title: Stimulated human leukocytes cause activating mutations in the K-ras protooncogene.
abstract: Human tissues which are chronically infiltrated with inflammatory leukocytes are more likely to develop malignancies than non-inflamed tissues, however the mechanism(s) by which leukocytes contribute to carcinogenesis is unknown. Stimulated human leukocytes release superoxide anion and hydrogen peroxide which, in the presence of iron, can be converted into the potent oxidant, hydroxyl radical (.OH). Previous studies have shown that leukocyte-derived .OH (or a .OH-like species) can cause DNA damage, however a relationship between leukocyte-induced DNA damage and carcinogenesis has not been established. The present report demonstrates that leukocyte-derived .OH-induced DNA damage can cause K-ras oncogene activation, and suggests that there may be a characteristic pattern of .OH-induced K-ras oncogene activation. Since activation of the K-ras oncogene is believed to play a crucial role in the pathogenesis of many human malignancies, .OH-induced K-ras oncogene activation could be an important mechanism by which human leukocytes contribute to carcinogenesis.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Jackson
authors.forename: M
authors.initials: M
authors.lastname: Vollenweider
authors.forename: J
authors.initials: J
authors.lastname: Hill
authors.forename: H
authors.initials: H
authors.lastname: Rodriguez
authors.forename: A W
authors.initials: AW
authors.lastname: Schwabacher
authors.forename: G
authors.initials: G
authors.lastname: Mitra
authors.forename: C Y
authors.initials: CY
authors.lastname: Kuo
mesh_terms: D016475:3T3 Cells; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D017665:Hydroxyl Radical; D007962:Leukocytes / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D014162:Transfection; D014969:Xanthine Oxidase / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D011687:Purines; D017665:Hydroxyl Radical; D000080242:8-Hydroxy-2'-Deoxyguanosine; D014969:Xanthine Oxidase; D018631:ras Proteins; D003849:Deoxyguanosine