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(PP057) Multicellular resistance and HPRT mutation in the tumor microenvironment.
Banath, Judit*,1, MacPhail, Susan1, Larrivee, Bruno1, Olive, Peggy1, 1 Medical Biophysics Dept., Vancouver, BC, Canada
ABSTRACT- Introduction: A Chinese hamster V79 tumor model was developed to determine whether cells subjected to a hypoxic tumour microenvironment would be more likely to undergo mutation at the HPRT locus. Results: V79-171b cells were stably transfected with both VEGF and EGFP and grown subcutaneously in immunodeficient NOD/SCID mice. V79-VE tumours were characterized for host cell infiltration, doubling time, hypoxic fraction, vascular perfusion, and response to ionizing radiation. When irradiated in vitro, the mutant frequency for a given surviving fraction was not significantly different for cells grown in vivo or in vitro. Similar results were obtained using HCT116 human colorectal carcinoma cells grown as xenografts. However, V79-VE cells grown as xenografts were significantly more resistant to killing than monolayers. The background mutant frequency and the radiation-induced mutant frequency were not significantly different for cells close to or distant from blood vessels. In addition, cells from well-perfused tumour regions showed the same rate of strand break rejoining and the same rate of loss of phosphorylated histone H2AX as cells sorted from poorly perfused regions. Conclusions: Deleterious effects of the tumour microenvironment on DNA repair efficiency or mutation induction could not be demonstrated. Rather, for a given dose of radiation, development of multicellular resistance in V79-VE tumours acted to reduce mutant frequency relative to monolayers.
Key words: HPRT mutation, tumor hypoxia, H2AX
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