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R.A. Yee

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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-003 - Synergetic study of chemotherapeutic drugs according to ATM status in NSCLC cell lines (ID 3441)

      09:30 - 16:30  |  Author(s): R.A. Yee

      • Abstract

      The ataxia telangiectasia mutated (ATM) gene produces a protein essential in mechanisms responsible for regulating the controlled growth and proliferation of cells, as well as the DNA damage response. The lack of ATM expression can lead to a predisposition to cancer due to the inability for the protein to actively respond to DNA damage. Previous work in the Bebb lab has shown that the lack of ATM gene expression in non-small cell lung cancer (NSCLC) cells increases sensitivity to ionizing radiation, however little is known about whether ATM status can influence sensitivity to commonly used chemotherapeutic agents. In this study we will explore the chemosensitivity of NSCLC cells in relation to their ATM status, as well as the synergistic effects of combining multiple agents to help develop new treatment strategies for patients with low or absent ATM expression.

      Several NSCLC cell lines were screened to identify the ATM and p53 status. Of the cell lines screened, four NSCLC cell lines: NCI-H460, NCI-H226, NCI-H23, and NCI-H1395 were chosen to treat with various chemotherapeutic agents. Optimization of cell proliferation for each cell line was conducted to determine the appropriate concentration of cells that allows for continued proliferation after a 72 hour period. Each of the agents used for cytotoxicity assays target a different mechanism of the cell, including topoisomerase I inhibitors, DNA damaging and alkylating agents, and mitotic and cell cycle inhibitors. The Chou-Talalay method for drug combinations was utilized as the combination index theorem provides a quantitative definition for examining additive, synergistic and antagonistic effects with our primary focus of observing synergy.

      Several NSCLC cell lines were characterized for their ATM status, and four were selected for cytotoxicity assays: H460 and H226 (ATM normal), and H23 and H1395 (ATM deficient). We observed a noticeable difference in growth rate between cell lines in addition to the differences in ATM and p53 status. Similarly, the cytotoxic response to the chemotherapeutic agents varied greatly, and the relationship of drug sensitivity to ATM status in the cells, as well as the synergistic response to combinational therapy will be presented and discussed.

      The results of this study have several important implications. Our previous work has shown that resected, early stage NSCLC patients with low ATM expression have worse overall survival, however our demonstration that ATM deficient cell lines are more sensitive to cancer therapy could indicate that these same patients would respond better to certain lines of treatment. Similarly, increased sensitivity to combinational therapy will help mitigate detrimental side effects, leading to better quality of life during treatment periods.