O6-Methylguanine-DNA methyltransferase activity in human liver tumors

Abstract

Previous studies have shown that in about one-fifth of human tumor cell strains, the activity of O6-methylguanine-DNA methyltransferase (MGMT), which can repair O6-alkylguanine in DNA produced by alkylating agents, is deficient. These strains are termed Mer- cells. To see if there is any human tumor lacking MGMT activity, we measured the MGMT activity in extracts from liver tumors of 21 patients, and compared it to the activity in normal peritumoral tissues derived from the same patients. The MGMT activity was assayed by measuring the 3H radioactivity transferred from the substrate DNA containing [methyl-3H]-labeled O6-methylguanine to an acid-insoluble protein fraction. There was considerable variation in MGMT activity among individual extracts; the interindividual variation was approximately 6-fold in normal liver tissue and much larger in liver tumors. Although in many cases similar high levels of MGMT activity were found both in liver tumors and in the normal counterpart, six tumors had greater than 3-fold less activity compared with the normal liver tissue from the same patient. Liver tumors from two patients did not have any detectable level of MGMT activity by the present method used, in spite of the fact that the corresponding normal liver samples demonstrated significant activities. We also measured in the same tissue extracts the activities of two common enzymes, glutamic pyruvic transaminase (GPT) and lactic dehydrogenase (LDH). The activities of GPT and LDH in the liver tumor samples that showed undetectable levels of MGMT activity were similar to those in the surrounding normal liver tissues. These results may suggest the existence of human Mer- tumors, deficient or very low MGMT activity.