Cancer Research and Treatment

Review Article

Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy: Chang W Song, Hyunkyung Kim, Mi-Sook Kim, Heon J Park, Sun-Ha Paek, Stephanie Terezakis, L Chinsoo Cho; Cancer Res Treat. 2025;57(1):1-10. Published online June 5, 2024; DOI: https://doi.org/10.4143/crt.2024.255

Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor-associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and natural killer cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells, activation of regulatory T cells, inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.

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Original Articles

A Feasibility Study of Adenosine Triphosphate-based Chemotherapy Response Assay (ATP-CRA) as a Chemosensitivity Test for Lung Cancer: Shin Myung Kang, Moo Suk Park, Joon Chang, Se Kyu Kim, Haeryoung Kim, Dong-Hwan Shin, Kyung Young Chung, Dae Joon Kim, Joo Hyuk Sohn, Sung Ho Choi, Jeongmi Kim, Eun Jin Yoon, Joo-Hang Kim; Cancer Res Treat. 2005;37(4):223-227. Published online August 31, 2005; DOI: https://doi.org/10.4143/crt.2005.37.4.223

Abstract PDF PubReader ePub

Purpose

A chemosensitivity test can reflect the differences in responses of individual cancer patients to chemotherapeutic agents. The adenosine triphosphate-based chemotherapy response assay (ATP-CRA)is an accurate method, which does not require a large amount of tissue specimen. So far, no studies have evaluated the utility of the ATP-CRA in Korea. Therefore, we investigated the clinical usefulness of the ATP-CRA in 53 patients with lung cancer.

Materials and Methods

Tumor tissues were obtained from bronchoscopic biopsies or surgical resections. The validity of ATP-CRA was assessed focusing on the success rate, experimental error level (intraassay mean coefficient of variation [CV]) and reproducibility.

Results

The overall success rate of ATP-CRA was 90.6% (48/53). Normal cells were effectively eliminated from the tumor tissues with the use of ficoll gradient centrifugation and immunomagnetic separation, which was confirmed using loss of heterozygosity analysis of the 3p deletion. The mean CV of ATP assays was 10.5±4.6%. The reproducibility of ATP assays was 94±3.8%. The results of the ATP assays were reported to physicians within 7 days of specimen collection. More than 6 anticancer drugs were tested on the tumor specimens obtained from bronchoscopic biopsies.

Conclusion

The ATP-CRA is a stable, accurate and potentially practical chemosensitivity test in patients with lung cancer.

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In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay as a Predictor of Clinical Response to Fluorouracil-Based Adjuvant Chemotherapy in Stage II Colorectal Cancer
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Correlation of Early Recurrence With In Vitro Adenosine Triphosphate Based Chemotherapy Response Assay in Pancreas Cancer With Postoperative Gemcitabine Chemotherapy
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Journal of Clinical Laboratory Analysis.2016; 30(6): 804. CrossRef
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Jee Youn Lee, Taeil Son, Jae-Ho Cheong, Woo Jin Hyung, Sung Hoon Noh, Choong-Bai Kim, Chung-Gyu Park, Hyoung-Il Kim
Journal of Gastric Cancer.2015; 15(4): 223. CrossRef
ATP-Based Chemotherapy Response Assay in Primary or Recurrent Ovarian and Peritoneal Cancer
Maria Lee, Sang Wun Kim, Eun Ji Nam, Hanbyoul Cho, Jae Hoon Kim, Young Tae Kim, Sunghoon Kim
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Adenosine triphosphate‐based chemotherapy response assay (ATP‐CRA)‐guided platinum‐based 2‐drug chemotherapy for unresectable nonsmall‐cell lung cancer
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Growth Suppression and Induction of Chemosensitivity in Human Gallbladder Epithelial Carcinoma Cells (GBCE) by Adenovirus-Mediated Transfer of the Wild-type p53 Gene: Sung Bae Kim, Myung Hwan Kim, Sung Koo Lee, Tae Won Kim, Cheolwon Suh, Jeong Sik Shin, Jung Sun Park, Eun Soon Kim, Gyungyub Gong, Jung Shin Lee, Woo Kun Kim, Sang Hee Kim; Cancer Res Treat. 2003;35(6):521-527. Published online December 31, 2003; DOI: https://doi.org/10.4143/crt.2003.35.6.521

