Kavanagh B D, Coffey B E, Needham D, Hochmuth R M, Dewhirst M W
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710.
Br J Cancer. 1993 Apr;67(4):734-41. doi: 10.1038/bjc.1993.134.
Flunarizine is a class IV calcium channel blocker which increases oxygen delivery to hypoxic regions in solid tumours, exerting a radiosensitising effect in vivo in animal tumour models. Precisely how the drug improves oxygenation is not well understood. We hypothesised that metabolic conditions present within solid tumours reduce red blood cell (RBC) deformability and that flunarizine exerts its in vivo effect by preventing this loss of RBC deformability. A microrheometer was used to compare the viscosity of rat and human RBC suspensions in conditions of hypoxia (pO2 < 10 mmHg), acidic environment (pH 6.8), and elevated lactate concentration (lactate 5 mMol l-1), without or with flunarizine at concentrations of 5, 10, and 50 mg l-1. The effects of flunarizine on RBC density and morphology were also recorded. Hypoxia, low pH, and lactate exposure together increased both human and rat RBC suspension viscosity. Flunarizine at concentrations of 5 and 10 mg l-1 prevented the increases in viscosity. The drug caused dose-dependent shifts toward lower cell density while inducing a characteristic cupped shape (stomatcytic morphology), suggesting a mechanism involving calmodulin inhibition. The results support the hypothesis that flunarizine improves tumour blood flow and oxygenation by enhancing flow properties of RBC's in solid tumours.
氟桂利嗪是一种IV类钙通道阻滞剂，可增加实体瘤缺氧区域的氧气供应，在动物肿瘤模型中具有体内放射增敏作用。目前尚不清楚该药物改善氧合的确切机制。我们推测实体瘤内的代谢条件会降低红细胞（RBC）的变形能力，而氟桂利嗪通过防止RBC变形能力的丧失发挥其体内作用。使用微流变仪比较在缺氧（pO2 < 10 mmHg）、酸性环境（pH 6.8）和乳酸浓度升高（乳酸5 mMol l-1）条件下，添加或不添加浓度为5、10和50 mg l-1氟桂利嗪的大鼠和人RBC悬液的粘度。还记录了氟桂利嗪对RBC密度和形态的影响。缺氧、低pH值和乳酸共同作用会增加人和大鼠RBC悬液的粘度。浓度为5和10 mg l-1的氟桂利嗪可防止粘度增加。该药物导致剂量依赖性地向较低细胞密度转变，同时诱导出特征性的杯状形状（口形细胞形态），提示其作用机制涉及钙调蛋白抑制。这些结果支持了氟桂利嗪通过增强实体瘤中RBC的流动特性来改善肿瘤血流和氧合的假说。
