Differential expression of drug resistance genes and chemosensitivity in glial cell lineages correlate with differential response of oligodendrogliomas and astrocytomas to chemotherapy

The two principal subtypes of glial neoplasms, astrocytomas and oligodendro gliomas, exhibit striking differences in response to chemotherapy. This dif ferential chemosensitivity might be explained by the specific genetic alter ations causing gliomas but could also be attributable to specific propertie s intrinsic to the cells from which gliomas arise. To examine the possibili ty that chemosensitivity might be associated with lineage-specific properti es of potential ancestors of these tumors, we explored: (a) the expression of drug resistance genes in rat glial cells; (b) the sensitivity of rat gli al subtypes to the bifunctional alkylating agent, 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU); and (c) the effect of O-6-methylguanine-DNA methyltrans ferase (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 mu, GST pi, p53, MDR, an d MT. Oligodendrocytes were more sensitive to BCNU than either astrocytes o r O-2A progenitors, The increased resistance of astrocytes in comparison to oligodendrocytes was modulated, at least in part, by both O-6-benzylguanin e (BG) and DL-buthionine-(S,R)-sulfoximine, suggesting a role for both MGMT and glutathione in the resistance of astrocytes to BCNU. The sensitivity o f O-2A progenitors to BCNU following BG pretreatment is virtually indisting uishable from that of oligodendrocytes depleted of MGMT, suggesting that th e down-regulation of MGMT is sufficient to account for the increased sensit ivity of oligodendrocyte lineage cells to BCNU as they differentiate. These experiments provide support for the hypothesis that properties of glial ce lls retained in gliomas may contribute to the differential chemosensitivity of glial neoplasms.