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Basic Sciences

Inactivation of O6-Methylguanine-DNA Methyltransferase and Sensitization of Human Tumor Cells to Killing by Chloroethylnitrosourea by O6-Methylguanine as a Free Base

Daniel B. Yarosh, Susan Hurst-Calderone, Michael A. Babich and Rufus S. Day III
Daniel B. Yarosh
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Susan Hurst-Calderone
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Michael A. Babich
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Rufus S. Day III
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DOI:  Published April 1986
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Abstract

Human fibroblasts and tumor cells with constitutive levels of the DNA repair protein O6-methylguanine-DNA methyltransferase were incubated with mm concentrations of the free base O6-methylguanine for up to 24 h. This treatment depleted the cells of their transferase activity, and sensitized the cells to killing by the antineoplastic drug 1-[2-chloroethyl]-1-nitrosourea. Cells constitutively lacking the methyltransferase were not sensitized to cell killing. Cell free extracts incubated with O6-methylguanine also lost methyltransferase activity. Other alkylpurines, such as O6-methylguanosine, S6-methylthioguanine, O6-ethylguanine, and 3-methyladenine, did not have this effect on extracts of human tumor cells, while O6-methylguanosine and O6-methylguanine inactivated purified methyltransferase from Escherichia coli. The data suggest that the free base O6-methylguanine is probably a substrate for the methyltransferase. Calculation of the second order rate constants for free base versus O6-methylguanine in DNA, and experiments in which the free base was mixed with DNA containing O6-methylguanine before reaction with methyltransferase, indicated that the base in DNA is about 4 × 107 better as a substrate than is the free base. These results demonstrate that DNA repair capacity of tumor cells can be diminished without DNA damage, and suggest a method for increasing the efficiency of chemotherapy.

Footnotes

  • ↵3 To whom requests for reprints should be addressed.

  • Received May 6, 1985.
  • Revision received November 21, 1985.
  • Accepted December 31, 1985.
  • ©1986 American Association for Cancer Research.
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April 1986
Volume 46, Issue 4 Part 1
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Inactivation of O6-Methylguanine-DNA Methyltransferase and Sensitization of Human Tumor Cells to Killing by Chloroethylnitrosourea by O6-Methylguanine as a Free Base
Daniel B. Yarosh, Susan Hurst-Calderone, Michael A. Babich and Rufus S. Day III
Cancer Res April 1 1986 (46) (4 Part 1) 1663-1668;

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Inactivation of O6-Methylguanine-DNA Methyltransferase and Sensitization of Human Tumor Cells to Killing by Chloroethylnitrosourea by O6-Methylguanine as a Free Base
Daniel B. Yarosh, Susan Hurst-Calderone, Michael A. Babich and Rufus S. Day III
Cancer Res April 1 1986 (46) (4 Part 1) 1663-1668;
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