Human brain tumor O(6)-methylguanine-DNA methyltransferase mRNA and its significance as an indicator of selective chloroethylnitrosourea chemotherapy.
O(6)-methylguanine-DNA methyltransferase (MGMT) removes and repairs chloroethylnitrosourea (CENU)-induced O(6)-methylguanine-DNA by accepting the alkyl group at a cysteine moiety. MGMT activity is, therefore, predictive of resistance or sensitivity to CENU chemotherapy. We measured the levels of MGMT mRNA expression in human brain tumors using a reverse transcription-polymerase chain reaction (RT-PCR) method, and studied the significance of MGMT mRNA levels in CENU chemotherapy. The level of MGMT mRNA was represented as a percentage relative to the MGMT mRNA in U138MG brain tumor cells. Forty-three patients with brain tumors were entered into the study. High-grade gliomas had significantly lower levels of MGMT mRNA than did low-grade gliomas and non-glial tumors (p < 0.05 determined by analysis of covariance). Out of 14 high-grade gliomas, 4 had a level of MGMT mRNA below 10%, indicating chemosensitivity to CENU. Out of 11 patients who received CENU chemotherapy, 3 had a partial response. All 3 responders had a low level of MGMT mRNA. The time to tumor progression (TTP) for 6 patients with a level lower than the median was short, but significantly longer than the TTP for 5 patients with a higher level (p < 0.05 determined by Gehan's Wilcoxon test). These results indicate that a fraction of brain tumors have a low expression of MGMT mRNA, and that the level of MGMT mRNA is a useful indicator of effectiveness in selective CENU chemotherapy.
Mineura
K
K
Neurosurgical Service, Akita University Hospital, Japan. mineura@med.akita-u.ac.jp
Yanagisawa
T
T
Watanabe
K
K
Kowada
M
M
Yasui
N
N
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D015415:Biomarkers; D001932:Brain Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism*; D002330:Carmustine / Q000627:therapeutic use*; D004260:DNA Repair; D005910:Glioma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008579:Meningioma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D008780:Methyltransferases / Q000032:analysis / Q000378:metabolism*; D009442:Neurilemmoma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010911:Pituitary Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis*
D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D012333:RNA, Messenger; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine