Skip to main content
SpringerLink
Log in

Linkage between O6-methylguanine-DNA methyltransferase (O6-MT) activity and cellular resistance to antitumour nitrosoureas in cultured rat brain tumour cell strains

  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Summary

We have examined O6-methylguanine-DNA methyltransferase (O6-MT) activity of rat brain tumour cell strains with reference to cellular resistance to antitumour nitrosoureas, 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (nimustine, ACNU) and methyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-α-D-glucopyranoside (ramustine, MCNU). The values of O6-MT activity were 52 and 160 fmol/mg protein extract in 9 L and C 6 rat brain tumour cells, respectively; while HeLa S 3 cells, as a methyl excision repair positive (Mer+) cell strain, revealed a rather high value of 488 fmol/mg. 9 L cells indicative of a low O6-MT activity showed 13 μM for ACNU and 18 μM for MCNU at a 10% survival dose (SD10), determined by a clonogenic cell assay as an index of cellular resistance. In contrast to this, C 6 cells revealed a SD10 value of 67 μM and 36 μM for ACNU and MCNU, respectively, indicating higher resistance than 9 L cells. HeLa S 3 cells showed the highest SD10 value as follows: 84 μM for ACNU and 73 μM for MCNU. The relationship between the O6-MT activity and the cellular resistance was almost linear, with relatively resistant cell lines exhibiting the higher levels of the O6-MT activity. This correlation between the O6-MT activity and the cellular resistance to nitrosoureas as ACNU and MCNU was not observed among other antitumour drugs, which included bleomycin (BUM), neocarzinostatin (NCS),cis-diamminedichloroplatinum (II) (CDDP), and etoposide (VP-16) in clinical use for brain tumour chemotherapy. This indicates that O6-MT activity can be an indicator of cellular resistance to antitumour nitrosoureas in the chemotherapy of brain tumours.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Benda P, Lightbody J, Sato G, Levine L, Sweet W (1968) Differentiated rat glial cell strain in tissue culture. Science 161: 370–371

    PubMed  Google Scholar 

  2. Erickson LC, Laurent G, Sharkey NA, Kohn KW (1980) DNA cross-linking and monoadduct repair in nitrosourea-treated human tumor cells. Nature 288: 727–729

    PubMed  Google Scholar 

  3. Ikenaga M, Tsujimura T, Chang HR, Fujio C, Zhang YP, Ishizaki K. Kataoka H, Shima A (1987) Comparative analysis of O6-methylguanine methyltransferase activity and cellular sensitivity to alkylating agents in cell strains derived from a variety of animal species. Mutation Res 184: 161–168

    PubMed  Google Scholar 

  4. Karran P, Lindahl T, Griffin B (1979) Adaptive response to alkylating agents involves alteration in sites of O6-methylguanine residues in DNA. Nature 280: 76–77

    PubMed  Google Scholar 

  5. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275

    PubMed  Google Scholar 

  6. Lowry OH, Berger SJ, Carter JG, Chi MMY, Manchester JK, Knor J, Pusateri ME (1983) Diversity of metabolic patterns in human brain tumors: Enzymes of energy metabolism and related metabolites and cofactors. J Neurochem 41: 994–1010

    PubMed  Google Scholar 

  7. Mineura K, Fushimi S, Itoh Y, Kowada M (1988) DNA lability induced by nimustine (ACNU) and ramustine (MCNU) in rat glioma cell. J Neurol Neurosurg Psychiatry 51: 1391–1394

    PubMed  Google Scholar 

  8. Schimizu F, Arakawa M (1975) Effect of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride on lymphoid leukemia L-1210. Jpn J Cancer Res (Gann) 66: 149–154

    Google Scholar 

  9. Schmidek HH, Nielisen SL, Schiller AL, Messer J (1971) Morphological studies of rat brain tumors induced by N-nitrosomethylurea. J Neurosurg 34: 335–340

    PubMed  Google Scholar 

  10. Sekido S, Ninomiya K, Iwasaki M (1979) Biologic activity of MCNU: A new antitumor agent. Cancer Treat Rep 63: 961–970

    PubMed  Google Scholar 

  11. Takakura K, Abe H, Tanaka R, Kitamura K, Miwa T, Takeuchi K, Yamamoto S, Kageyama N, Handa H, Mogami H, Nishimoto A, Uozumi T, Matsutani M, Nomura K (1986) Effects of ACNU and radiotherapy on malignant glioma. J Neurosurg 64: 53–57

    PubMed  Google Scholar 

  12. Tong WP, Kirk MC, Ludlum DB (1982) Formation of the crosslink 1-(N 3-deoxycytidyl)-2-(N 1-deoxyguanosinyl)ethane in DNA treated with N,N′-bis(2-chloroethyl)-N-nitrosourea. Cancer Res 42: 3102–3105

    PubMed  Google Scholar 

  13. Tsujimura T, Zhang Y, Fujio C, Chang HR, Watatani M, Ishizaki K, Kitamura H, Ikenaga M (1987) O6-methylguanine methyltransferase activity and sensitivity of Japanese tumor cell strains to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride. Jpn J Cancer Res (Gann) 78: 1207–1215

    Google Scholar 

  14. Walker MD, Green SB, Bvar DP, Alexander E, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS, Owens G, Ransohoff J, Robertson JT, Shapiro WR, Smith KR, Wilson CB, Strike TA (1980) Randomize comparisons of radiotherapy and nitrosoureas for the treatment of malignant gliomas after surgery. N Engl J Med 303: 1323–1329

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurosurgical Service, Akita University Hospital, Akita

    K. Mineura, S. Fushimi & M. Kowada

  2. Radiation Biological Center, Kyoto University, Kyoto, Japan

    G. Isowa, K. Ishizaki & M. Ikenaga

Authors
  1. K. Mineura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Fushimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Kowada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Isowa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Ishizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Ikenaga
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mineura, K., Fushimi, S., Kowada, M. et al. Linkage between O6-methylguanine-DNA methyltransferase (O6-MT) activity and cellular resistance to antitumour nitrosoureas in cultured rat brain tumour cell strains. Acta neurochir 103, 62–66 (1990). https://doi.org/10.1007/BF01420193

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01420193

Keywords

Search

Navigation