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Inhibition of O6-alkylguanine-DNA alkyltransferase in animal and human ovarian tumor cell lines by O6-benzylguanine and sensitization to BCNU

  • Short Communication
  • Ovarian Cancer, O6-Alkylguanine-DNA Alkyltransferase, Carmustine Resistance
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Abstract

O6-Alkylguanine-DNA alkyltransferase (O6-AGT) activity in rat ovarian tumor lines O-342 and O-342/DDP was 103.4±18.4 and 240.9±40.2 fmol/mg protein, respectively; thus, cisplatin (DDP) resistance was paralleled by an increase in O6-AGT activity by a factor of approximately 2.3. The DDP-resistant line expressed a collateral resistance to BCNU. Both lines could be sensitized to BCNU by O6-BG, with sensitization factors of 6.0 and 2.1, respectively. In neither line did depletion of O6-AGT have any sensitizing effect towards DDP. In the human ovarian cancer lines SK-OV-3 and OAW 42, O6-AGT activity was 337.6±18.2 and 180.0±39.9 fmol/mg protein, respectively; in these lines depletion of O6-AGT activity by O6-BG treatment resulted in sensitization factors of 3.0 and 4.1, respectively. The increase in sensitivity of ovarian tumor cell lines against a chloroethylating agent by O6-AGT depletion and possible pharmacological advantages of regional (i.p.) administration of this combination might be beneficial in advanced ovarian cancer.

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Abbreviations

BCNU:

(1,3-bis(2-chloroethyl)-1-nitrosourea)

CENU:

2-chloroethylnitrosourea

DDP:

cisplatin ED50, the effective dose required to inhibit colony formation or cell proliferation by 50%

O6-AGT:

O6-alkylguanine-DNA alkyltransferase

O6-BG:

O6-benzylguanine SF sensitization factor

References

  1. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principles of protein-dye binding. Anal Biochem 72: 248

    Google Scholar 

  2. Chen G, Frei E, Zeller WJ (1989) Determination of intracellular reduced glutathione and glutathione related enzyme activities in cisplatin-sensitive and resistant experimental ovarian carcinoma cell lines. Cancer Lett 46: 207

    Google Scholar 

  3. Chen G, Hutter K-J, Bullerdiek J, Zeller WJ (1991) Karyotypic change from heteroploidy to near diploidy associated with development of cisplatin resistance in a rat ovarian tumour cell line. J Cancer Res Clin Oncol 117: 539

    Google Scholar 

  4. Dolan ME, Moschel RC, Pegg AE (1990) Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents. Proc Natl Acad Sci USA 87: 5368

    Google Scholar 

  5. Dolan ME, Mitchell RB, Mummert C, Moschel RC, Pegg AE (1991) Effect of O6-benzylguanine analogues on the sensitivity of human tumor cells to the cytotoxic effects of alkylating agents. Cancer Res 51:3367

    Google Scholar 

  6. Friedman HS, Dolan ME, Moschel RC, Pegg AE, Felker M, Rich J, Bigner DD, Schold SC Jr (1992) Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. J Natl Cancer Inst 84: 1926

    Google Scholar 

  7. Gerard B, Aamdal S, Lee S-M, Leyvraz S, Lucas C, D'Incalci M, Bizzari J-P (1993) Activity and unexpected lung toxicity of the sequential administration of two alkylating agents — dacarbazine and fotemustine — in patients with melanoma. Eur J Cancer 29 A: 711

    Google Scholar 

  8. Godfrey TE, King A, Rentschler R (1973) 1,3-Bis(2-chloroethyl)-1-nitrosourea: effects on advanced ovarian carcinoma. Am J Obstet Gynecol 115: 576

    Google Scholar 

  9. Hay R, Macy M, Hamburger A, Weinblatt A, Chen TR (eds.) (1983) Cell lines. In: American Type Culture Collection, Cell lines, Viruses, Antisera, Fourth Edition, ATCC, Rockville, Maryland, p. 12

    Google Scholar 

  10. Hoogstraten B, Gottlieb JA, Caoili E, Tucker WG, Talley RW, Haut A (1973) CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea, NSC-79037) in the treatment of cancer. Cancer 32: 38

    Google Scholar 

  11. Jorgensen EO, Malkasian GD, Webb MJ Hahn RG (1973) Pilot study evaluating 1,3-bis(2-chloroethyl)-1-nitrosourea in the treatment of advanced ovarian carcinoma. Am J Obstet Gynecol 116: 769

    Google Scholar 

  12. Micetich KC, Futscher B, Koch D, Fisher RI, Erickson LC (1992) Phase I study of streptozotocin and carmustine-sequenced administration in patients with advanced cancer. J Natl Cancer Inst 84: 256

    Google Scholar 

  13. Myrnes B, Norstrand K, Giercksky K-E, Sjunneskog C, Krokan H (1984) A simplified assay for O6-methylguanine-DNA methyltransferase activity and its application to human neoplastic and non-neoplastic tissues. Carcinogenesis 5: 1061

    Google Scholar 

  14. Panella TJ, Smith DC, Schold SC, Rogers MP, Winer EP, Fine RL, Crawford J, Herndon JE, Trump DL (1992) Modulation of O6-alkylguanine-DNA alkyltransferase-mediated carmustine resistance using streptozotocin: a phase I trial. Cancer Res 52: 2456

    Google Scholar 

  15. Pegg AE (1990) Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50: 6119

    Google Scholar 

  16. Shapiro JR, Shapiro WR (1983) Specific karyotypic and tumorigenic changes in cloned subpopulations of human gliomas exposed to sublethal doses of BCNU. In: Chabner BA (ed) Rational basis for chemotherapy. Liss, New York, p 45

    Google Scholar 

  17. Tagliabue G, Citti L, Massazza G, Damia G, Giavazzi R, D'Incalci M (1992) Tumour levels of O6-alkylguanine-DNA-alkyltransferase and sensitivity to BCNU of human xenografts. Anticancer Res 12: 2123

    Google Scholar 

  18. Wilson AP (1984) Characterization of a cell line derived from the ascites of a patient with papillary serous cystadenocarcinoma of the ovary. J Natl Cancer Inst 72: 513

    Google Scholar 

  19. Zeller WJ, Berger MR, Henne T, Weber E (1986) More than additive toxicity of the combination of 1-methyl-1-nitrosourea plus 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat. Cancer Res 46: 1714

    Google Scholar 

  20. Zeller WJ, Komitowski D (1986) Pronounced damage of intestinal tract mucosa by the combination of 1-methyl-1-nitrosourea plus 1,3-bis-(2-chloroethyl)-1-nitrosourea. Effect of drug sequence and time interval of administration. Toxicol Lett 32: 59

    Google Scholar 

  21. Zeller WJ, Frühauf S, Chen G, Keppler BK, Frei E, Kaufmann M (1991) Chemoresistance in rat ovarian tumours. Eur J Cancer 27: 62

    Google Scholar 

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  1. Division 0420, German Cancer Research Center, D-69120, Heidelberg, Germany

    Achim Magull-Seltenreich & Walter Jens Zeller

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  1. Achim Magull-Seltenreich
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  2. Walter Jens Zeller
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Magull-Seltenreich, A., Zeller, W.J. Inhibition of O6-alkylguanine-DNA alkyltransferase in animal and human ovarian tumor cell lines by O6-benzylguanine and sensitization to BCNU. Cancer Chemother. Pharmacol. 35, 262–266 (1995). https://doi.org/10.1007/BF00686559

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  • DOI: https://doi.org/10.1007/BF00686559

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