Abstract PDF: PURPOSE
Mutations in the p53 gene are reported in 50~90% of gallbladder and bile duct cancer, and have been implicated in chemoresistance. We undertook this study to determine whether the introduction of the wild type p53 gene into GBCE (human gallbladder cancer cell line with a heterozygous p53 mutation) by an adenoviral vector could increase the sensitivity of the cell to 5-FU, a commonly used drug in the treatment of gallbladder cancer. MATERIALS AND METHODS: GBCE cells were transfected with either Ad/p53 or Ad/E1 in the presence of 5-FU. Gene expression was confirmed by western blotting. Nude mice were injected subcutaneously with GBCE cells. When tumors formed, intratumoral injection of Ad/p53 was performed. Reduction of tumor size was compared in two weeks of Ad/p53 gene transfection. RESULTS: Ad/53 transfection induced a dose-dependent inhibition of tumor growth. Tumor colony formation was more inhibited with p53 gene transfection than with mock transfection in the presence of 5-FU. The reduction in tumor size was more pronounced with p53 transfection than with mock infection.
CONCLUSION
These treatment modalities could be utilized in the treatment of p53 mutant human gallbladder cancers.

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5-FU Induces Apoptosis of Fas (+), HepG2 Cells Via Activation of Fas-mediated Caspase and Mitochondria Dysfunction: Channy Park, Kui hyun Yoon, Young Jin Lee, Yong Kweon Kim, Yee Cheon Choi, Jae Hoon Shin, Jeong Hwan Cho, RaeKil Park; Cancer Res Treat. 2002;34(2):128-138. Published online April 30, 2002; DOI: https://doi.org/10.4143/crt.2002.34.2.128

Abstract PDF

PURPOSE
In order to investigate the role of Fas on the chemosensitivity of cancer cells in regards to chemotherapeutic agents, the Fas/FasL signaling pathway of apoptosis was explored in human hepatoma cells.
MATERIALS AND METHODS
Fas expression of hepatoma cells including Chang, Huh7, HepG2, and Hep3B cells, was determined by RT-PCR and flow cytometry analysis. Cell viability was measured by MTT assay and apoptosis was assessed by DNA fragmentation assay. The catalytic activity of the caspase-family proteases including caspase-3, 6, 8, and 9 proteases, was tested using fluorogenic biosubstrates. The expression of apoptotic mediators including cytochrome c, PARP, and Bcl2 family proteins were measured from cytosolic and mitochondrial compartments. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123.
RESULTS
Fas mRNA was constitutively expressed in Chang and HepG2 as defined as Fas (+) cells, but not in Huh7 and Hep3B cells, defined as Fas (-) cells. Fas (+) cells were markedly sensitive to 5-FU whereas Fas (-) cells were resistant and able to survive. 5-FU increased Fas expression of Fas (+) HepG2 cells and simultaneously resulted in apoptotic death, characterized by the ladder-pattern fragmentation of genomic DNA. Moreover, it increased the catalytic activity of caspase-8 protease, which eventually cleaved the Bid into truncated Bid which translocated into mitochondria only in Fas (+) cells. It also increased the caspase-9 protease activity with Bax expression, cytosolic release of cytochrome c, and mytochondrial dysfunction only in Fas (+) HepG2 cells. Furthermore, 5-FU increased the enzymatic activity of caspase-3 protease with PARP digestion in HepG2 cells.
CONCLUSION
5-FU exerted cytotoxicity against hepatoma cells via activation of Fas-mediated apoptotic signaling including caspase cascades and mytochondrial dysfunction. Our data suggests that Fas may be an important modulator of the chemosensitivity of cancer cells vis- -vis anticancer chemotherapeutic agents.

