DOES TIRAPAZAMINE (SR-4233) HAVE ANY CYTOTOXIC OR SENSITIZING EFFECT ON 3 HUMAN TUMOR-CELL LINES AT CLINICALLY RELEVANT PARTIAL OXYGEN-PRESSURE

Solid human rumours contain areas with low oxygen tension (pO(2)). For bioreductive drugs it is important to define the cytotoxic effect acc ording to drug concentration and to clinically relevant pO(2). In this study, the pO(2) dependence of the survival of three human cell lines (HRT 18, Na11 +, and MEWO), exposed to tirapazamine (SR-4233) alone o r combined with ionizing radiation, was studied in vitro. Gas changes were made to obtain five different oxygen concentrations: air (20.9% O -2), 10, 2, 0.2 and 0.02% O-2 (hypoxia). Tirapazamine below a concentr ation of 100 mu M was not cytotoxic in air or at 10% O-2. At 100 mu M tirapazamine was toxic in 2% O-2, and at 50 mu M in 0.2% O-2. For pO(2 ) <0.2% O-2, there was a marked increase in cell killing when 10 mu M tirapazamine was combined with 2 Gy, compared with either 10 mu M or 2 Gy given alone (p<0.03). The cytotoxic effect of tirapazamine on huma n tumour cells in vitro is highly dependent on clinically relevant pO( 2)'s. The activation of tirapazamine at a low concentration and at a p O(2) found mainly in rumours could yield a very beneficial therapeutic ratio.