We have reported in the preceding paper that the treatment of plateau phase mouse EMT6 tumour cells with a combination of
hyperthermia (HT; 44 degrees C) and
trifluoperazine (TFP; 30 micrograms ml-1; an inhibitor of
calmodulin) greatly enhances the cytotoxicity of the antitumour
drug belomycin (BLM). The cytotoxic action of BLM is thought to arise from the induction of DNA damage in a manner which reflects
chromatin accessibility. Thus we have studied the effects of the two modifiers (HT and TFP) on
chromatin structure and BLM-induced DNA damage. Co-treatment of cells with HT and TFP altered
chromatin organisation by the formation and slow resolution of new
DNA attachment sites at the nuclear matrix. HT increased
drug-induced DNA damage (strand breaks and
alkali-labile lesions) by the general depression of repair rather than through the generation of new sites for
drug action. TFP produced a more discrete block in the repair of
alkali-labile lesions in
DNA. Both processes appear to occur for the combination of BLM, HT and TFP, and we propose that the novel
chromatin configuration permits the accumulation of potentially lethal
DNA strand breaks. Our study indicates the potential value of
chromatin/DNA repair modifying regimens for overcoming the poor responsiveness of some tumour cells to chemotherapeutic drugs and provides a rational basis for the use of
calmodulin inhibitors in thermochemotherapy.