Clinical response of O6-methylguanine-DNA methyltransferase levels to 1,3-(2-chloroethyl)-1-nitrosourea chemotherapy in glioma patients

Abstract

Adjuvant nitrosourea chemotherapy fails to prolong patient survival significantly as many tumors demonstrate resistance to these drugs. It has been documented in cell lines that O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in chloroethylnitrosourea (CENU) drug resistance. The authors evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence assay and compared the results with clinical response of the patients to CENU-based chemotherapy. The patients were treated with CENU after evidence of progressive disease following surgery and radiotherapy. Eight tumor samples had no detectable MGMT, whereas other samples had from 9989 to 982,401 molecules/nucleus. In one group (12 patients), the tumor decreased in size or was stable (effective group), whereas in the other group (10 patients), the tumor demonstrated continuous growth during chemotherapy (progressive group). The median time to progression (TTP) was 6.7 months with a median survival of 13 months. The Mer− patients (MGMT < 60,000 molecules/nucleus) appeared to have more chance of stable disease or response to CENU therapy than the Mer+ patients (MGMT > 60,000 molecules/nucleus) (chi-square = 4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the TTP of Mer+ patients was shorter than that of Mer− patients (t = 2.04, p = 0.049). As a corollary, the MGMT levels were significantly higher in GBM tumors from the progressive group than those from the effective group (t = -2.26, p = 0.029). The TTP and survival time in the effective GBM group were also longer than those in the progressive GBM group. However, there was no significant correlation between MGMT levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.107, p = 0.6444). Results from this study suggested that MGMT positivity is indicative of more aggressive disease that progresses more rapidly when exposed to CENU therapy. However, MGMT-negative tumors are not always sensitive to CENU agents, suggesting that other factors may also be important.