevan State Medical University, Armenia, between 2008-2014. Results: All patients had classic HL and among them 19 (53%) had nodular sclerosis subtype, 8 (22%) mixed cellularity and 9 (25%) lymphocyte-rich. 16 (44.5%) patients were at stage II, 13 (36%) stage III and 7 (19.5%) stage IV. Median follow-up time was 24.5 months (range 1-71 months) and during the whole follow-up period only two relapses (early) were documented and there were no deaths. Twenty-three (64%) patients received a BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, and 13 (36%) ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) regimen. A total of 25 (69.5%) patients received radiation in addition to chemotherapy. Conclusions: Although the number of patients involved in the study is small and the median follow-up time was just two years, this retrospective study shows that treatment of HL can be successfully organized in a resource-limited setting.

• Korean Journal of Head & Neck Oncology
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• v.15 no.1
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• pp.22-28
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• 1999

Purpose: We performed this study retrospectively to evaluate local control, survival, prognostic factors, and failure patterns in patients with non-Hodgkin's lymphoma of Waldeyer's ring. Materials and Methods: From April 1984 to November 1996,41 patients with non-Hodgkin's lymphoma of Waldeyer's ring were treated with combined chemotherapy and radiation therapy. Age was ranged from 19 to 73 years old with a median age of 55 years, and there were 26 male and 15 female patients. Primary site was tonsil in 26 and base of the tongue in 7 and nasopharynx in 8, and stage distribution showed stage I in 12 and stage II in 29 patients. Pathologic classification was done according to Working Formulation. There were 1 with follicular mixed small cleaved and large cell, 8 with diffuse small cleaved cell, 7 with diffuse mixed small and large cell, and 25 cases with diffuse large cell. All patients were treated with combination of chemotherapy and radiation therapy. Chemotherapy regimen consisted of either CHOP-Bleo(cyclophosphamide, adriamycin, vincristine, prednisolone, bleomycin) or COP-BLAM III(cyclophosphamide, vincristine, prednisolone, bleomycin, adriamycin, procarbazine). Radiation dose ranged from 3600cGy to 6620cGy with a median dose of 5040cGy. Follow-up time was ranged from 15 months to 159 months(median 55 months). Results: The complete response was achieved in 98%(40/41) and partial response in 2%(1/41). The complete response rate were the followings: 66.7% for stage I and 51.7% for stage II after chemotherapy, 100% for stage I and 96.6% for stage II after overall treatment respectively. The overall survival rate and disease-tree survival rates at 5 years were 82.6% and 79.5%, respectively. Prognostic factors for overall survival were age(p=0.007), stage(p=0.03), nodal status(p=0.006) and radiation dose(p=0.003). The factors associated with disease-tree survival were stage(p=0.04), nodal status(p=0.004) and radiation dose(p=0.009). The failure patterns were analized in evaluable 35 patients with complete response. Locoregional failure was noted in 2 patients and distant metastasis in 5 patients. Conclusion: Our results suggest that combined modality therapy is the appropriate treatment for stage I-II intermediate grade non-hodgkin's lymphoma of the Waldeyer's ring. However, our material is small and the analysis is retrospective. Randomized prospective studies for combined therapy, radiation therapy alone and chemotherapy alone are needed.

• Radiation Oncology Journal
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• v.13 no.3
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• pp.233-241
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• 1995

Purpose : To analyse clinical outcome and prognostic factors according to treatment modality, this paper report our experience of retrospective study of patients with esophageal cancer Materials and Methods : One hundred and ten patients with primary esophageal cancer who were treated in Presbyterian Medical Center from May 1985 to December 1992. We analysed these patients retrospectively with median follow up time of 28 months, one hundred and four patients($95{\%}$) were followed up from 15 to 69 months. In methods, twenty-eight patients were treated with median radiation dose irradiated 54.3Gy only. Fifty-six patients were treated with combined chemoradiotherapy. Sixteen cases of these patients were treated with concurrent chemoradiation and the other patients(forty cases) were treated sequential chemoradiotherapy. In concurrent chemoradiotherapy group, patients received 5-FU continuous IV infusion for 4 days. Cisplatin IV bolus. and concurrent esophageal irradiation to 30 Gy. After that patients received 5-FU continuous IV, Cisplatin bolus injection and Mitomycin-C bolus IV, Bleomycin continuous IV, and irradiation to 20 Gy. In sequential chemoradiotherapy group, the chemotherapy consisted of 5-FU 1,000mg/$m^2$ administered as a continuous 24 hour intravenous infusion during five days and Cisplatin 80-100mg/$m^2$ bolus injected, or Bleomycin, Vinblastine, Cisplatin, Methotrexate were used of 1 or 2 cycles. After preoperative concurrentm chemoradiation twenty-six patients underwent radical esophagectomy. Results : Ninety-three patients could be examined for response assessment, By treatment modality, response rates were $85.1{\%}$ for radiation alone group and $86.3{\%}$ for combined chemoradiation group. But in operation group, after one cycle of concurrent chemoradiation treatment, response rate was $61.9{\%}$. The pathologic complete response were $15.4{\%}$ in operation group. Overall median survival was II months and actuarial 5-year survival rate was $8{\%}$. The median survival interval was 6 months for radiation alone group, 11 months for combined chemoradiation group and 19 months for operation group. And also median survival was 19 months for complete responder group that 8 months for noncomplete responder group. In univariative analysis, statistically significant prognostic factors were tumor size, clinical stage, tumor response, and operation. In multivariative analysis, significantly better survival was associated with clinical stage, tumor response, radiation dose, and operation. Conclusion : Compared with radiotherapy alone, combined multimodality may improve the median survival in patients with localized carcinoma of the esophagus and toxicity is acceptable.

• IMMUNE NETWORK
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• v.23 no.6
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• pp.45.1-45.22
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• 2023

Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DWMSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.

• Journal of Microbiology
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• v.37 no.2
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• pp.90-96
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• 1999

The core protein of the hepatitis C virus (HCV) is a multifunctional protein. The HCV core protein was reported to regulate cellular gene expression and transform primary rat embryo fibroblast cells. However, the role of the core protein in the pathogenesis of HCV-associated liver diseases is not well understood. To investigate the functional role of the core protein in cytophathogenicity, we have constructed stable expression systems of full length or truncated HCV core protein lacking the C-terminal hyderophobic domains and established HepG2 cell clones constitutively expressing the core protein. The full length core protein was localized in the cytoplasm and the C-terminal truncated core protein was localized in the nucleus. HepG2 cells expressing nuclear, truncated core protein showed elevated cell death during cultivation compared to untransfected cells and full length core-expressing cells. In the treatment with bleomycin, both cell clones expressing full length or truncated core protein appeared to be more sensitive to blemoycin than the parental HepG2 cells. These results suggest that the core protein may play a role in HCV pathogenesis promoting apoptotic cell death of infected cells.