Citations

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Sex-dependent liver cancer xenograft models for predicting clinical data in the evaluation of anticancer drugs
Sungryong Oh, Joohee Jung
Laboratory Animal Research.2021;[Epub] CrossRef
Lead bioactive compounds of Aloe vera as potential anticancer agent
Ranabir Majumder, Chandan Kanta Das, Mahitosh Mandal
Pharmacological Research.2019; 148: 104416. CrossRef
Extract from Artemisia annua Linn? Induces Apoptosis through the Mitochondrial Signaling Pathway in HepG2 Cells
Bo Min Kim, Guen Tae Kim, Eun Ji Kim, Eun Gyeong Lim, Sang-Yong Kim, Young Min Kim
Journal of the Korean Society of Food Science and Nutrition.2016; 45(12): 1708. CrossRef
Dexamethasone Inhibits TRAIL- and Anti-cancer Drugs-induced Cell Death in A549 Cells through Inducing NF-κB-independent cIAP2 Expression
Youn Seup Kim, Jae Seuk Park, Young Koo Jee, Kye Young Lee
Cancer Research and Treatment.2004; 36(5): 330. CrossRef

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The Reliability of Histoculture Drug Response Assay (HDRA) in Chemosensitivity Tests for Breast Cancer: Hee Joon Kang, Chang Dae Ko, Ho Sung Yoon, Moon Bo Kim, Sei Hyun Ahn; Cancer Res Treat. 2001;33(5):392-397. Published online October 31, 2001; DOI: https://doi.org/10.4143/crt.2001.33.5.392

Abstract PDF

PURPOSE
Cancers are highly individual in their response to chemotherapy, however attempts to predict tumor response to drugs using in vitro cell culture have largely failed. A new technology, the histoculture drug response assay (HDRA), appears to have solved many previous problems. The purpose of this study is to evaluate the reliability of HDRA in a chemosensitivity test for breast cancer.
MATERIALS AND METHODS
Tumor specimens from breast cancer patients were evaluated by HDRA using different chemotherapeutic agents. Each specimen was tested using a blind method in order to determine the reproducibility of HDRA results for the same tissue and with a triplicated assay in order to determine reproducibility by different examiners. The evaluative power of this assay and the chemosensitivity of drugs for each specimen was determined.
RESULTS
Specimens of 92.9% (65/70) were successfully cultured and evaluated for chemosensitivity. The reproducibility of HDRA for the same tissue was 75% (100% agreement) and 100% (over 70% agreement), respectively. And the reproducibility by different examiners was 78.9% (100% agreement) and 94.7% (over 70% agreement), respectively. Each specimen demonstrated a response to at least one agent.
CONCLUSION
The evaluative power and reproducibility of HDRA were high, therefore it might serve as a reliable clinical method for chemosensitivity testing. However, there is a need for clinical trial in which patients are initially randomized for treatment either by HDRA direction or by clinician's choice.

Citations

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Patient-Derived Ex Vivo Cultures and Endpoint Assays with Surrogate Biomarkers in Functional Testing for Prediction of Therapeutic Response
Yoshiyuki Tsukamoto, Yuka Hirashita, Tomotaka Shibata, Shoichi Fumoto, Shusaku Kurogi, Chisato Nakada, Keisuke Kinoshita, Takafumi Fuchino, Kazunari Murakami, Masafumi Inomata, Masatsugu Moriyama, Naoki Hijiya
Cancers.2023; 15(16): 4104. CrossRef
Comparison of Forcep-biopsy and Cryo-biopsy by a Flexible Bronchoscopy
Jae Hyun Kim, Jung Min Choi, Sung Eun Song, Eun Mi Lee, Song Ju Lee, Chul Ho Oak, Tae Won Jang, Man Hong Jung, Hee Kyung Jang
Tuberculosis and Respiratory Diseases.2009; 66(2): 110. CrossRef
Can the Histoculture Drug Response Assay Predict the Clinical Results of Chemotherapy in Breast Cancer?
Yong Sik Jung, Young Up Cho, Young Jin Suh, Jeong Soo Kim, Se-Jeong Oh, Cheol Wan Lim, Moon Bo Kim, Heung Kyu Park
Journal of Breast Cancer.2007; 10(3): 193. CrossRef
A Feasibility Study of Adenosine Triphosphate-based Chemotherapy Response Assay (ATP-CRA) as a Chemosensitivity Test for Lung Cancer
Shin Myung Kang, Moo Suk Park, Joon Chang, Se Kyu Kim, Haeryoung Kim, Dong-Hwan Shin, Kyung Young Chung, Dae Joon Kim, Joo Hyuk Sohn, Sung Ho Choi, Jeongmi Kim, Eun Jin Yoon, Joo-Hang Kim
Cancer Research and Treatment.2005; 37(4): 223. CrossRef

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An Experimental Study on In Vitro Chemosensitivity Tests Using Human Cancer Cell Lines: Dae Hyun Yang, Jin Pok Kim; J Korean Cancer Assoc. 1989;21(2):376-406.

