Whaun J M, Brown N D
Division of Pathology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Ann Trop Med Parasitol. 1990 Jun;84(3):229-37. doi: 10.1080/00034983.1990.11812462.
The esters of cephalotaxine-harringtonine, homoharringtonine and deoxyharringtonine--have been reported by both Chinese and American oncologists as useful in the treatment of human nonlymphoblastic leukaemias and selected solid tumours of the head and neck. We report our results with homoharringtonine, currently a Phase II clinical trial drug with the National Cancer Institute, in the treatment of malaria. Homoharringtonine, 2.7-3.4 nM, was effective in causing 50% growth inhibition of two strains of chloroquine-resistant Plasmodium falciparum malaria in vitro. In vivo tests in mice infected with P. yoelii showed that this drug was effective in inhibiting parasite growth in this system as well. Histologically, the drug was associated with karyorrhexis. Drug-exposed cells showed decreased levels of putrescine and spermidine and increased spermine levels. Our findings not only demonstrate the potential usefulness of homoharringtonine in the treatment of chloroquine-resistant malaria, but also demonstrate the advantage of applying comparative biochemistry and an understanding of biological mechanisms in a rational approach to the development and treatment of diseases including malaria.
中国和美国的肿瘤学家均报告说，三尖杉酯碱 - 高三尖杉酯碱、高哈林通碱和脱氧哈林通碱的酯类化合物对治疗人类非淋巴细胞白血病以及某些头颈实体瘤有效。我们报告了高哈林通碱（目前是美国国立癌症研究所的II期临床试验药物）治疗疟疾的结果。2.7 - 3.4 nM的高哈林通碱在体外对两株耐氯喹恶性疟原虫产生50%生长抑制效果显著。对感染约氏疟原虫的小鼠进行的体内试验表明，该药物在该系统中抑制寄生虫生长也有效。在组织学上，该药物与核碎裂有关。药物处理过的细胞中腐胺和亚精胺水平降低，精胺水平升高。我们的研究结果不仅证明了高哈林通碱在治疗耐氯喹疟疾方面的潜在效用，还证明了应用比较生物化学以及理解生物学机制对于包括疟疾在内的疾病的合理开发和治疗方法的优势。
