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Role of 06-Methylguanine-DNA Methyltransferase in Resistance of Human Brain Tumor Cell Lines to the Clinically Relevant Methylating Agents Temozolomide and Streptozotocin1

We have analyzed the sensitivity of 14 human medulloblastoma- and glioma-derived cell lines to the clinically used methylating agents temozolomide and streptozotocin. The cell lines responded similarly to these agents, displaying a 3-fold range in cytotoxicity, assessed as the 10% survival dose (LD10). The contribution of 06-methylguanine-DNA methyltransferase (MGMT) to resistance, measured as reduction in the LD10 by 06-benzylguanine (06-BG), varied among the lines by 1 order of magnitude for both agents. However, in all MGMT-expressing lines, 06-BG eliminated a threshold dose that accounted for up to one-half of the LD10. The effect of 06-BG on the rate of killing varied 13-fold for temozolomide and 14-fold for streptozotocin. Some lines displayed two subpopulations with different rates of killing, with one subpopulation that comprised 20-60% of cells showing essentially no dependence of the rate of killing on MGMT. 06-BG increased the range of the LD10 for both agents. The persistent, heightened variability in cytotoxicity in the absence of MGMT, the lack of correlation between MGMT content of the lines and cytoxicity (LD10), and the lack of correlation between MGMT content and the contribution of MGMT to resistance (06-BG-mediated reduction of the LD10) reflect the operation of resistance mechanisms other than MGMT. We also analyzed sensitivity to methyl methanesulfonate, observing little dependence of resistance on MGMT and persistent variability in cytotoxicity in the presence of 06-BG. We discuss the implications for clinical use of methylators and 06-BG. in the contribution of resistance of cell lines to a methylating in wide experimental use (1 In the present work, we analyze the contribution of MGMT to resistance to two clinically used methylating agents, TMZ and STZ, and to the MMS.