Interaction of dexrazoxane with anticancer drugs

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Kozlowska, Hanna
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This thesis work consists of two major projects. In the first project the effects of combination of the cardioprotective agent, dexrazoxane, with the anticancer drugs mafosfamide, 5-fluorouracil, vinblastine, doxorubicin, daunorubicin, mitoxantrone and bleomycin were tested on Chinese hamster ovary cells. Four different methods were chosen for drug interaction analysis: the combination index, envelope of additivity, response surface and comparison of slopes. In the second project the cytotoxic mechanism of the anticancer drug mitindomide was evaluated in comparative studies with dexrazoxane. The combined 72 h and 48 h effects of dexrazoxane and mafosfamide was proven to be antagonistic by the combination index, response surface and slope comparison methods; although, the envelope of additivity showed additive effect of the drugs. The antagonistic effect of dexrazoxane and 5-fluorouracil as indicated by four methods used. The analysis of 48 h dexrazoxane-vinblastine data with the slope method showed antagonism. It was indicated by the slope comparison method, that the 48 h combined effects of dexrazoxane with doxorubicin, daunorubicin and mitoxantrone were antagonistic. When dexrazoxane was preincubated for 18 h with the cells before bleomycin was added the combination index, envelope of additivity and response surface methods showed synergy. The anticancer drug mitindomide was shown to inhibit topoisomerase II and not to be cytotoxic towards a dexrazoxane-resistant cell line. It was shown that mitindomide did not stabilize DNA-topoisomerase II cleavable complexes. The similarities between mitindomide and dexrazoxane functions toward cells and topoisomerase II classify mitindomide as topoisomerase II catalytic inhibitor.