Modulation of novel DNA adducts during human uterine cervix cancer progression.
Progressive accumulation of DNA lesions leads to genetic mutations that are central to the process of tumorigenesis. Human cervix provides an ideal system to determine progressive accumulation of DNA adducts in the target tissue because of its accessibility during routine diagnostic checkups. Uterine cervix samples from various pathologies, i.e. normal (n=13), inflammation (n=9), dysplasia (n=5) and different stages of invasive cancer (n=47), were analyzed for DNA adduct burden by modified 32P-postlabeling/TLC systems. Six subgroups of adducts were detected in the following descending order of polarities: P-1, P-2, PL-1, PL-2, L-1 and L-2 (P, polar; L, lipophilic; PL, between polar and lipophilic). No qualitative differences were observed in adduct profiles in the various cervix pathologies analyzed. However, significant quantitative differences were found. Previously known lipophilic adducts increased significantly from normal to cancer (144+/-61 to 503+/-51 adducts/10(9) nucleotides). Interestingly, the newly discovered polar adducts were present at 61- to 527-fold higher levels than lipophilic adducts. Of all the polar adducts, the known mutagenic lesion, 8-oxodeoxyguanosine, predominated in all cervix conditions. Notably, this lesion was elevated 27-fold in inflammation compared with normal cervix (51,058+/-9,863 versus 1,886+/-507 adducts/10(9) nucleotides). The P-1, PL-1, PL-2 and L-1 adducts were elevated 3- to 13-fold in inflammation compared with normal cervix, and were also higher in dysplasia and cancer. Our data suggest that inflammation may be involved in directing the course of disease progression by accumulating higher levels of DNA lesions. The data further suggest the biomarker potential of the newly detected array of DNA adducts.
Ravoori
Srivani
S
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Vadhanam
Manicka V
MV
Davey
Diane D
DD
Srinivasan
Cidambi
C
Nagarajan
Bala
B
Gupta
Ramesh C
RC
D002855:Chromatography, Thin Layer / Q000379:methods; D018736:DNA Adducts / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D018736:DNA Adducts; D004273:DNA, Neoplasm; D017382:Reactive Oxygen Species