To improve the efficacy of thermochemotherapy we have investigated the individual and combined effects of hyperthermia (44 degrees C) and the calmodulin inhibitor trifluoperazine (30 micrograms/ml) on early plateau phase cultures of mouse EMT6 cells for simultaneous exposures to bleomycin. We found that a non-toxic combination of hyperthermia and trifluoperazine: enhanced the cytotoxicity of bleomycin, increased the frequency of long-lived attachment sites of cellular DNA at the nuclear matrix, and resulted in an accumulation of DNA damage (strand-breaks and alkali-labile lesions) caused by the inhibition of strand-break rejoining and the impaired processing of DNA sites involving base loss. Our findings implicate a role for calmodulin in the control of chromatin structural changes during DNA repair and the study provides a rational basis for the use of calmodulin inhibitors in thermochemotherapy.
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