Durand R E, Olive P L
Medical Biophysics Unit, BC Cancer Research Centre, Vancouver, Canada.
Br J Cancer. 1989 Oct;60(4):517-22. doi: 10.1038/bjc.1989.305.
Endogenous and exogenous thiols are thought to influence cellular radiosensitivity directly by radical scavenging and/or hydrogen donation processes, and indirectly, by regulating the amount of oxygen (or other electron affinic radiosensitiser) able to reach the radiosensitive targets of the cell. The relative importance of these two mechanisms was evaluated in multicell spheroids treated with two agents currently undergoing clinical testing, the thiophosphate WR-2721 and the glutathione synthesis inhibitor BSO. Fluorescence-activated cell sorting techniques were used to recover cells selectively from different depths (different oxygenation status) within the spheroids. The radiosensitivity of cell populations recovered from different regions suggested that both agents acted primarily by affecting the oxygenation status of the spheroid. Similarly, the binding of a fluorescent marker for hypoxic cells, the nitrofuran AF-2, was markedly enhanced by WR-2721 addition, and decreased by BSO-induced thiol depletion. We conclude that the major radiobiological consequence of thiol manipulation in multicell systems is to increase or decrease the availability of oxygen.
内源性和外源性硫醇被认为可通过自由基清除和/或氢供体过程直接影响细胞放射敏感性，并且可通过调节能够到达细胞放射敏感靶点的氧气（或其他亲电子放射增敏剂）量间接影响细胞放射敏感性。在用目前正在进行临床试验的两种药物——硫代磷酸酯WR - 2721和谷胱甘肽合成抑制剂BSO处理的多细胞球体中评估了这两种机制的相对重要性。使用荧光激活细胞分选技术从球体内部不同深度（不同氧合状态）选择性地回收细胞。从不同区域回收的细胞群体的放射敏感性表明，这两种药物主要通过影响球体的氧合状态起作用。同样，缺氧细胞荧光标记物硝基呋喃AF - 2的结合在添加WR - 2721后显著增强，而在BSO诱导的硫醇耗竭后降低。我们得出结论，在多细胞系统中硫醇操纵的主要放射生物学后果是增加或减少氧气的可用性。
