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6 "Tumor necrosis"
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TRAIL-Mediated Apoptosis in Human Liver Chang Cells
Channy Park, Sung Wook Hong, Sung Ho Jin, Nam Song Kim, Kyung Ho Cho, Jin Ho Cheon, Jae Yeon Ahn, Jung Ku Yang, Raekil Park
Cancer Res Treat. 2003;35(4):341-348.   Published online August 31, 2003
DOI: https://doi.org/10.4143/crt.2003.35.4.341
AbstractAbstract PDF
PURPOSE
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL)/APO-2L is a member of the TNF family that can kill a wide variety of tumor cells, but not normal cells. This study was designed to investigate the down stream target proteins in TRAIL-mediated apoptosis of human liver, Chang cells.
MATERIALS AND METHODS
The expressions of DR4/DR5 in hepatoma cells, including Chang, HepG2 and Hep3B cells, were determined by RT-PCR. Cell viability was measured by MTT assay and apoptosis was assessed by DNA fragmentation assay. The catalytic activity of caspase- family proteases, including caspase-3 and -9, was tested by using fluorogenic biosubstrates. Expression of apoptotic mediators, including procaspase-3 and PARP proteins, was measured by Western blotting. The expression profile of proteins in Chang cells by using two-dimensional (2-D) gel electrophoresis and MALDI-TOF.
RESULTS
The results demonstrated that TRAIL (100 ng/ml) induced the apoptotic death of Chang cells, as characterized by the ladder-pattern fragmentation of genomic DNA. TRAIL increased the enzymatic activity of caspase- 3, corresponding to the time of appearance of cleaved PARP and caspase-9. In 2-D gel electrophoresis and MALDI- TOF analysis, the comparison of control versus apoptotic cells in the protein expressions revealed that signal intensity of 7 spots were decreased, whereas 6 spots were increased among 300 spots. These spots were resolved and identified as a protein information by MALDI-TOF.
CONCLUSION
We suggested that TRAIL induces the apoptotic death of Chang cells via proteome alterations inducing caspase cascade.

Citations

Citations to this article as recorded by  
  • Upregulation of NAD(P)H:Quinone Oxidoreductase By Radiation Potentiates the Effect of Bioreductive β-Lapachone on Cancer Cells
    Eun K. Choi, Kaoru Terai, In-Mi Ji, Yeon H. Kook, Kyung H. Park, Eun T. Oh, Robert J. Griffin, Byung U. Lim, Jin-Seok Kim, Doo S. Lee, David A. Boothman, Melissa Loren, Chang W. Song, Heon Joo Park
    Neoplasia.2007; 9(8): 634.     CrossRef
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The Efficacy of Pre - operative Chamotherapy with Intra-arterial Cisplatin and Intravenous Adriamycin for High Grade Osteosarcoma
Sun Young Rha, Soo Jung Gong, Hee Cheol Chung, Kwang Yong Shim, Joong Bae Ahn, Nae Choon Yoo, Hyn Cheol Chung, Joo Hang Kim, Hae Kyung Roh, Jin Sik Min, Byung Soo Kim, Kyu Ho Shin, Woo Ick Yang, Chong In Lee
J Korean Cancer Assoc. 1999;31(1):134-143.
AbstractAbstract PDF
PURPOSE
Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment [pre-operative chemotherapy + surgery (limb salvage or amputation) + adjuvant chemotherapy] had improved the overall survival and quality of life. To improve the local control rate, we introduced pre-operative chemotherapy combined with intra-arterial (IA) cisplatin and continuous intravenous infusion (CI) of adriamycin. We evaluated the efficacy and feasibility, such as limb salvage rate, recurrence pattern and the survival impact, based on the histologic response of pre-operative chemotherapy.
MATERIALS AND METHODS
Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1996. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72hrs CI, was administered for 3 cycles with 3 week interval, followed by surgery. Post-operative chemotherapy was applied by the tumor necrosis rate. If the tumor necrosis of the specimen was more than 90%, the same regimen af the preoperative one was administered for 3 cycles. A salvage regimen (Ifosfamide 7.5 gm/m2/5d IV + high dose MTX 10 gm/m2 IV VP-16 360 mg/m2/3d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%.
RESULTS
Of 41 patients, 37 were evaluable for efficacy and toxicities, because 4 refused further chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 female, with the median age of 16 years (8-41). The tumor locations were as follows: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (10 with grade III, 27.8%; 17 with grade IV, 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lungs. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive care.
CONCLUSION
Pre-operative chemotherapy combined with IA cisplatin and CI adriamycin induced higher good response rate without survival benefits. To improve the survival rate, the design of good salvage chemotherapy with a non-cross resistant regimen should be considered.
