Relationship between O-6-methylguanine-DNA methyltransferase levels and clinical response induced by chloroethylnitrosourea therapy in glioma patients

Background: Adjuvant nitrosourea chemotherapy fails to prolong survival sig nificantly as many tumors demonstrate resistance to these drugs. It has bee n documented in cell lines that O-6-methylguanine DNA methyltransferase (MG MT) plays an important role in chloroethylnitrosourea (CENU) drug resistanc e. Methods: We evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence assay and compared the results with clinical responses of the patients to CENU-based chemotherapy. Results: Eight tumor samples ha d no detectable MGMT, whereas other samples had from 9,989 to 982,401 molec ules/nucleus. In one group (12 patients), the tumor decreased in size or wa s stable (effective group), whereas in the other group (10 patients), the t umor demonstrated continuous growth during chemotherapy (progressive group) . The Mer(-) patients (MGMT < 60,000 molecules/nucleus) appeared to have mo re chance of stable disease or response to CENU therapy than the Mer(+) pat ients (MGMT > 60,000 molecules/nucleus) (X-2 = 4.791, p = 0.0286). In patie nts with glioblastomas multiforme (GBMs), the median time to progression (T TP) of Mer(+) patient was shorter than that of Mer patient (t = 2.04, p = 0 .039). As a corollary, the MGMT levels were significantly higher in GEM tur ners from the progressive group than those from the effective group (t = 2. 26, p = 0.029). However, there was no significant correlation between MGMT levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.10 7, p = 0.6344). Conclusion: This study suggests that being MGMT positive is indicative of a more aggressive disease that progresses more rapidly with CENU therapy. However, MGMT negative tumors are not always sensitive to CEN U agents, suggesting that other factors are also important.