O6-methylguanine-DNA methyltransferase in tumors and cells of the oligodendrocyte lineage.
BACKGROUND
Oligodendrogliomas respond to nitrosourea-based chemotherapy and are induced in rats following transplacental exposure to ethylnitrosourea, observations suggesting that neoplastic and normal cells of the oligodendrocyte lineage are "sensitive" to nitrosoureas. Nitrosoureas alkylate DNA at O6-guanine with repair mediated by O6-methylguanine-DNA methyltransferase (MGMT). The cytotoxic and carcinogenic properties of the nitrosoureas appear related to MGMT activity.


METHODS
To explore why oligodendrogliomas respond to chemotherapy, we measured MGMT activity in five chemosensitive human oligodendrogliomas and in rat oligodendrocyte lineage cells. We also measured MGMT activity in rat astrocytes and compared the cytotoxic effects of carmustine (BCNU) on oligodendrocyte lineage cells and astrocytes.


RESULTS
Low levels of MGMT activity were found in five of five human oligodendrogliomas. Cultures of neonatal rat glia enriched for oligodendrocyte lineage cells also had low levels of MGMT activity, approximately one-third that found in astrocytes (p < 0.02), and oligodendrocyte lineage cells were more sensitive to BCNU than astrocytes.


CONCLUSIONS
Low MGMT activity may contribute to the chemosensitivity of some human oligodendrogliomas and rat oligodendrocyte lineage cells also have low levels. If drug resistance mechanisms in tumors reflect the biochemical properties of their cells of origin, then normal glia may serve as a laboratory substitute for human glioma.
Nutt
C L
CL
Department of Oncology, University of Western Ontario, London, Canada.
Costello
J F
JF
Bambrick
L L
LL
Yarosh
D B
DB
Swinnen
L J
LJ
Chambers
A F
AF
Cairncross
J G
JG
D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000201:enzymology*; D002330:Carmustine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005910:Glioma / Q000000981:diagnostic imaging / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase; D009836:Oligodendroglia / Q000201:enzymology*; D051381:Rats; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured
D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine