DETERMINANTS OF O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY IN HUMAN COLON-CANCER

The DNA repair protein O-6-alkylguanine-DNA alkyltransferase (alkyltra nsferase) repairs cytotoxic DNA O-6-alkylguanine adducts induced by th e nitrosoureas, triazines, and tetrazines, In this study, we determine d whether there was a relationship between alkyltransferase activity i n colon cancer and that of adjacent normal mucosa, and whether there w ere demographic patient characteristics which correlated with alkyltra nsferase expression in either tissue, Alkyltransferase activity and ex pression of the alkyltransferase gene, MGMT, were measured in 49 paire d primary colon cancer samples and adjacent normal appearing mucosa, A lkyltransferase activity was found in all samples, The mean activity w as higher in the tumor than the mucosa (r = 0.374, P < 0.01), although the low correlation coefficient suggested that multiple factors influ ence the alkyltransferase activity, MGMT mRNA could also be detected i n all samples and was highly correlated with alkyltransferase activity (r = 0.64, P < 0.001), No correlation was found between alkyltransfer ase activity and age, or gender of the patient, or location of the tum or, although activity tended to be higher in patients with lower stage disease, Thus, alkyltransferase activity is present in most, if not a ll, colon cancer samples, suggesting that it could play an important r ole in chemotherapeutic resistance of human colon cancer. Patients wit h colon cancer would appear to be prime candidates for studies utilizi ng O-6-benzylguanine to deplete alkyltransferase prior to therapy with a nitrosourea, triazine, or tetrazine.