Determinants of O6-alkylguanine-DNA alkyltransferase activity in human colon cancer.
The DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) repairs cytotoxic DNA O6-alkylguanine adducts induced by the nitrosoureas, triazines, and tetrazines. In this study, we determined whether there was a relationship between alkyltransferase activity in colon cancer and that of adjacent normal mucosa, and whether there were demographic patient characteristics which correlated with alkyltransferase expression in either tissue. Alkyltransferase activity and expression of the alkyltransferase gene, MGMT, were measured in 49 paired primary colon cancer samples and adjacent normal appearing mucosa. Alkyltransferase activity was found in all samples. The mean activity was higher in the tumor than the mucosa (r = 0.374, P < 0. 01), although the low correlation coefficient suggested that multiple factors influence the alkyltransferase activity. MGMT mRNA could also be detected in all samples and was highly correlated with alkyltransferase activity (r = 0.64, P < 0.001). No correlation was found between alkyltransferase activity and age, or gender of the patient, or location of the tumor, although activity tended to be higher in patients with lower stage disease. Thus, alkyltransferase activity is present in most, if not all, colon cancer samples, suggesting that it could play an important role in chemotherapeutic resistance of human colon cancer. Patients with colon cancer would appear to be prime candidates for studies utilizing O6-benzylguanine to deplete alkyltransferase prior to therapy with a nitrosourea, triazine, or tetrazine.
Gerson
S L
SL
Department of Medicine and The Cancer Center, BRB-3, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4937, USA.
Allay
E
E
Vitantonio
K
K
Dumenco
L L
LL
D003106:Colon / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology*; D007700:Kinetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic
D012333:RNA, Messenger; D019853:O(6)-Methylguanine-DNA Methyltransferase