Abstract PDF: The more effective chemosensitivity tests should be developed as useful tools in cancer biology research, anticancer drug screening, individualized chemotherapy, and development of other cancer treatment modalities. For practical use of chemosensitivity tests enormous efforts are necessary to improve previous tests or to develop new ideal tests. In this study, the experiments to achieve more efficient experimental conditions such as proper plating cell numbers and reasonable anticancer drug exposure (concentration and timel in the clonogenic assay using 5 human cancer cell lines were performed, and the inhibitory effects of anticancer agents on in vitro tumor marker levels of 2 cancer cell lines were evaluated, and then the value of simple dye exclusion assay was reassessed. The human cancer cell lines used in this study were SC-I of colon cancer, PLC/PRF/5 of hepatoma. ZR-75-1 of breast cancer, G 361 and Bowes melanoma of malignant melanoma. The anticancer drugs used were 5 FU, methotrexate, mitomycin C, adriamycin, cisplatin and BCUN. The clonogenic assay of SC-1 was done at various plating cell numbers, and clonogenic assay as chemosensitivity test was performed at various drug concentrations with continuous or 1-hour exposures. Clonogenic assays of 5 human cancer cell lines were carried out at the drug concentrations of 1/10 peak plasma concentra- tion (PPC) and 1/100 PYC of continuous exposure, or 1/1(l PPC of I-hour exposure. The tumnor marker inhibition of SC-I and PLC/RRF/5 by anticancer drug was measured by radioimmunoassay on the third and the fifth incubation day, and the cell survival fraction by dye exclusion assay with trypan blue was calculated. In clonogenic assay of SC-I; the number of colrmies was increased with the increase of plating cell number, and the piating of: 5 x 10(4) cells/mi formed the sufficient number of colonies (over 500 per well) with reasonable coefficiency of variance. Other cell lines also formed sufficient number of colonies with the plating of 5 x 10(4) cells/mi. In clonogenic assay of SCI as chemosensitivity test; continuous exposures of 1/10 PPC and 1/100 PPC of anticancer drug and 1-hour exposure of 1/10 PPC showed valuable results which were able to differentiate more sensitive drugs from less sensitive drugs. In clonogenic assay of 5 cancer cell lines: continuous exposures of 1/10 and 1/100 PPC identified sensitive drugs more clearly than 1-hour exposure of 1/10 PPC. Most anticancer drugs of long in vitro half life revealed more sensitive activity than those of short half life in the clonogenic assay of continuos exposure. Among three kinds of in vitro chemosensitivity tests of continuous drug exposure, the clonogenic assay showed more sensitive data in anticancer activity than the tumor marker inhibition test and the dye exclusion assay. And the results of 3 tests were closely interrelated in many series of the experiment. Anticancer drugs of longer in vitro half life usually revealed more sensitive activity also in the tumor marker inhibition test and the dye exclusion assay of continuous exposure. In conclusion: in the experiments of in vitro chemasensitivity tests using human cancer cell lines, the proper plating numbers of the clonogenic assay were approximately 5x10(4) cells/ml, and the continuous drug exposures (1/10 PPC and 1/100 PPC) identified sensitive drugs more clearly than the 1-hour exposure (1/10 PPC), and the effects of the exposure time and especially the in vitro drug half life in media as well as the in vitro anticancer drug concentration were significant on the sensitivity data in the clonogenic assay and also in the tumor marker inhibition test and the dye exclusion assay, and the results of three tests were closely interrelated in many series of the experiment.

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In Vitro Chemosensitivaty Test of SK-302 on Human Gastric Carcinoma Cell Lines: Soo Kie Kim, Woon Seob Shin, Yoon Sun Park, Sun Ju Choi, Kyung Ho Lee, Joo Young Park, Choon Myung Koh, Chan Mug Ahn, Weon Sub Park; J Korean Cancer Assoc. 1995;27(5):703-711.

