Research on the Antitumor Compounds from Cephalotaxus Hainanensis

Cephalotaxus hainanensis, commonly known as Hainan plum-yew, is a species of the family of Cephalotaxaceae and distributes mainly in southern China. Fujian folk medicine already had a record of treating tumors with the bark ofCephalotaxus fortunei, and the 187th Hospital of the Chinese People’s Liberation Army (PLA) had used the crude preparations ofCephalotaxus hainanensisin cancer patients. In 1972, Powellet al. reported the isolation of four ester alkaloids including harringtonine, homoharringtonine, iso-harringtoine, and deoxyharringtoine fromCephalotaxus harringtonia, although they did not continue the studies. In 1973, the Institute of Materia Medica (IMM) of Chinese Academy of Medical Sciences and the 187th Hospital of the Chinese People’s Liberation Army began to investigate the antitumor activities ofCephalotaxus hainanensisand its active pharmaceutical ingredients (APIs) in terms of plant resources, chemical composition, synthesis and analysis of APIs, and pharmacology. A total of 19 monomers have been identified, among which eight compounds were for the first time obtained from the plant. Pharmacological tests showed that all the four ester alkaloids had remarkable anti-tumor activities, especially harringtonine and homoharringtonine.

A clinical trial demonstrated that patients with acute myeloid leukemia were highly responsive to harringtonine and homoharringtonine, with a complete response rate of 27%. Furthermore, the researchers completed the establishment of the determination methods and the quality control standards of harringtonine and homoharringtonine, the acute and chronic toxicity tests, and the studies on the absorption, distribution, excretion,and action mechanisms of these APIs in human body. Harringtonine has been clinically applied in treating 107 patients with various leukemias(including 58 cases of acute myeloid leukemia), and the overall response rate reached 86.2%. It has also shown certain efficacy in treating erythroid leukemia and acute monocytic leukemia.

Further research on the plant resources of the genus Cephalotaxus has confirmed that the contents of APIs are highest inCephalotaxus hainanensisisamong the eight Cephalotaxaceae species in China. In addition, the research group for the first completed the semi-synthesis and pharmacological research of the active ester alkaloids. A high-performance thin-layer chromatography (HPTLC)method has also been developed for the analysis of the crude alkaloids and harringtonine isolated fromCephalotaxus hainanensisis. The Pharmaceutical Plant of the Institute of Materia Medica of Chinese Academy of Medical Sciences produced 360 000 vials of Harringtonine Injection during the period from 1982 to 1985, with a total output value of 350 000 yuan.

The HOAP regimen (harringtonine or homoharringtonine, vincristine,Ara-C, and prednisone) has been used as one of the first-line regimens for acute non-lymphocytic leukemia in many institutions in China.