Sunday, October 16, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP085) Synergistic effect in presence of 17AAG followed by X—ray radiation exposure in human lymphoblastoid cells.

Tsai, Mong-Hsun*,1, 3, Tseng, Jennifer2, Chuang, Eric1, 3, 4, 1 Center for Genomic Medicine, Taipei, Taiwan, Taiwan3 Radiation Oncology Science Program/ Center for Cancer Research, Bethesda, MD, US2 Molecular, Cellular and Developmental Biology Department, Ann Arbor, MI, US4 Department of Electrical Engineering, Taipei, Taiwan, Taiwan

ABSTRACT- 17AAG, an anticancer agent which is currently in clinical trial I/ II, is recently proven to have enhanced radiosensitization in killing tumor cells. Here we hypothesize that cells treated with 17AAG prior to ionizing radiation (IR) will enhance radiation-induced mutagenesis. In addition, since the p53 protein has been implicated in multiple cellular responses related to DNA damage, our previous studies showed that cells with different p53 status exhibit different responses to IR induced mutagenesis. Therefore, in this study we use two closely-related cell lines differed in their p53 status to explore whether p53 play a role in the combined treatment of 17AAG and IR. Human lymphoblast cell lines, TK6 (wild -type p53) and NH32 (p53-null), were used to analyze the survival and mutation after exposed to 17AAG with or without 2Gy IR. TK- mutants after treatments were also isolated for molecular analysis of mutational spectrum by loss of heterozygosity (LOH) analysis. Our preliminary data indicate that both TK6 and NH32 after 17AAG+IR treatment showed synergistic effect of induced mutations at the TK locus compared to 17AAG or IR alone. However, NH32 was more mutable than TK6, which suggests p53 might play a role. Molecular analysis revealed that there was higher degree of similarity in the mutational spectra of the TK- mutants isolated from TK6 or NH32 after IR or 17AAG+IR treatments; whereas the TK- mutants isolated from 17AAG treatment exhibited different mutational spectra between TK6 and NH32. Currently, we are still surveying more TK- mutants to examine with LOH analysis.

Key words: 17-AAG, Radiation, Synergistic

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2005 RRS