Abstract PDF: SK-30ZB with quinomycin-related structure is considered to be potent antitumor antibiotic. There were several reports that quinomycins and their derivatives showed wide spectrum of anti-tumor activity. But there were no reports on anti-gastric tumor activity. We fould SK- 302B with anti-gastric tumor activity in vitro using our established anti-tumorsubstance screening system. Recent attention has been focused on the possibility of predicting the effectiveness of anti-cancer drugs on individual tumor through chemosensitivity tests. However, optimal conditions for in vitro chemosensitivity test on human gastric carcinoma cell lines were not well established. We attempted to establish optimal conditions and to evaluate compara- tively in vitro tumor cell cytotoxicity between SK-302B and adriamycin, using 7 human gastric carcinoma celi lines. The optimal cell number and culture duration for in vitro tumor cell cytotoxicity(TCC) and colony formation inhibition assay(CFIA) is 5x10(3) - 1x10(4) cells/well (TCC) and 2.510(3) - 10(3) cells/well(CFIA), 4 days(TCC) and 10 - l4 days(CFIA), respectively, for all gestric cancer cell lines. Under these conditions, we performed chemosensitivity test. Measurement of cytotoxicity(IC50) and colony forming efficiency revealed higher tumoricidal activity of SK-302 B against all tested gastric cancer cell lines than compared to that of adriamycin. In conclusion, we preseneted optimal conditions for in vitro chemosensitivity test on human gastric carcinoma cell lines. Using optimal conditions of this sytem, it could be demonstrated that SK-302B exerted a potent gastric cancer cell growth inhibition in vitro. Therefor, These data suggest that SK-302B may have a possibility of development as promising candidate of anti-gastric cancer chemotherapeutic agent.

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Establishment and Chemosensitivity ( 5 - FU ) Test of Colon Cancer Cell Lines with Enhanced Invasive Potential: Jae Gahb Park, Song Kim, Yung Jue Bang, Hynda K. Kleinman, Jin Pok Kim; J Korean Cancer Assoc. 1990;22(3):424-431.

Abstract PDF: The in vitro chemosensitivity of 3 human colorectal cancer cell lines and those invasive cells which were repeatedly selected with in vitra matrigel invasion assay to the anticancer agent, 5-FU, was determined using a semiautomated tetrazolium-based colorimetric assay (MTT assay). The IDvalues of control cells of SNU-C1, SNU-CZA, SNU-61 were 2.37+-4.S2ug/ml, 0.85+0.40ug/ml, 23.9+-13.3ug/ml, respectively, and those of invasive cell groups obtained by matrigel invasion assay were 0.37+-0.24ug/ml, 1.37+1.04ug/ml, 40.5+19.1ug/ml. There were no statistically significant differences between the ID,. values of control cell groups, SNU-C1(0), SNU-C2A(0), SNU-61(0) and those of invasive cell groups(p>0.05). This result was considered to be caused by the homogenization of the established cell lines during passage and maintenance cultivation.

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Anticarcinogenic Activity of Copolang : Suppression of N , N'-Dimethyl Nitrosamine - Induced Activation of Hepatic Glutathione S-Transferase: Tai Ho Chung, Jung Chul Kim, In Sun Lee, In Su Lee, Moon Kyu Kim; J Korean Cancer Assoc. 1990;22(3):431-440.

Abstract PDF: Dimethylnitrosamine (DMV)-induced renal mesenchymal preneoplastic loci and hepatic glutath- ione S-transferase P (GST-P) gene expression in weanling F344 male rats were used as early carcinogenic biomarkers to evaluate anticarcinogenicity of Copolang. Continuous daily intake of 0. 85 1.1 g Copolangiday/kg b. wt. for 3 weeks immediately following a single intraperitoneal administration of DMN (15, 30 and 60 mg/kg body weight) significantly blocked these DMN-induced biomarkers. The dose response slopes for DMN with or without Copolang treatment (1% Copolang in drinking water) were 0.27 and 0,47, respectively. Copolang treatment significantly inhibited DMN-induced small renal mesechymal cell proliferation, Likewise hepatic GST-P enzyme expression in the lowest DMN dose group (15 mg/kg) and the highest dose (60 mg/kg) was blocked nearly completely. In the highest dose group, multicellular GST-P enzyme loci were not observed in this experimental group, however, there was GST-P positive single cells were observed. On the other hand, in the middle dose group, GST-P histochemical staining was much more diffuse and not as intense. The results of this study demonstrate that Copolang treatment significantly inhibits expression of DMN-induced early carcinogenic biomarkers. A long term whole animal carcinogenic bioassay study is necessary to confirm anticarcinogenic activtiy of Copolang.

