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- Antitumor Activity of Oxaliplatin, 5-FU and Paclitaxel Given Alone or in Combination with ZD1839 in Human Gastric Carcinoma Cells in vitro
- Ji Hyun Jang, Sang Hak Lee, Jin Hyoung Kang, Hee Sik Sun, Kazuto Nishio, Nagahiro Saijo, Hyo Jeong Kuh
- Cancer Res Treat. 2002;34(5):372-381. Published online October 31, 2002
- DOI: https://doi.org/10.4143/crt.2002.34.5.372
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Abstract
PDF - PURPOSE
Oxaliplatin (LOHP), 5-FU, and paclitaxel (PTX) are considered highly active against advanced gastric carcinomas, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, ZD1839 is considered as a good candidate for the treatment of gastric cancers when given alone or in combination with cytotoxic agents. The present study evaluated the antitumor effects of these agents in SNU-1 human gastric cancer cells either alone or when given as a doublet (i.e., as a cytotoxic-cytostatic combination).
MATERIALS AND METHODS
We selected SNU-1 cells that showed DNA mismatch repair (MMR) deficiency and EGFR overexpression. Growth inhibition was measured by MTT and by direct cell counting and cell cycle distribution by flow cytometry. The combination index (CI) was used to describe synergistic interaction.
RESULTS
The four drugs showed IC50s ranging from 1.81 nM to 13.2microM. MTT assay appeared to underestimate the cytotoxicity of PTX, which was attributed to a significant resistant fraction (32%). LOHP and PTX induced G2/M arrest, 5-FU increased in S phase, and ZD1839 in-creased in G1 in a concentration dependent manner. PTX ZD1839 showed the greatest synergism and LOHP ZD1839 showed a similar result. The cell cycle effect of PTX was potentiated by the coadministration of ZD1839. A previously developed cytostatic TPi model was used to assess the contribution of cell cycle arrest to overall growth inhibition, and 64% and 80% of the overall growth inhibition was attributed to cell cycle arrest for LOHP and PTX, when exposed to 7.55microM and 10 nM for 72 hr, respectively.
CONCLUSION
This study demonstrates the antitumor activity and significant cell cycle arrest effect of ZD1839 against human gastric carcinoma cells and its synergistic interaction with LOHP and PTX. These results provide a preclinical rationale for the clinical development of ZD1839 and its use in combination with LOHP or PTX against human gastric cancers that express EGFR. -
Citations
Citations to this article as recorded by
- An efficient and flexible framework for inferring global sensitivity of agent-based model parameters
Daniel R. Bergman, Trachette Jackson, Harsh Vardhan Jain, Kerri-Ann Norton, Nicholas Geard
PLOS Computational Biology.2025; 21(9): e1013427. CrossRef - Connecting Agent-Based Models with High-Dimensional Parameter Spaces to Multidimensional Data Using SMoRe ParS: A Surrogate Modeling Approach
Daniel R. Bergman, Kerri-Ann Norton, Harsh Vardhan Jain, Trachette Jackson
Bulletin of Mathematical Biology.2024;[Epub] CrossRef - A confidence building exercise in data and identifiability: Modeling cancer chemotherapy as a case study
Marisa C. Eisenberg, Harsh V. Jain
Journal of Theoretical Biology.2017; 431: 63. CrossRef
- An efficient and flexible framework for inferring global sensitivity of agent-based model parameters
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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.
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Abstract
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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