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Persistent Oxidative Stress in Chromosomally Unstable Cells¹

Department of Radiation Oncology, University of California, San Francisco, CA 94103-0806 [C. L. L., E. G.]; Radiation Oncology Research Laboratory and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201-1559 [W. F. M.]; Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 [S. G. S.]; Department of Oncology, University of Leicester, Leicester LE1 7RH, United Kingdom [G. D. D. J.]; and Laboratory for Cell Analysis, Cancer Center, University of California, San Francisco, California 94143-0808 [W. H.]

Past work using the human-hamster hybrid line GM10115 has demonstrated that exposure to a variety of DNA damaging agents can lead to the persistent destabilization of chromosomes. To gain insight into the potential biochemical mechanisms involved in perpetuating the unstable phenotype, groups of clones characterized as stable or unstable were analyzed for indications of oxidative stress. All of the clones were derived from single progenitor cells surviving exposure to ionizing radiation or chemicals. Compared with their stable counterparts, unstable clones possessed elevated levels of reactive oxygen species (ROS) as measured by their enhanced ability to oxidize fluorogenic dyes. Fluorescence automated cell sorting analysis indicated that unstable clones had significantly higher mean fluorescence signals of 2-fold and 1.25-fold, respectively, as derived from the dyes 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and dihydrorhodamine 123, respectively. To determine whether mitochondria might constitute a potential source of ROS, stable and unstable clones of cells were analyzed for mitochondrial content using nonyl acridine orange and function using rhodamine 123. Fluorescence automated cell sorting data indicated that compared with stable clones, unstable clones possessed an elevated number (15% increase in mean nonyl acridine orange fluorescence) of dysfunctional mitochondria (27% decrease in mean rhodamine 123 fluorescence). Interestingly, the consequences of elevated ROS did not translate to an increase in oxidative base damage in nuclear DNA. Analysis of nine different base damage adducts by gas chromatography/mass spectrometry did not reveal significant differences between stable and unstable clones. The data suggest that the perpetuation of many of the abnormal phenotypes associated with genomic instability may be linked to a state of chronic oxidative stress derived in part from dysfunctional mitochondria.

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