Ether Lipids and Derivatives as Investigational Anticancer Drugs

Abstract

There is considerable evidence that certain ether lipids represent a new class of antineoplastic agents. The activity of some of these structures is partially mediated through non-specific host resistance cells. In addition, more importantly, these ether lipids have been shown to be cytotoxic for cells from a wide variety of tumors and leukemias. The site of the cytotoxic action of ether lipids appears to be the cell membrane. They inhibit the biosynthesis of phosphatidylcholine as well as the activity of protein kinase C and might interfere with some growth factor receptors. Higher concentrations of some of these compounds are not compatible with the lipid bilayer matrix of the membrane. However, it remains uncertain whether or not these effects represent the only mechanisms for the cytotoxic action of this material. Further experiments elucidating the molecular mechanisms in the cytotoxicity of these compounds are necessary. In vivo a wide variety of mouse and rat tumors have been found to be sensitive to the therapeutic activity of ether lipids, with other tumor and leukemia models, however, being resistant to this material. Clinical phase I pilot trials have been completed, showing tumor response in a small number of patients treated, and 3 drugs are currently in phase II studies. Some of these ether lipids are preferentially cytotoxic to leukemic cells in comparison with normal bone marrow cells within a certain dose range. Thus, they are suitable for purging residual leukemic cells from remission bone marrow used for autologous bone marrow transplantation. A phase I/II study of autologous bone marrow transplantation in acute leukemia using bone marrow cells treated with ether lipids is in progress.