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Expression of Carcinoembryonic Antigen by Immunohistochemical Staining Method in Primary Male Breast Cancer: Hyun Cheol Chung, Dong Lip Kim, Eun Hee Koh, Joo Hang Kim, Jae Kyung Roh, Jin Sik Min, Kyung Shik Lee, Woo Ik Yang, Byung Soo Kim, Byung Soo Kim; J Korean Cancer Assoc. 1990;22(3):440-451.

Abstract PDF: Carcinoembryonic antigen (CEA) immunohistochemistry was evaluated with 12 sections of male breast cancer diagnosed at Severance Hospital during the year of 1979-1990. Ten of twelve (83.3%) primary breast masses and four of five (80%) metastatic lymph nodes were CEA positive. There was concordance of CEA positivity and CEA positivity grade between primary mass and metastatic lymph nodes. The grade of CEA positivity did not appear to be related to size, tumor depth (T) and pathological stages. It was difficult to find a relationship between nuclear grade and CEA positive grade, because there was no nuclear grade 3 patient. Tumor heterogeneity was a constant feature of CEA staining with positivity varying from region to region.

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Induction of Natural Killer and Lymphokine Activated Killer Cell Activities in Patients with Advanced Cancer Treated with Combination of Interleuki: Kyoo Hyung Lee; J Korean Cancer Assoc. 1990;22(3):451-458.

Abstract PDF: Peripheral blood lymphucytes were obtained from 14 patients with advanced cyncer receiving combination therapy with interleukin-2 (IL-2) and a-interferon (a-IFN) as a part of a phase I study and killer cell activities were assayed against k-562 and Daudi cell lines before, during, and after the therapy. There was significant natural killer (NK) activity before the treatment (74+-77 Lytic Unit) and it increased during the treatment (day 5, 262+195 L.U., p<0.01); day 15, 431+-328 L.U., p<0.01; and day 26, 743+-506 L.U., p<0.01). Lymphokine activated killer (LAK) activity before the treatment was low (13+9 L.U.) but also increased significantly during and after the treatment (day 5,71+59 L. U., p<0.01; day 15. 63+-77 L.U.; and day 26, 290+419 L.U.). In l0 patients same assay was repeated during the second course of therapy and showed similar increase in killer cell activities without evidence of cumulative increment. Out study showed that immunotherapy with combination of IL-2 and rz-IFN induces significant levels of NK and LAK cell activities in patients with advanced cancer. This biological phenomena can be utilized as a paramenter with which the IL-2 therapy can be tailored to augment clinical efficacy and tolerability.

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In Vitro Chemosensitivity Test for the Evaluation of Efficiency of Hyperthermia in Gastrointestinal Cancer Cell Lines: Jeong Hwan Yook, Byeong Yul Ahn, Geum Hee Koo, Hun Seo, Choon Sik Jeong, Sung Tae Oh, Byung Sik Kim, Kun Chun Park, Jin Cheon Kim; J Korean Cancer Assoc. 1999;31(5):931-938.

Abstract PDF: PURPOSE
This study was designed to establish the experimental background of intra- peritoneal hyperthermo-chemotherapy in gastrointestinal cancer.
MATERIALS AND METHODS
We established stomach cancer cell lines; KATO-III, MKN45, AMC1 and colon cancer cell lines; AMC5, AMC6, CloneA, CCL188, C106, KM-12C. We performed chemosensitivity test by using MTT assay and calculated ICso of each chemotherapeutic agent. We confirmed antitumor effect of hyperthermia at 40C and 43C and antitumor synergistic effect with each chemotherapeutic agent at 40C and 43C.
RESULTS
The ICso was calculated in 7 (78%) of 9 cell lines for 5-FU, 6 (67%) for MMC, 5 (56%) for ADM, 1 (11%) for CDDP and VP-16. Antitumor effect of hyperthermia at 40C was not found, but, that at 43C was found except KATO-III and AMC6. In stomach cancer cell lines, antitumor synergistic effect of hyperthermia with anticancer drugs at 43C was found in VP-16 for MKN45 and KATO-III and in all of 5 drugs for AMC1. In colon cancer cell lines, this effect at 43C was found in all of 5 drugs for CCL188, in S-FU, CDDP, ADM for AMC5, in 5-FU, MMC, ADM, VP-16 for CloneA, KM-12C, and in 5-FU, CDDP, MMC, ADM for C106.
CONCLUSION
Hyperthermia itself had antitumor effect at 43C. Hyperthermo-chemotherapy had antitumor synergistic effect, especially at 43C.

