O-6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: Frequency and time to tumor progression after alkylating agent-based chemotherapy

The DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) contr ibutes to the resistance of human brain tumor cell lines and xenografts to methylating and chloroethylating agents. We assayed MGMT in 174 newly diagn osed or recurrent gliomas to (a) quantitate changes in MGMT activity associ ated with alkylating agent-based chemotherapy; and (b) assess the contribut ion of MGMT to clinical outcome. Glioma MGMT activity ranged 300-fold, aver aging 3,800 +/- 7,200 molecules/cell. Twenty-four percent of tumors lacked detectable activity [Methyl repair-deficient (Mer(-)) phenotype, defined he re as <151 molecules/cell or <0.25 fmol/10(6) cells]. Tumors treated with s urgery alone and tumors recurring after surgery and radiotherapy did not di ffer significantly in frequency of the Mer(-) phenotype (29% versus 24%), H owever, the frequency of the Mer(-) phenotype among tumors recurring after surgery, radiation, and alkylating agent-based chemotherapy was 7-fold lowe r than in tumors treated with surgery alone (4.3% versus 29%; P less than o r equal to 0.02) and 6-fold lower than in tumors recurring after surgery an d radiation (4.3 % versus 24%; P less than or equal to 0.05), In contrast t o gliomas, there was no relationship of alkylating agent-based therapy with the frequency of the Mer(-) phenotype in paired histologically normal brai n. These data suggest that alkylating agents, either alone or synergistical ly with radiotherapy, selectively kill Mer(-) glioma cells in situ, Importa ntly, Mer(-) and Mer(+) tumors did not differ in time to tumor progression following treatment with alkylating agents, indicating that although Mer(-) glioma cells may be differentially killed by alkylators, factors other tha n Mer phenotype were the principal determinants of time to clinical progres sion, Nonetheless, our results support the possibility that complete ablati on of glioma MGMT with substrate analogue inhibitors could improve the effi cacy of alkylating agent-based chemotherapy.