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Differential Expression of Drug Resistance Genes and Chemosensitivity in Glial Cell Lineages Correlate with Differential Response of Oligodendrogliomas and Astrocytomas to Chemotherapy¹

Departments of Oncology [C. L. N., A. F. C., J. G. C.], Pathology [C. L. N., A. F. C., J. G. C.], and Clinical Neurological Sciences [J. G. C.], University of Western Ontario, and London Regional Cancer Centre [C. L. N., A. F. C., J. G. C.], London, Ontario, Canada N6A 4L6, and Huntsman Cancer Institute, Salt Lake City, Utah 84112 [M. N.]

The two principal subtypes of glial neoplasms, astrocytomas and oligodendrogliomas, exhibit striking differences in response to chemotherapy. This differential chemosensitivity might be explained by the specific genetic alterations causing gliomas but could also be attributable to specific properties intrinsic to the cells from which gliomas arise. To examine the possibility that chemosensitivity might be associated with lineage-specific properties of potential ancestors of these tumors, we explored: (a) the expression of drug resistance genes in rat glial cells; (b) the sensitivity of rat glial subtypes to the bifunctional alkylating agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU); and (c) the effect of O⁶-methylguanine-DNA methyltransferase (MGMT) and glutathione modulation on resistance to BCNU. Astrocytes, O-2A progenitors, and oligodendrocytes each displayed a unique pattern of expression of six drug resistance genes: MGMT, GST µ, GST , p53, MDR, and MT. Oligodendrocytes were more sensitive to BCNU than either astrocytes or O-2A progenitors. The increased resistance of astrocytes in comparison to oligodendrocytes was modulated, at least in part, by both O⁶-benzylguanine (BG) and DL-buthionine-(S,R)-sulfoximine, suggesting a role for both MGMT and glutathione in the resistance of astrocytes to BCNU. The sensitivity of O-2A progenitors to BCNU following BG pretreatment is virtually indistinguishable from that of oligodendrocytes depleted of MGMT, suggesting that the down-regulation of MGMT is sufficient to account for the increased sensitivity of oligodendrocyte lineage cells to BCNU as they differentiate. These experiments provide support for the hypothesis that properties of glial cells retained in gliomas may contribute to the differential chemosensitivity of glial neoplasms.

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