Does Tirapazamine (SR-4233) Have Any Cytotoxic or Sensitizing Effect on Three Human Tumour Cell Lines at Clinically Relevant Partial Oxygen Pressure?

Abstract

Solid human tumours contain areas with low oxygen tension (pO₂). For bioreductive drugs it is important to define the cytotoxic effect according to drug concentration and to clinically relevant pO₂. In this study, the pO₂ dependence of the survival of three human cell lines (HRT 18, Na11+, and MEWO), exposed to tirapazamine (SR-4233) alone or combined with ionizing radiation, was studied in vitro. Gas changes were made to obtain five different oxygen concentrations: air (20·9% O₂), 10, 2, 0·2 and 0·02% O₂ (hypoxia). Tirapazamine below a concentration of 100 μM was not cytotoxic in air or at 10% O₂. At 100 μM tirapazamine was toxic in 2% O₂, and at 50 μM in 0·2% O₂. For pO₂ < 0·2% O₂, there was a marked increase in cell killing when 10 μM tirapazamine was combined with 2 Gy, compared with either 10 μM or 2 Gy given alone (p < 0·03). The cytotoxic effect of tirapazamine on human tumour cells in vitro is highly dependent on clinically relevant pO₂'s. The activation of tirapazamine at a low concentration and at a pO₂ found mainly in tumours could yield a very beneficial therapeutic ratio.