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5 "Chang Yeol Yim"
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Randomized, Multicenter, Phase III Trial of Heptaplatin 1-hour Infusion and 5-Fluorouracil Combination Chemotherapy Comparing with Cisplatin and 5-Fluorouracil Combination Chemotherapy in Patients with Advanced Gastric Cancer
Kyung Hee Lee, Myung Soo Hyun, Hoon-Kyo Kim, Hyung Min Jin, Jinmo Yang, Hong Suk Song, Young Rok Do, Hun Mo Ryoo, Joo Seop Chung, Dae Young Zang, Ho-Yeong Lim, Jong Youl Jin, Chang Yeol Yim, Hee Sook Park, Jun Suk Kim, Chang Hak Sohn, Soon Nam Lee
Cancer Res Treat. 2009;41(1):12-18.   Published online March 31, 2009
DOI: https://doi.org/10.4143/crt.2009.41.1.12
AbstractAbstract PDFPubReaderePub
Purpose

Heptaplatin (Sunpla) is a cisplatin derivative. A phase IIb trial using heptaplatin resulted in a 34% response rate with mild nephrotoxicity. We conducted a randomized phase III trial of heptaplatin plus 5-FU compared with cisplatin plus 5-FU in patients with advanced gastric cancer.

Materials and Methods

One hundred seventy-four patients (heptaplatin, n=88; cisplatin, n=86) from 13 centers were enrolled. The eligibility criteria were as follows: patients with pathologically-proven adenocarcinoma, chemonaive patients, or patients who had received only single adjuvant chemotherapy, and who had a measurable or evaluable lesion. On day 1, heptaplatin (400 mg/m2) or cisplatin (60 mg/m2) was given over 1 hour with 5-FU (1 gm/m2) on days 1~5 every 4 weeks.

Results

At the time of survival analysis, the median overall survival was 7.3 months in the 5-FU + heptaplatin (FH) arm and 7.9 months in the 5-FU + cisplatin (FP) arm (p=0.24). Of the FH patients, 34.2% (complete response [CR], 1.3%; partial response [PR], 32.9%) experienced a confirmed objective response compared with 35.9% (CR 0%, PR 35.9%) of FP patients (p=0.78). The median-time-to-progression was 2.5 months in the FH arm and 2.3 months in the FP arm. The incidence of neutropenia was higher with FP (28%) than with FH (16%; p=0.06); grade 3~4 nausea and vomiting were more frequent in the FP than in the FH arm (p=0.01 and p=0.05, respectively). The incidence of increased proteinuria and creatininemia was higher with FH than with FP; however, there was no statistical difference. There were no treatment-related deaths.

Conclusion

Heptaplatin showed similar effects to cisplatin when combined with 5-FU in advanced gastric cancer patients with tolerable toxicities.

