Lartigau E, Guichard M
Laboratoire de Radiobiologie Cellulaire, Institut Gustave Roussy, Villejuif, France.
Int J Radiat Biol. 1995 Feb;67(2):211-6. doi: 10.1080/09553009514550261.
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 microM was not cytotoxic in air or at 10% O2. At 100 microM tirapazamine was toxic in 2% O2, and at 50 microM in 0.2% O2. For pO2 < 0.2% O2, there was a marked increase in cell killing when 10 microM tirapazamine was combined with 2 Gy, compared with either 10 microM 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.
实体人类肿瘤包含低氧张力（pO2）区域。对于生物还原药物而言，根据药物浓度以及临床相关的pO2来确定细胞毒性作用非常重要。在本研究中，体外研究了单独暴露于替拉扎明（SR-4233）或与电离辐射联合作用下的三种人类细胞系（HRT 18、Na11 +和MEWO）存活情况对pO2的依赖性。通过改变气体来获得五种不同的氧浓度：空气（20.9% O2）、10%、2%、0.2%和0.02% O2（低氧）。浓度低于100 microM的替拉扎明在空气或10% O2环境中无细胞毒性。在2% O2环境中，100 microM的替拉扎明具有毒性，在0.2% O2环境中，50 microM时具有毒性。对于pO2 < 0.2% O2，当10 microM替拉扎明与2 Gy联合使用时，与单独给予10 microM或2 Gy相比，细胞杀伤作用显著增加（p < 0.03）。替拉扎明在体外对人类肿瘤细胞的细胞毒性作用高度依赖于临床相关的pO2。在低浓度且主要在肿瘤中发现的pO2条件下替拉扎明的激活可能会产生非常有益的治疗比率。
