Hostname: page-component-848d4c4894-pjpqr Total loading time: 0 Render date: 2024-06-25T09:40:19.343Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  18 September 2015

Catherine L. Nutt ,
Joseph F. Costello ,
Linda L. Bambrick ,
Daniel B. Yarosh ,
Lode J. Swinnen ,
Ann F. Chambers  and
J. Gregory Cairncross
Catherine L. Nutt
Affiliation:
Department of Pathology, University of Western Ontario London Regional Cancer Centre, London, Ontario N6A 4L6
Joseph F. Costello
Affiliation:
Neuroscience Program, Loyola University Medical Center, Maywood, Illinois
Linda L. Bambrick
Affiliation:
Department of Clinical Neurological Sciences, University of Western Ontario
Daniel B. Yarosh
Affiliation:
Applied Genetics Incorporated, Freeport, New York
Lode J. Swinnen
Affiliation:
Department of Medicine, Loyola University Medical Center, Maywood, Illinois
Ann F. Chambers
Affiliation:
Department of Oncology, University of Western Ontario Department of Pathology, University of Western Ontario London Regional Cancer Centre, London, Ontario N6A 4L6
J. Gregory Cairncross*
Affiliation:
Department of Oncology, University of Western Ontario Department of Clinical Neurological Sciences, University of Western Ontario London Regional Cancer Centre, London, Ontario N6A 4L6
*
London Regional Cancer Centre. 790 Commissioners Road. East, London. Ontario. Canada N6A 4L6
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
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.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 22 , Issue 2 , May 1995 , pp. 111 - 115
Copyright
Copyright © Canadian Neurological Sciences Federation 1995

References

1.Cairncross, JG., Macdonald, DR.Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 1988; 23: 360–364.CrossRefGoogle ScholarPubMed
2.Macdonald, DR., Gaspar, LE., Cairncross, JG.Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol 1990; 27: 573–574.CrossRefGoogle ScholarPubMed
3.Glass, J., Hochberg, FH., Gruber, ML., et al. The treatment of oligodendrogliomas and mixed oligodendroglioma-astrocytomas with PCV chemotherapy. J Neurosurg 1992; 76: 741–745.CrossRefGoogle ScholarPubMed
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: 271–303.CrossRefGoogle Scholar
5.Burger, PC., Shibata, T., Aguzzi, A., Kleihues, P.Selective induction by N-nitrosoethylurea of oligodendrogliomas in fetal forebrain transplants. Cancer Res 1988; 48: 2871–2875.Google ScholarPubMed
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: 3293–3296.Google ScholarPubMed
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: 1857–1867.Google ScholarPubMed
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: 178–185.CrossRefGoogle Scholar
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: 371–377.CrossRefGoogle Scholar
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: 5499–5502.CrossRefGoogle ScholarPubMed
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: 463–468.CrossRefGoogle ScholarPubMed
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: 573–577.CrossRefGoogle ScholarPubMed
13.McCarthy, KD., de Vellis, J.Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 1980; 85: 890–902.CrossRefGoogle ScholarPubMed
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: 390–396.CrossRefGoogle ScholarPubMed
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: 6229–6235.Google ScholarPubMed
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: 65–73.CrossRefGoogle ScholarPubMed
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: 1061–1064.CrossRefGoogle Scholar
18.Cole, SPC.Rapid chemosensitivity testing of human lung tumor cells using the MTT assay. Cancer Chemother Pharmacol 1986; 17: 259–263.CrossRefGoogle ScholarPubMed
19.Grafstrom, RC., Pegg, AE., Trump, BF., Harris, CC.O6-alkylguanine-DNA alkyltransferase activity in normal human tissues and cells. Cancer Res 1984; 44: 2855–2857.Google ScholarPubMed
20.Paleologos, NA., Zemrus, T., Allen, CV., et al. Oligodendrogliomas: CT measurement of transcapillary permeability and response to chemotherapy. Ann Neurol 1992; 32: 289.Google Scholar
21.Wiestler, O., Kleihues, P., Pegg, AE.O6-alkylguanine-DNA alkyltransferase activity in human brain and brain tumors. Carcinogenesis 1984; 5: 121–124.CrossRefGoogle ScholarPubMed
22.Frosina, G., Rossi, O., Arena, G., et al. O6-alkylguanine-DNA alkyltransferase activity in human brain tumors. Cancer Lett 1990; 55: 153–158.CrossRefGoogle ScholarPubMed
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: 76–81.CrossRefGoogle Scholar
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: 3416–3420.Google Scholar
25.Brown, M., Cairncross, JG., Vick, NA., et al. Differential response of recurrent oligodendrogliomas versus astrocytomas to intravenous melphalan. Neurology 1990; 40 (Suppl 1): 397–398.Google Scholar
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: 57–62.CrossRefGoogle ScholarPubMed