Relationship between O6-methylguanine-DNA methyltransferase levels and clinical response induced by chloroethylnitrosourea therapy in glioma patients.
BACKGROUND
Adjuvant nitrosourea chemotherapy fails to prolong 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.


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 had no detectable MGMT, whereas other samples had from 9,989 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 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) (X2 = 4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the median time to progression (TTP) of Mer+ patient was shorter than that of Mer- patient (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). 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).


CONCLUSIONS
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 CENU agents, suggesting that other factors are also important.
Chen
Z P
ZP
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec.
Yarosh
D
D
Garcia
Y
Y
Tampieri
D
D
Mohr
G
G
Malapetsa
A
A
Langleben
A
A
Panasci
L C
LC
D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015254:DNA Modification Methylases / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009603:Nitroso Compounds / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000970:Antineoplastic Agents; D009603:Nitroso Compounds; D006147:Guanine; C041148:N-(2-chloroethyl)-N-nitrosoacetamide; C008449:O-(6)-methylguanine; D015254:DNA Modification Methylases