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The Effect of the Degree of Tumor Necrosis on Survival in Patients with Hepatocellular carcinoma Treated with Curative Resection Following Preoperative Transcatheter Arterial Therapy
Chang Mok Lee, Dong Sup Yoon, Sung Won Kwon, Hoon Sang Chi, Byong Ro Kim
J Korean Cancer Assoc. 1998;30(6):1168-1174.
AbstractAbstract PDF
PURPOSE
To investigate the effect of patient and tumor factors on the degree of tumor necrosis and the effect of the degree of the tumor necrosis on the survival in patients treated with curative resection following transcatheter arterial therapy.
MATERIALS AND METHODS
90 patients diagnosed as having hepatocellular carcinoma and treated with curative resection following transcatheter arterial therapy at Yonsei Medical Center between January 1986 and December 1995. The subjects were classified into four groups: 100% necrosis group (Group I, n=29), over 95% necrosis group (Group II, n=28), 50-95% necrosis group (Group III, n=13) and below 50% necrosis group (Group IV, n=20). The factors which affect on the necrosis of the tumor were compared. The overall and disease-free survival rates according to the degree of tumor necrosis were illustrated.
RESULTS
There was no statistical difference in the degree of the tumor necrosis according to age, sex, HBsAg, g-FP, liver cirrhosis, tumor size and morphological classification. In the comparison between the preoperative transcatheter arterial therapies, however, transcatheter arterial chemo-oily embolization (TACOE), which used the injection of the mixture of 3 10 cc Lipiodol and 30-50 mg Adriamycin followed by Gelfoam em- bolization, showed the higher number of 100% necrosis and over 95% necrosis cases. The 1, 3 year overall survival rates were greater for Group I, although not statistically significant. The 1, 5 year disease-free survival rates were greater for Group I, although not statistically significant.
CONCLUSION
In the preoperative transcatheter arterial embolization, TACOE was most effective to get total necrosis of tumor. However overall survival and disease free survival were not affected by the amount of tumor necrosis.
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Retroviral Vector - mediated Tumor Necrosis Factor - α Gene Transfer into Human Gastric Carcinoma Cell Lines
Jung Ae Rhee, Jung Ae Lee, Dae Seog Heo, Sung Koo Han, Noe Kyeong Kim
J Korean Cancer Assoc. 1994;26(5):677-688.
AbstractAbstract PDF
The tumor necrosis factor a (TNF-a) is a potent cytokine with antitumor activities including a direct cytotoxic effect on human cancer cells and the enhancement of a cytotoxic immune response against the tumor. However, its effectiveness in the human clinical trials is limited due to severe systemic toxicities. An alternative approach, that tumor cells are genetically engineered to secrete TNF-a locally to stimulate the immune system without systemic toxicities, is suggested as a form of gene therapy (tumor-cell-targeted lymphokine gene therapy). In this trial, cDNA encoding human TNF-a (TNF-NeoR) was introduced into five human gastric carcinoma cell lines using a retroviral vector to examine whether TNF-a gene could be transfected and expressed in gastric carcinoma cell lines in vitro. Successful transfer of TNF-a gene into five gastric csrcinoma cell lines was confirmed by polymerase chain reaction techniques. Supernatants (1: 2 dilution) from cultures of transduced gastric carcinoma cell lines demonstrated cytotoxicity to TNF-sensitive WEHI 164 cell lines in the range of 20-49%. TNF- transduced gastric carcinoma cell lines secreted TNF-a at the concetration of 479-8869 pg/10(6) cells-24 hours, whereas the parental cell lines did not secrete TNF-a. There were no differences in the growth rates between parental and TNF-transduced cell lines in vitro. The four TNF-transduced SNU cell lines showed the resistance to endogenous and exogenous TNF, except SNU-668 cell line. In conclusion, TNF-a gene was successfully transfected and expressed in gastric carcinoma cell lines in vitro. These data will be helpful in the development of tumor-cell-targeted lymphokine gene therapy for the treatment of advanced gastric carcinoma.
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The Comparison of Blood TNF - α Level between Normal Person and Cancer Patients , and the Change of Blood TNF - α Level in Cancer Patients Receivint the Ablation Chemotherapy Regimens
Yong Koo Lee, Kyoung Nyeon Kim
J Korean Cancer Assoc. 1994;26(5):815-822.
