Interaction of bleomycin, hyperthermia and a calmodulin inhibitor (trifluoperazine) in mouse tumor cells

Abstract

To improve the efficacy of thermochemotherapy we have investigated the individual and combined effects of hyperthermia (44°C) and the calmodulin inhibitor trifluoperazine (30,μg/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: (a) enhanced the cytotoxicity of bleomycin, (b) increased the frequency of long-lived attachment sites of cellular DNA at the nuclear matrix, and (c) 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 Camodulin in the control of chromatin structural changes during DNA repair and the study provides a rational basis for the use of Camodulin inhibitors in thermochemotherapy.