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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 Jan;93(1):93–102. doi: 10.1111/j.1349-7006.2002.tb01205.x

O6‐Methylguanine‐DNA Methyltransferase (MGMT) as a Determinant of Resistance to Camptothecin Derivatives

Ryo Okamoto 1, Hiroshi Takano 1, Tatsunori Okamura 2, Ji‐Seon Park 1, Keiji Tanimoto 1, Takashi Sekikawa 3, Wataru Yamamoto 3, Alex Sparreboom 4, Jaap Verweij 4, Masahiko Nishiyama 1,✉
PMCID: PMC5926864  PMID: 11802813

Abstract

The precise mechanisms of resistance to camptothecin (CPT)‐derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O6‐methylguanine‐DNA methyltransferase(MGMT), participated in resistance to irinotecan hydrochloride (CPT‐11), its active metabolite SN‐38, and a novel CPT derivative, DX‐8951f. In 17 human cancer cell lines, MGMT gene expression level closely correlated with sensitivity to the CPT derivatives, and inhibition of MGMT activity by nontoxic 5 μM O6‐benzylguanine augmented the drug activity in relation to the MGMT expression levels in 8 cell lines examined. Transfection of pCR/MGMT‐sense into U‐251MG and pCR/MGMT‐antisense into T98G and HEC‐46 cells revealed that increased MGMT expression decreased the sensitivity to CPT‐11, SN‐38, and DX‐8951f, whereas repressed MGMT expression sensitized cells to the drugs. Western analysis revealed that treatment of MGMT‐expressing T98G cells with the drugs caused a decrease of both MGMT and topo I in a dose‐dependent manner. Although, in the transfectants, MGMT expression did not so closely correlate with the sensitivity to drugs as to nimustine hydrochloride (ACNU), MGMT is probably an important resistance determinant to CPT derivatives, and may play some role in the topo I‐mediated DNA damage and/or the repair process.