Citations

Citations to this article as recorded by  
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  • Quantum mechanical approaches and molecular docking analysis of platinum metal-based anticancer drugs Lobaplatin and Heptaplatin targeting cancer DNA - a comparative analysis
    Madhavi Sahadevan, Mullainathan Sundaram, Karunagaran Subramanian
    Chemical Physics Letters.2024; 842: 141191.     CrossRef
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Uptake of Ga-67 by Cultured Cells: Transferrin-dependent and Transferrin-independent Mechanisms
Myung Hee Sohn, Seok Tae Lim, Jae Yong Kwak, Chang Yeol Yim
J Korean Cancer Assoc. 2000;32(4):742-749.
AbstractAbstract PDF
PURPOSE
We determined whether the uptake of Ga-67 by cultured cells occur by both transferrin (Tf)-dependent and independent mechanisms and the mechanism and magnitude of its uptake may vary as the degree of expression of the transformed phenotype.
MATERIALS AND METHODS
Uptake of Ga-67 between the tansformed and untransformed cells was compared. Cells were incubated with Ga-67 in either the presence or absence of Tf and with complete medium containing Ga-67 after preincubating with anti-Tf receptor antibodies at 37oC in 8% CO2. Monolayers of cells were washed and trypsinized. Radioactivity and protein content of the samples were determined.
RESULTS
Uptake of Ga-67 by cultured cells occurred both in Tf-bound and ionic form and was increased with radioactivity and time. The magnitude for the uptake of Tf-bound form was approximately 3 and 6-fold greater than ionic form. In the presence of Tf, uptake of Ga-67 was 2-fold greater in the transformed cells. Conversely, In the absence of Tf, it was 1.5-fold greater in the untransformed cells. Regardless of blocking the Tf receptor by anti-Tf receptor antibodies, a significant amount of intracellular Ga-67 uptake was found.
CONCLUSION
Dual mechanisms exist for the uptake of Ga-67 by cultured cells. The primary important one was the Tf-dependent system. Tf-dependent and independent mechanisms and the magnitude operated oppositely in the transformed cells when compared to their untransformed counterpart.
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IL-2 Induced Nitric Oxide Synthesis by Tumor Cells in Corultures of Lymphocytes and Tumor Cells
Chang Yeol Yim, Sang Youel Park, Wan Hee Yoo, Jae Yong Kwak, Soo Teik Lee, Myung Hee Sohn, Dae Ghon Kim, Deuk Soo Ahn
J Korean Cancer Assoc. 1999;31(2):339-347.
AbstractAbstract PDF
PURPOSE
Nitric oxide (NO) synthesis has been known to be induced during interleukin-2 (IL-2) therapy. The present study was designed to elucidate mechanisms and roles of IL-2-induced NO synthesis in tumor cells.
MATERIALS AND METHODS
Mechanisms of IL-2-induced NO synthesis were evaluated using in vitro culture systems of BALB/c mouse splenic lymphocytes and Meth-A tumor cells. Effects of IL-2-induced NO synthesis by Meth-A tumor cells on the tumor cell proliferation were also evaluated using an NO synthase inhibitor, N -monomethyl- L-arginine (MLA).
RESULTS
Cultures of both lymphocytes alone and Meth-A tumor cells alone did not produce any significant amounts of nitrite, a stable metabolite of NO during IL-2 stimulation. In contrast, cocultures of lymphocytes and Meth-A tumor cells produced a large amount of nitrite during IL-2 stimulation. Addition of culture supernatants of lymphocytes incubated with IL-2 induced nitrite production in Meth-A tumor cell cultures. However, addition of culture supernatants of Meth-A tumor cells incubated with IL-2 did not induce nitrite production in lymphocyte cultures. Nitrite accumulation was markedly inhibited by addition of anti-interferon-y antibody, confirming the role of the cytokine in mediating tumor cell NO synthesis. MLA inhibited nitrite production by Meth-A tumor cells in a dose-dependent manner in the presence of culture supernatants of lymphocytes incubated with IL-2. Meth-A tumor cell nitrite production in the presence of increasing concentrations of MLA correlated inversely with tumor cell proliferation.
CONCLUSION
NO synthesis can be induced by tumor cells by the secondarily released cytokines from lymphocytes during IL-2 stimulation. Autologous NO synthesized by tumor cells during IL-2 stimulation inhibits proliferation of tumor cells themselves.
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The Effect of Metallothionein on the Resistance to Cisplatin in Transfected Mouse NIH/3T3 Cells
Myung Hee Sohn, Jae Yong Kwak, Chang Yeol Yim
J Korean Cancer Assoc. 1997;29(4):576-583.
AbstractAbstract PDF
PURPOSE
Metallothionein is an intracellular cystein-rich thiol-containing protein. Increased metallothionein content in tumor cells has been suggested to be a mechanism of resistance to cisplatin. In most of previous studies evaluating the role of metallothionein in cisplatin resistance, tumor cells were usually exposed to cadmium to increase metallothionein content. Therefore, cisplatin resistance of the cells may be related to cadmium exposure itself, which induces various changes in cell characteristics, but not to increased metallothionein content. The purpose of this study is to evaluate the role of metallothionein content alone in cellular resistance to cisplatin without exposure of cells to cadmium.
MATERIALS AND METHOD
We measured the toxicity of cisplatin in mouse NIH/3T3 cells that vary in their content of metallothionein as a consequence of transfection with a plasmid that result in the constitutive expression of metallothionein. MT cells were derived from NIH/3T3 cells by transfection with a plasmid containing the genome of bovine papilloma virus and the mouse metallothionein-I, derived by the promoter for the glucose-regulated protein of 78kD. Control cells were similary transfected with bovine papilloma virus-based plasmids with the gene for metallothionein inverted and thus separated from the promoter (TM), or deleted, along with promoter (BPA). The number of copies of the plasmid were similar in each kind of transfected cells. Expression of metallothionein required neither selection nor maintenance of cells in the presence of heavy metals.
RESULTS
Synthesis of metallothionein was 15-fold greater in the MT cells than in the TM or BPA cells. The concentration of cisplatin sufficient to reduce the cells per well by one-half (IC-50) was 0.40+/-0.075 uM in MT cells. In TM and BPA cells, it was 0.36 0.035 uM and 0.423+/-0.032 uM. There were no significant differences in IC-50 between three cell lines.
CONCLUSION
In spite of large differences between MT and control cells in their cellular content of metallothionein, no differences in resistance to cisplatin were observed.
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Nitric Oxide Synthesis in Murine Skin Cancers
Chang Yeol Yim, Chang Hwan Lee, Soo Mi Choi, Wan Hee Yoo, Sung Joong Lee, Seong Hee Lim, Myung Hee Sohn
J Korean Cancer Assoc. 1995;27(1):101-111.
AbstractAbstract PDF
Nitric oxide(NO) is a major cytotoxic effector molecule of activated macrophages. Although the antitumor activity of NO produced by activated macrophages was demonstrated in in vitro experiments, the in vivo role of tumor infiltrating macropheges in tumor growth is currently uncertain. It is also unknown that tumor infiltrating macrophages produce NO, and thereby contribute either a host antitumor immune defense mechanism or a promoting mechanism of in vivo tumor growth by suppressing immune function. The purpose of the current study was to evaluate whether the NO synthesizing pathway is activated in in vivo growing tumor tissue, and thereby the produced NO inhibits tumor growth using various murine skin tumor models. Further experiments were designed to test whether tumor infiltrating macrophages are the major source of NO produced by the in vivo growing tumor tissue. Freshly diesociated murine skin tumors were found to have much higher levels of nitric axide secretion into culture medi- um than long-term cultured tumor. Immunomagnetic depletion of macrophages from freshly dissociated tumor cells using anti-Mac-1 antibody decreased NO production(17.5+-1.5 vs 5.0+-1.1 uM nitrite). Addition of the nitric oxide synthase inhibitor N-monomethyl-L-arginine(MLA) resulted in a dose-dependent decrease in nitric oxide synthesis in freshly dissociated tumor. There was a reciprocal relationship of NO synthesis with tritiated thymidine incorporation in these cultures. Strong iron-dithiol-dinitrosyl and heme-nitrosyl electron paramagnetic resonance signals were observed in freshly dissociated, but not long-term cultured tumor cells. Inhibition of NO synthesis using in vivo MLA administration resulted in a trend of increased growth rate of RD-995 murine skin cancer. This study demonstrates the role of macrophage NO synthesis as a host defense against tumor in vivo.
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