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O6-Methylguanine-DNA Methyltransferase in Tumors and Cells of the Oligodendrocyte Lineage

  • Catherine L. Nutt (a1) (a2), Joseph F. Costello (a3), Linda L. Bambrick (a4), Daniel B. Yarosh (a5), Lode J. Swinnen (a6), Ann F. Chambers (a7) (a1) (a2) and J. Gregory Cairncross (a7) (a4) (a2)...

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-methyIguanine-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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Copyright

Corresponding author

London Regional Cancer Centre. 790 Commissioners Road. East, London. Ontario. Canada N6A 4L6

References

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1.Cairncross, JG., Macdonald, DR.Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 1988; 23: 360364.
2.Macdonald, DR., Gaspar, LE., Cairncross, JG.Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol 1990; 27: 573574.
3.Glass, J., Hochberg, FH., Gruber, ML., et al. The treatment of oligodendrogliomas and mixed oligodendroglioma-astrocytomas with PCV chemotherapy. J Neurosurg 1992; 76: 741745.
4.Druckrey, H.Specific carcinogenic and teratogenic effects of “indirect” alkylating methyl and ethyl compounds, and their dependency on stages of ontogenic developments. Xenobiotica 1973; 3: 271303.
5.Burger, PC., Shibata, T., Aguzzi, A., Kleihues, P.Selective induction by N-nitrosoethylurea of oligodendrogliomas in fetal forebrain transplants. Cancer Res 1988; 48: 28712875.
6.Ding, R., Ghosh, K., Eastman, A., Bresnick, E.DNA-mediated transfer and expression of a human DNA repair gene that demethylates O6-methylguanine. Mol Cell Biol 1985; 5: 32933296.
7.Kaina, B., Fritz, G., Mitra, S., Coquerelle, T.Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells: the role of MGMT in protection against the genotoxic effects of alkylating agents. Carcinogenesis 1991; 12: 18571867.
8.Dolan, ME., Young, GS., Pegg, AE.Exposure of HeLa cells to O6-alkylguanines increases sensitivity to the cytotoxic effects of alkylating agents. Biochem Biophys Res Commun 1985; 132: 178185.
9.Dolan, ME., Stine, L., Mitchell, RB., Moschel, RC., Pegg, AE.Modulation of mammalian O6-alkylguanine-DNA alkyltrans-ferase in vivo by O6-benzylguanine and its effects on the sensitivity of a human glioma tumor to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. Cancer Commun 1990; 2: 371377.
10.Swenberg, JA., Bedell, MA., Billings, KC., Umbenhauer, DR., Pegg, AE.Cell-specific differences in O6-alkylguanine DNA repair activity during continuous exposure to carcinogen. Proc Natl Acad Sci USA 1982; 79: 54995502.
11.Wani, G., Wani, AA., D’Ambrosio, SM.In situ hybridization of human kidney tissue reveals cell-type-specific expression of the O6-methylguanine-DNA rnethyltransferase gene. Carcinogenesis 1992; 13: 463468.
12.Schold, SC Jr, Brent, TP., von Hofe, E., et al. O6-Alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts. J Neurosurg 1989; 70: 573577.
13.McCarthy, KD., de Vellis, J.Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 1980; 85: 890902.
14.Raff, MC., Miller, RH., Noble, M.A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 1983; 303: 390396.
15.Wu, RS., Hurst-Calderone, S., Kohn, KW.Measurement of O6-alkylguanine-DNA alkyltransferase activity in human cells and tumor tissues by restriction endonuclease inhibition. Cancer Res 1987; 47: 62296235.
16.Futscher, BW., Micetich, KC., Barnes, DM., Fisher, RI., Erickson, LC.Inhibition of a specific DNA repair system and nitrosourea cytotoxicity in resistant human cancer cells. Cancer Commun 1989; 1: 6573.
17.Myrnes, B., Norstrand, K., Giercksky, K-E., Sjunneskog, C., Krokan, H.A simplified assay for O6-methylguanine-DNA rnethyltransferase activity and its application to human neoplastic and nonneoplastic tissues. Carcinogenesis 1984; 5: 10611064.
18.Cole, SPC.Rapid chemosensitivity testing of human lung tumor cells using the MTT assay. Cancer Chemother Pharmacol 1986; 17: 259263.
19.Grafstrom, RC., Pegg, AE., Trump, BF., Harris, CC.O6-alkylguanine-DNA alkyltransferase activity in normal human tissues and cells. Cancer Res 1984; 44: 28552857.
20.Paleologos, NA., Zemrus, T., Allen, CV., et al. Oligodendrogliomas: CT measurement of transcapillary permeability and response to chemotherapy. Ann Neurol 1992; 32: 289.
21.Wiestler, O., Kleihues, P., Pegg, AE.O6-alkylguanine-DNA alkyltransferase activity in human brain and brain tumors. Carcinogenesis 1984; 5: 121124.
22.Frosina, G., Rossi, O., Arena, G., et al. O6-alkylguanine-DNA alkyltransferase activity in human brain tumors. Cancer Lett 1990; 55: 153158.
23.Mineura, K., lzumi, I., Watanabe, K., Kowada, M.Influence of O6methylguanine-DNA rnethyltransferase activity on chloroethyl-nitrosourea chemotherapy in brain tumors, Int J Cancer 1993; 55: 7681.
24.Silber, JR., Mueller, BA., Ewers, TG., Berger, MS.Comparison of O6methylguanine-DNA rnethyltransferase activity in brain tumors and adjacent normal brain. Cancer Res 1993; 53: 34163420.
25.Brown, M., Cairncross, JG., Vick, NA., et al. Differential response of recurrent oligodendrogliomas versus astrocytomas to intravenous melphalan. Neurology 1990; 40 (Suppl 1): 397398.
26.Saarinen, UM., Pihko, H., Makipernaa, A.High-dose thiotepa with autologous bone marrow rescue in recurrent malignant oligodendroglioma: a case report. J Neurooncol 1990; 9: 5762.

O6-Methylguanine-DNA Methyltransferase in Tumors and Cells of the Oligodendrocyte Lineage

  • Catherine L. Nutt (a1) (a2), Joseph F. Costello (a3), Linda L. Bambrick (a4), Daniel B. Yarosh (a5), Lode J. Swinnen (a6), Ann F. Chambers (a7) (a1) (a2) and J. Gregory Cairncross (a7) (a4) (a2)...

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