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 ± 1.6 10⁶ bases in control cells to 17.3 ± 1.5 10⁶ bases in CLO-treated cells and from 2.8 ± 0.1 10⁶ bases in control cells to 5.5 ± 0.4 10⁶ in CLO-treated cells when BCNU was the damaging agent. Similarly the cross-linking frequency rose from 3.5 ± 0.1 10⁶ bases in control cells to 12.1 ± 0.5 10⁶ 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.