AbstractAbstract PDF
Tumor Necrosis Factor(TNF) is a polypeptide hormone produced in vivo by activated macrophages and lymphocytes, and they called TNF-a and TNF4 respectively. TNF has diverse biological effects which may provide either benefical or detrimental to the host depending on the amount of TNF produced. Blood concentration of tumor necrosis factor- a(TNF-a)were measured by enzyme-linked immunosorbent assay(ELISA) methods in 28 patients receiving the ablative chemotherapy regimens. And serum TNF-a level of patients with solid tumors were examined(esophegeal 10, gastric 10, and lung 8)along with 27 healthy controis. The most striking finding was spontaneous production of TNF-a in a significant proportion of cancer patients(28.72+-23.74 pg/ml: p<0.005) against control person. We also found that chemotherapy increased TNF-a production with 48.4+-23.69 pg/mL This increase was significant(p<0.005) compared to the prechemotherapy. Activated macrophage have been shown to exhibit selective cytotoxicity for neoplastic cells and are thought to play a significant role in tumor regression. There is experimental evidence for its interaction with other biological agents and cytotoxic drugs. Several chemotherapy agents might increase macrophage-generated TNF-a through some mechanisms. For TNF-a the biological agents and importance is certain and methods designed to antagonize the release or effects of TNF may have clinical application.
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Effect of Combined Modality Treatment and Clinical Significance of P-Glycoprotein Overexpression in Patients with Osteosarcoma
Yong Seok Yun, Jae Kyung Roh, Hyun Cheol Chung, Jae Yong Cho, Kyoo Ho Shin, Soo Bong Han, Beom Seok Kim, Joon Oh Park, Soo Jung Gong, Sun Young Rha, Nae Choon Yoo, Joo Hang Kim, Jin Sik Min, Byung So
J Korean Cancer Assoc. 1996;28(6):1104-1117.
AbstractAbstract PDF
Osteosarcoma is a highly malignant bone tumor and usually encountered in the first three decades of life. The Prognosis of osteasarcoma treated with surgery alone had been poor, with 20% of the patients surviving 5 years. The addition of adjuvant chemotherapy after surgery has siginificantly improved the outcome of osteosarcoma. The new concept of pre-operative chemotherapy has permitted histological assessment of treatment effect and limb salvage procedures. As the role of chemotherapy has been raised, the resistance of tumors to multiple drugs, such as p-glycoprotein overexpression, has become a major problem in the treatment of osteosarcoma. We retrospectively reviewed the clinical records of 53 patients with stage IIB osteosarcoma who were treated at Yonsei Medical Center and Yonsei Cancer Center between March 1, 1986 and June 30, 1996. The purpose of this study was to assess the efficacy and toxicity of cisplatin(IA)-adriamycin(IV) combination pre-operative chemotherapy and the clinical significance of p-glycoprotein status and histologic response as prognostic factors. Among 53 patients, 33 were male and 20 were female with a median age of 21 years(range: 5~61). The tumor locations were as follows: distal femur 24(45.3%), proximal tibia 17(32.1%), humerus 7(13.2%), proximal femur 3(5.4%), fibular 1(1.9%), radius 1(1.9%). Histologic subclassifications were as follows: osteoblastic type 42(78.2%), telangiectatic type 4(7.5%), chondrablastic type 3(5.7%), fibroblastic type 2(3.8%) and undetermined 2(2.8%). The three year overall survival and disease-free survival rates were 66.1% and 61.9% respectively in all patients. Thirty-two patients were treated by pre-operative cisplatin(IA)-adriamycin(IV) combination chemotherapy and 21 patients were taken only post-operative adjuvant chemotherapy. No significant difference was found between the two groups in probability of survival and recurrence rates. The histological response ta pre-operative chemotherapy was scored by degree of tumor necrosis. Twenty-two patients had a good response [grade IV, 13(40.6%);grade III, 8(25.0%)] and 11 patients had a poor response [grade II, 6(18.8%);grade I, 5(15.6%)]. The histological response was not significantly related to the probability of the survival rate. However, the recurrence rate was higher in the poor-response group(p=0.04). Overexpression of p-glycoprotein was found in tumors from 11 of l8 patients(61.1%) who were given only post-operative adjuvant chemotherapy. No relation was found between the p-glycoprotein expression and survival rate. The degree of tumor necrosis after pre-operative chemotherapy and initial serum alkaline-phosphatase level were considered as prognositic factors. Other clinicopathologic features including age, gender, anatomical site, histological subclassification,operation types,tumor size.p-glycoprotein expression were not associate with patient outcome. Treatment-related side effects were relatively tolerable and reversible by conservative treatment. Pre-operative cisplatin(IA)-adriamycin(IV) combination chemotherapy in our study did not show improved survival than conventional post-operative chemotherapy with limited follow-up duration. The degree of histologic response after chemotherapy and the initial alkaline phosphatase level were found to be the major predictor for tumor recurrences, while p-glycoprotein overexpression did not alter the clinical outcome. Further studies are warranted to improve the efficacy of adjuvant chemotherapy and to evaluate the significance of multiple resistance gene overexpression in osteosarcoma.
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