Cytotoxicity of bioreductive drug tirapazamine is increased by applicationof electric pulses in SA-1 tumours in mice

The application of electrical pulses (electroporation) is a local tumour tr eatment resulting in the facilitated accumulation of non-permeant chemother apeutic drugs (electrochemotherapy), as well as in the transient reduction of tumour blood flow. The aim of our study was to determine whether. the ap plication of electric pulses to tire tumour increased the antitumour effect iveness of the bioreductive drug tirapazamine (TPZ). The survival of SA-I f ibrosarcoma cells was 150-fold lower after the exposure of cells for 1 h To TPZ under anoxic compared with normoxic conditions. The exposure of cells to electric pulses did not increase the cytotoxicity of TPZ. However; the i n vivo treatment of subcutaneous tumours with a combination of TPZ (i.p. 25 mg/kg) injected 20 min before the application of electrical Pulses signifi cantly enhanced tumour response. Treatment with TPZ and electric pulses, re peated three times at 24-hour intervals resulted in tumour growth delay of 7.2 days. The results of our study showed that the observed antitumour effe ctiveness is unlikely to be due to increased cellular accumulation of TPZ b y application of electric pulses, as indicated from in vitro experiments. T he effect is more likely to be attributed to increased tumour hypoxia as a consequence of reduced tumour blood flow induced by application of electric pulses.