Bray P G, Boulter M K, Ritchie G Y, Howells R E, Ward S A
Liverpool School of Tropical Medicine, UK.
Mol Biochem Parasitol. 1994 Jan;63(1):87-94. doi: 10.1016/0166-6851(94)90011-6.
Control of falciparum malaria has become almost impossible in many areas due to the development of resistance to chloroquine and other antimalarial drugs. Verapamil and a number of unrelated compounds which chemosensitise multi-drug resistant cancer cells also enhance chloroquine susceptibility in Plasmodium falciparum. Chloroquine is accumulated to lower levels in resistant plasmodia, hence the reversal of chloroquine resistance has been attributed to the ability of chemosensitising agents to increase the amount of chloroquine accumulated by the resistant parasite. We have conducted a detailed examination of the effect of verapamil on chloroquine sensitivity and its relationship to chloroquine accumulation. The ability of verapamil to increase steady-state chloroquine accumulation was found to be totally insufficient to explain the increase in chloroquine sensitivity caused by the drug. In contrast, when chloroquine accumulation was increased by raising the pH gradient, the corresponding shifts in sensitivity to chloroquine could be accurately predicted. These results were confirmed with other classes of chemosensitisers and we conclude that an alternative mechanistic explanation is required to completely explain the reversal of chloroquine resistance in P. falciparum.
由于对氯喹及其他抗疟药物产生耐药性，在许多地区控制恶性疟几乎已变得不可能。维拉帕米及一些可使多药耐药癌细胞产生化学增敏作用的不相关化合物，也能增强恶性疟原虫对氯喹的敏感性。氯喹在耐药疟原虫体内的蓄积水平较低，因此氯喹耐药性的逆转被归因于化学增敏剂增加耐药寄生虫对氯喹蓄积量的能力。我们已对维拉帕米对氯喹敏感性的影响及其与氯喹蓄积的关系进行了详细研究。发现维拉帕米增加氯喹稳态蓄积的能力完全不足以解释该药物引起的氯喹敏感性增加。相反，当通过提高pH梯度增加氯喹蓄积时，对氯喹敏感性的相应变化能够被准确预测。这些结果在其他类别的化学增敏剂中得到了证实，我们得出结论，需要一种替代性的机制解释来完全解释恶性疟原虫中氯喹耐药性的逆转。