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MDR1 Gene Expression and Chemosensitivity to Anticancer Drugs in SNU Hepatocellular Carcinoma Cell Lines: In Gyu Hong, Sung Gyu Lee, Hyun Ju Lee, Gyung Hwa Him, Hun Sik Kim, Jae Gahb Park; J Korean Cancer Assoc. 1994;26(2):219-231.

Abstract PDF: Using recently established 8 SNU human hepatocellular carcinoma cell lines and Hep 3B cell line, we performed in vitro chemosensitivity test using semiautomated tetrazolium-based colorimetric(MTT) assay. We also measured the MDRl gene expression of these cell lines by measuring MDR1 RNA level using slot blot analysis. IC values(concentration of chemotherapeutic agent which produces 50% growth inhibition of tested cells) were in the range of 1.92~5000 ↑ ug/ml for 5-fluorouracil, 0.24~32.00 ug/ml for doxorubicin, 0.16-10.29 pg/ml for mitomycin-c, 2.00~16.56 ug/ml for cisplatin, 1.15-182.32 ug/ml for etoposide, and 0.002 ↓L -24 ↑ug/ml for vincristine. Assay area under the curve(A-AUC) at IC: values showed that only A-AUC of VP-16 was in a clinically achievable range for only one of the 9 cell lines. All other drugs were out of the range of clinically achievabie AUC. Three cell lines(SNU-354, SNU-368, SNU-449) were MDR-positive. When these 3 cell lines were compared to MDR-negative cell lines, IC value for doxorubicin was significantly higher (P<0.05), suggesting that high expression of MDRl gene is responsible for doxorubicin resistance in hepatocellular carcinoma cell lines.

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In Vitro Growth Inhibition of Human Ovarian Cancer Cell Lines by Mitosene Analogues: Dong Soo Cha, Soo Kie Kim, Chan Mug Ahn, Sun Ju Choi, Yoon Sun Park, Sang Won Han; J Korean Cancer Assoc. 1997;29(3):437-444.

Abstract PDF: No abstract available

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Expression of p53, bcl-2 Protein in Small Cell Lung Cancer (SCLC) Cell Lines in Relation to Sensitivity to Chemotherapy: In Sook Woo, Myung Jae Park, Young Seok Park, Sung Won Jung, Mi Ae Yeo, Soo Hyun Park, Si Young Kim, Hwi Joong Yoon, Kyung Sam Cho, Jae Kyung Park, Young Il Kim; J Korean Cancer Assoc. 2000;32(5):904-910.

Abstract PDF: PURPOSE
Sensitivity of tumor cells to chemotherapeutic regimen may be accentuated by their abnormal expression of oncogene. p53 is required for the efficient activation of apoptosis following irradiation or treatment with chemotherapeutic agents. The aim of this study was to evaluate the relationship between chemosensitivity and apoptosis related proteins such as p53, bcl-2 in small cell lung cancer cell lines. MATERIAL AND METHODS: Six human small cell lung cancer cell lines, NCI-H69, NCI-H128, NCI-H1436, NCI-H1092, derived from untreated and treated patients were tested for chemo sensitivity and the expression of the p53, bcl-2 genes were examined in each cell lines with western blot analysis. We used 4 drugs including adriamycin, cisplatin, vincristine and VP-16.
RESULTS
NCI-H128 was the most sensitive cell line to four drugs. NCI-H82 and NCI-H1092 were highly resistant to VP-16, adriamycin and vincristine and determination of an IC50 was not possible. In western blot analysis, NCI-H128 alone was strong positive to p53 monoclonal antibody and the rest of cell lines were negative. All but NCI-H128 were positive to bcl-2 monoclonal antibody. NCI-H128 which was strong positive to p53 and negative to bcl-2. NCI-H1092 was strong positive to bcl-2 and negative to p53 monoclonal antibody.
CONCLUSION
We were not able to explain the expression of p53 in small cell lung cancer cell lines in relation to senitivity to anti-cancer chemotherapeutic agents. But the expression of bcl-2 in small cell lung cancer cell lines was correlated with the chemosensitivity well.

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