Effect of O6-Methylguanine on DNA Interstrand Cross-Link Formation by Chloroethylnitrosoureas and 2-Chloroethyl(methylsulfonyl)methanesulfonate

M. Eileen Dolan, Anthony E. Pegg, Nancy K. Hora, Leonard C. Erickson

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35 Scopus citations

Abstract

Exposure of HT29 cells in culture to O6-methylguanine is known to result in a reduction in O6-alkylguanine-DNA alkyltransferase (AGT) activity and an enhancement of sensitivity to the cytotoxic effects of chloroethylating agents. Since cytotoxicity of these agents may be mediated by the formation of interstrand cross-links, alkaline elution analysis was performed on HT29 cells treated with l-(2-chloroethyl)-l-nitro-sourea, 1 -(2-chloroethyl)-3-cyclohexyl-l -nitrosourea, and Clomesone [2-chloroethyl(methylsulfonyl)methanesulfonate] in the presence or absence of O6-methylguanine pretreatment to determine if the enhanced toxicity was due to an increase in the number of cross-links formed. Interstrand cross-linking by l-(2-chk)roethyl)-l-nitrosourea or l-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was increased by pretreatment with 0.4 mM O6- methylguanine for 24 h. Cross-linking by Clomesone was observed only in cells exposed to 0.4 mM O6-methylguanine for 24 h prior to administration of the drug and for 12 h after administration, suggesting that the resynthesis of the AGT may prevent the cross-linking by Clomesone. Complete recovery of AGT activity after reduction to 20 to 30% of the basal level upon treatment with 0.4 mM O6-methylguanine required between 8 h and 15 h in both HT29 cells and in Raji cells which were also sensitized to l-(2-chloro-ethyl)-3-cyclohexyl-l-nitrosourea by exposure to O6-methylguanine. These data suggest that the enhancement of chloroethylnitrosourea toxicity after treatment with O6-methylguanine may be related to an increase in the number of DNA cross-links and that the relatively rapid rate of AGT recovery plays a role in prevention of cross-links resulting from Clomesone.

Original languageEnglish (US)
Pages (from-to)3603-3606
Number of pages4
JournalCancer Research
Volume48
Issue number13
StatePublished - 1988

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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