O6-Methylguanine-DNA Methyltransferase in Tumors
and Cells of the Oligodendrocyte Lineage
Catherine L Nutt, Joseph F Costello, Linda L Bambrick, Daniel
B Yarosh, Lode J Swinnen, Ann F Chambers and J Gregory Cairncross
Abstract:
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.
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Can.
J. Neurol. Sci. 1995; 22: 111-115
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