Reduced O6-methylguanine repair in fibroblast cultures from patients with lung cancer.
The activity of O6-methylguanine-DNA methyltransferase was determined in fibroblast cultures from 45 patients with lung cancer, 39 patients with cutaneous malignant melanoma, and 29 healthy controls. This enzyme is a critical parameter for the capacity to repair O6-methylguanine (O6-mGua) adducts in DNA, and a decreased activity might therefore be responsible for an enhanced susceptibility to cancer. The assay was performed with 8 x 10(6) fibroblasts which were homogenized and incubated with a known amount of O6-mGua containing DNA. The remaining substrate was determined fluorimetrically after high performance liquid chromatographic separation. O6-mGua repair was significantly reduced in lung cancer patients [6.64 +/- 4.32 (SD) pmol O6-methylguanine repaired/8 x 10(6) cells] as compared to healthy controls [10.35 +/- 5.42, P less than 0.0022] or patients with cutaneous malignant melanoma [10.83 +/- 6.66]. The lowest mean values were detected in a subgroup of 16 lung cancer patients with a tumor manifestation below 46 years of age (5.06 +/- 3.89). Fibroblasts from 4 patients with lung cancer had no detectable repair. We conclude that a reduced capacity to remove O6-mGua adducts may represent a further mechanism of individually enhanced lung cancer risk.
Rüdiger
H W
HW
Department of Occupational Health, University of Hamburg, Federal Republic of Germany.
Schwartz
U
U
Serrand
E
E
Stief
M
M
Krause
T
T
Nowak
D
D
Doerjer
G
G
Lehnert
G
G
D000328:Adult; D000368:Aged; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004260:DNA Repair; D005260:Female; D005347:Fibroblasts; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase
D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase