title: Evidence for upregulated repair of oxidatively induced DNA damage in human colorectal cancer.
abstract: Carcinogenesis may involve overproduction of oxygen-derived species including free radicals, which are capable of damaging DNA and other biomolecules in vivo. Increased DNA damage contributes to genetic instability and promote the development of malignancy. We hypothesized that the repair of oxidatively induced DNA base damage may be modulated in colorectal malignant tumors, resulting in lower levels of DNA base lesions than in surrounding pathologically normal tissues. To test this hypothesis, we investigated oxidatively induced DNA damage in cancerous tissues and their surrounding normal tissues of patients with colorectal cancer. The levels of oxidatively induced DNA lesions such as 4,6-diamino-5-formamidopyrimidine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 8-hydroxyguanine and (5'S)-8,5'-cyclo-2'-deoxyadenosine were measured by gas chromatography/isotope-dilution mass spectrometry and liquid chromatography/isotope-dilution tandem mass spectrometry. We found that the levels of these DNA lesions were significantly lower in cancerous colorectal tissues than those in surrounding non-cancerous tissues. In addition, the level of DNA lesions varied between colon and rectum tissues, being lower in the former than in the latter. The results strongly suggest upregulation of DNA repair in malignant colorectal tumors that may contribute to the resistance to therapeutic agents affecting the disease outcome and patient survival. The type of DNA base lesions identified in this work suggests the upregulation of both base excision and nucleotide excision pathways. Development of DNA repair inhibitors targeting both repair pathways may be considered for selective killing of malignant tumors in colorectal cancer.
authors.affiliation: Department of Biochemistry, School of Medicine, Dokuz Eylul University, Inciralti, 35340 Izmir, Turkey. gkirkali@gmail.com
authors.forename: Güldal
authors.initials: G
authors.lastname: Kirkali
authors.forename: Didem
authors.initials: D
authors.lastname: Keles
authors.forename: Aras E
authors.initials: AE
authors.lastname: Canda
authors.forename: Cem
authors.initials: C
authors.lastname: Terzi
authors.forename: Prasad T
authors.initials: PT
authors.lastname: Reddy
authors.forename: Pawel
authors.initials: P
authors.lastname: Jaruga
authors.forename: Miral
authors.initials: M
authors.lastname: Dizdaroglu
authors.forename: Gülgün
authors.initials: G
authors.lastname: Oktay
mesh_terms: D000328:Adult; D000368:Aged; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D003839:Deoxyadenosines / Q000032:analysis / Q000737:chemistry; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis / Q000737:chemistry; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000032:analysis / Q000737:chemistry; D015854:Up-Regulation
chemical_list: D003839:Deoxyadenosines; D011743:Pyrimidines; C056752:8,5'-cyclo-2'-deoxyadenosine; C071023:2,6-diamino-4-hydroxy-5-formamidopyrimidine; C039544:4,6-diamino-5-N-formamidopyrimidine; C024829:8-hydroxyguanine; D006147:Guanine