ARTEMISININ-DERIVED SESQUITERPENE LACTONES AS POTENTIAL ANTITUMOR COMPOUNDS - CYTOTOXIC ACTION AGAINST BONE-MARROW AND TUMOR-CELLS

We determined the in vitro cytotoxic activity of the sesquiterpene lac tone endoperoxide artemisinin (1) and some chemically prepared derivat ives, which have been found to display cytotoxicity to cloned murine E hrlich ascites tumour (EAT) cells and human HeLa cells and against mur ine bone marrow using a clonogenic assay for committed progenitor cell s of the granulocyte-monocyte lineage (CFU-GM assay). Comparing artemi sinin (1) to deoxyartemisinin (2), the endoperoxide group appeared to play a role in cytotoxicity to CFU-GM cells. Dimers of dihydroartemisi nin and dihydrodeoxyartemisinin revealed that the stereochemistry of t he ether linkage of the dimers was a more important determinant for th is cytotoxic activity. The nonsymmetrical dimer of dihydroartemisinin (3) and the corresponding endoperoxide-lacking dimer of dihydrodeoxyar temisinin (5) were equally cytotoxic to CFU-GM cells. Despite the diff erences between both systems, it may be stated that most compounds dis played higher cytotoxicity to CFU-GM cells than to EAT cells. Dimers o f dihydroartemisinin (3, 4) were selected as potential antitumour comp ounds and subjected to the National Cancer Institute drug-screening pr ogramme consisting of about sixty human cancer cell lines derived from nine different tissues. Both compounds displayed the same specific cy totoxicity pattern. Throughout the screen dimer 3 was more active than 4.