O-6-METHYLGUANINE-DNA METHYLTRANSFERASE IN TUMORS AND CELLS OF THE OLIGODENDROCYTE LINEAGE

Background: Oligodendrogliomas respond to nitrosourea-based chemothera py and are induced in rats following transplacental exposure to ethyln itrosourea, observations suggesting that neoplastic and normal cells o f the oligodendrocyte lineage are ''sensitive'' to nitrosoureas. Nitro soureas alkylate DNA at O-6-guanine with repair mediated by O-6-methyl guanine-DNA methyltransferase (MGMT). The cytotoxic and carcinogenic p roperties of the nitrosoureas appear related to MGMT activity. Methods : To explore why oligodendrogliomas respond to chemotherapy, we measur ed MGMT activity in five chemosensitive human oligodendrogliomas and i n 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 ce lls also had low levels of MGMT activity, approximately one-third that found in astrocytes (p < 0.02), and oligodendrocyte lineage cells wer e more sensitive to BCNU than astrocytes. Conclusions: Low MGMT activi ty may contribute to the chemosensitivity of some human oligodendrogli omas and rat oligodendrocyte lineage cells also have low levels. If dr ug resistance mechanisms in tumors reflect the biochemical properties of their cells of origin, then normal glia may serve as a laboratory s ubstitute for human glioma.