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Mutagenic Specificity of Oxygen Radicals Produced by Human Leukemia Cells¹

Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195

An important source of endogenous oxygen radicals are phagocytic cells such as neutrophils and macrophages. The human leukemia cell line HL-60 can be induced to differentiate into a neutrophil-like cell population. Among the properties of these differentiated cells is the ability to produce reactive oxygen species when stimulated by tumor promoters. Mutagenesis induced by HL-60-generated free radicals was assessed using the M13mp2 forward mutation assay. Single-stranded M13mp2 DNA was coincubated with phorbol ester-stimulated HL-60 cells, after which mutations were scored by transfecting the DNA into SOS-induced Escherichia coli. The mutation frequency was increased 6-fold above background in DNA incubated with HL-60 cells. The majority of the mutations were single-base substitutions. However, approximately 6% of the mutations were tandem double substitutions that occurred in runs of adjacent cytidines. Overall, the mutations were clustered at apparent "hot spots," many of which were similar to sites seen using iron to generate oxygen radicals. These results suggest that human cells able to produce oxygen radicals in response to tumor promoters might play a significant role in the generation of tumors.

¹ These studies were supported by NIH Grants F32-CA-08855 to T. M. R. and R35-CA-39903 and AG-00057 to L. A. L.

² To whom requests for reprints should be addressed, at University of Washington, Department of Pathology SM-30, Seattle, WA 98195.

Received 9/17/91. Accepted 12/13/91.

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