Clofibrate enhances the DNA damaging action and cytotoxicity of nitrosoureas.
The ability of N-ethyl-N-nitrosourea (ENU) to produce single strand breaks (SSB) and N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to produce SSB and DNA-DNA interstrand cross-links was measured in L1210 cells that had been pretreated with clofibrate (CLO). When ENU was used the SSB frequency rose from 12.4 +/- 1.6/10(6) bases in control cells to 17.3 +/- 1.5/10(6) bases in CLO-treated cells and from 2.8 +/- 0.1/10(6) bases in control cells to 5.5 +/- 0.4/10(6) in CLO-treated cells when BCNU was the damaging agent. Similarly the cross-linking frequency rose from 3.5 +/- 0.1/10(6) bases in control cells to 12.1 +/- 0.5/10(6) bases in CLO-treated cells when BCNU was the cross-linking agent. CLO treatment increased the production of superoxide anion four-fold over the controls and it increased the cytotoxicity of BCNU. Forty-two percent of the control+BCNU cells survived after 24 h whereas only 24% of the CLO+BCNU cells survived. The stimulation of the diffuse condition known as oxidative stress increased the interaction of nitrosoureas with DNA and resulted in increased biological responses, e.g. cytotoxicity.
Lawson
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Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805.
Gwilt
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D000818:Animals; D002330:Carmustine / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005038:Ethylnitrosourea / Q000633:toxicity*; D007939:Leukemia L1210 / Q000235:genetics*; D051379:Mice
D004273:DNA, Neoplasm; D002994:Clofibrate; D005038:Ethylnitrosourea; D002330:Carmustine