DNA base modifications in chromatin of human cancerous tissues.
Free radical-induced damage to DNA in vivo is implicated to play a role in carcinogenesis. Evidence exists that DNA damage by endogenous free radicals occurs in vivo, and there is a steady-state level of free radical-modified bases in cellular DNA. We have investigated endogenous levels of typical free radical-induced DNA base modifications in chromatin of various human cancerous tissues and their cancer-free surrounding tissues. Five different types of surgically removed tissues were used, namely colon, stomach, ovary, brain and lung tissues. In chromatin samples isolated from these tissues, five pyrimidine-derived and six purine-derived modified DNA bases were identified and quantitated by gas chromatography/mass spectrometry with selected-ion monitoring. These were 5-hydroxy-5-methylhydantoin, 5-hydroxyhydantoin, 5-(hydroxymethyl)uracil, 5-hydroxycytosine, 5,6-dihydroxycytosine, 4,6-diamino-5-formamidopyrimidine, 8-hydroxyadenine, xanthine, 2-hydroxyadenine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 8-hydroxyguanine. These compounds are known to be formed typically by hydroxyl radical attack on DNA bases. In all cases, elevated amounts over control levels of modified DNA bases were found in cancerous tissues. The amounts of modified bases depended on the tissue type. Lung tissues removed from smokers had the highest increases of modified bases above the control levels, and the highest overall amounts. Colon cancer tissue samples had the lowest increases of modified bases over the control levels. The results clearly indicate higher steady-state levels of modified DNA bases in cancerous tissues than in their cancer-free surrounding tissues. Some of these lesions are known to be promutagenic, although others have not been investigated for their mutagenicity. Identified DNA lesions may play a causative role in carcinogenesis.
Olinski
R
R
Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, MD 20899.
Zastawny
T
T
Budzbon
J
J
Skokowski
J
J
Zegarski
W
W
Dizdaroglu
M
M
D002843:Chromatin / Q000737:chemistry*; D002845:Chromatography; D004249:DNA Damage / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry*; D005609:Free Radicals; D006801:Humans; D006878:Hydroxides; D017665:Hydroxyl Radical; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D011687:Purines; D011743:Pyrimidines
D002843:Chromatin; D004273:DNA, Neoplasm; D005609:Free Radicals; D006878:Hydroxides; D011687:Purines; D011743:Pyrimidines; D017665:Hydroxyl Radical