Keywords: MGMT, CPT‐11, DX‐8951f, Drug resistance

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REFERENCES

  • 1. ) Pommier , Y. , Tanizawa , A. , Okada , K. and Andoh , T.Cellular determinants of sensitivity and resistance to camptothecins . In “ Camptothecins: New Anticancer Agents ,” ed. Potmesil M. and Pinedo H. , pp. 123 – 138 ( 1995. ). CRC Press; , Boca Raton . [Google Scholar]
  • 2. ) Takahashi , T. , Fujiwara , Y. , Yamakido , M. , Katoh , O. , Watanabe , H. and Mackenzie , P. I.The role of glucuronidation in 7‐ethyl‐10‐hydroxy‐camptothecin resistance in vitro . Jpn. J. Cancer Res. , 88 , 1211 – 1217 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Slichenmyer , W. J. , Rowinsky , E. K. , Donehower , R. C. and Kaufmann , S. H.The current status of camptothecin analogues as anti‐tumor agents . J. Natl. Cancer Inst. , 85 , 271 – 291 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Mitsui , I. , Kumazawa , E. , Hirota , Y. , Aonuma , M. , Sugimori , M. , Ohsuki , S. , Uoto , K. , Ejima , A. , Terasawa , H. and Sato , K. Anew water‐soluble camptothecin derivative, DX‐8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo . Jpn. J. Cancer Res. , 86 , 776 – 782 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Joto , N. , Ishii , M. , Minami , M. , Kuga , H. , Mitsui , I. and Tohgo , A.DX‐8951f, a water‐soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN‐38‐resistant variant . Int. J. Cancer , 72 , 680 – 686 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Nomoto , T. , Nishio , K. , Ishida , T. , Mori , M. and Saijo , N.Characterization of a human small‐cell lung cancer cell line resistant to a new water‐soluble camptothecin derivative, DX‐8951f . Jpn. J. Cancer Res. , 89 , 1179 – 1186 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Dennis , M. J. , Beijnen , J. H. , Grochow , L. B. and Van Warmaerdam , L. J. C.An overview of the clinical pharmacology of topotecan . Semin. Oncol. , 24 ( Suppl. 5 ), 12 – 18 ( 1997. ). [PubMed] [Google Scholar]
  • 8. ) Pommier , Y.Topoisomerase I‐mediated DNA damage and repair . Clin. Cancer Res. , 6 ( Suppl. ), 4479s ( 2000. ). [Google Scholar]
  • 9. ) Pourquier , P. , Loktionova , N. A. , Pegg , A. E. and Pommier , Y.O6‐Alkylation of guanine induces topoisomerase I‐DNA covalent complexes in vitro and in MNNG‐treated cells . Proc. Am. Assoc. Cancer Res. , 41 , 426 ( 2000. ). [Google Scholar]
  • 10. ) Okamura , T. , Kurisu , K. , Yamamoto , W. , Takano , H. and Nishiyama , M.NADPH/quinone oxidoreductase is a priority target of glioblastoma chemotherapy . Int. J. Oncol. , 16 , 295 – 303 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Sekikawa , T. , Takano , H. , Okamura , T. , Sasaki , M. , Kumazaki , T. and Nishiyama M.O6‐Methylguanaine‐DNA methytransferase is a critical determinant of cytotoxicity for DNA topoisomerase I inhibitors . Proc. Am. Assoc. Cancer Res. , 41 , 179 ( 2000. ). [Google Scholar]
  • 12. ) Nishiyama , M. , Suzuki , K. , Kumazaki , T. , Yamamoto , W. , Toge , T. , Okamura , T. and Kurisu , K.Molecular targeting of mitomycin C chemotherapy . Int. J. Cancer , 72 , 649 – 656 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Seto , M. , Jaeger , U. , Hockett , R. D. , Graninger , W. , Bennet , S. , Goldman , P. and Korsmeyer , S. J.Alternative promoters and exons, somatic mutation and deregulation of the Bcl‐2‐Ig fusion gene in lymphoma . EMBO J. , 7 , 123 – 131 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Baker , S. J. , Markowitz , S. , Fearson , E. R. , Willson , J. K. and Vogelstein , B.Suppression of human colorectal carcinoma cell growth by wild‐type p53 . Science , 249 , 912 – 915 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Doyle , L. A. , Yang , W. , Abruzzo , L. V. , Krogmann , T. , Gao , Y. , Rishi , A. K. and Ross , S. D.A multidrug resistance transporter from human MCF‐7 breast cancer cells . Proc. Natl. Acad. Sci. USA , 95 , 15665 – 15670 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Tano , K. , Shiota , S. , Collier , J. , Foote , R. S. and Mitra , S.Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for O6‐alkylguanine . Proc. Natl. Acad. Sci. USA , 87 , 686 – 690 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Wu , R. S. , Hurst‐Calderone , S. and Kohn , K. W.Measurement of O6‐alkylguanine‐DNA alkyltransferase activity in human cells and tumor tissues by restriction endonuclease inhibition . Cancer Res. , 47 , 6229 – 6235 ( 1987. ). [PubMed] [Google Scholar]
  • 18. ) Marathi , U. K. , Dolan , M. E. and Erickson , L. C.Extended depletion of O6‐methylguanine‐DNA methyltransferase activity following O6‐benzyl‐2′‐deoxyguanosine or O6‐benzylguanine combined with streptozocin treatment enhances 1, 3‐bis(2‐chloroethyl)‐1‐nitrosourea cytotoxicity . Cancer Res. , 54 , 4371 – 4375 ( 1994. ). [PubMed] [Google Scholar]
  • 19. ) Loos , W. J. , Verweij , J. , Gelderblom , H. J. , de Jonge , H. J. A. , Brouwere , E. , Dallaire , B. K. and Sparreboom , A.A role of erythrocytes and serum proteins in the kinetic profile of total 9‐amino‐20(S)‐camptothecin in human . Anticancer Drugs , 10 , 705 – 710 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Grombacher , T. , Einchorn , U. and Kina , B.p53 is involved in regulation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase (MGMT) by DNA damaging agents . Oncogene , 17 , 845 – 851 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Pegg , A. E. , Dolan , M. E. and Moschel , R. C.Structure, function and inhibition of O6‐methylguanine‐DNA alkyl‐transferase . Prog. Nucleic Acid Res. Mol. Biol. , 51 , 167 – 223 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Cai , Y. , Wu , M. H. , Ludeman , S. M. , Grdina , D. J. and Dolan , M. E.Role of O6‐alkylguanine‐DNA alkyltransferase in protecting against cyclophosphamide‐induced toxicity and mutagenicity . Cancer Res. , 59 , 3059 – 3063 ( 1999. ). [PubMed] [Google Scholar]
  • 23. ) Mineura , K. , Fukuchi , M. , Kowada , M. , Terashima , I. and Kohda , K.Differential inactivation of O6‐methylguanine‐DNA methyltransferase activity by O6‐arylmethylguanines . Int. J. Cancer , 63 , 148 – 151 ( 1995. ). [DOI] [PubMed] [Google Scholar]

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