Alkyl-lysophospholipids as anticancer agents and enhancers of radiation-induced apoptosis.
Synthetic alkyl-lysophospholipids (ALPs, also referred to as ether-phospholipids) have been studied as antitumor agents for more than a decade. Classical examples of these ALPs include 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH(3); Edelfosine) and hexadecylphosphocholine (HePC; Miltefosine). Unlike most currently available chemotherapeutic drugs that target the nuclear DNA, ALPs exert their action at the plasma membrane level, where they interfere with mitogenic signal transduction pathways. Whereas malignant cells are highly sensitive to the lethal action of ALPs, normal cells remain relatively unaffected, illustrating the potential selective antitumor properties of this class of drugs. Recently, ALPs have regained interest because of their capacity to induce apoptosis in various tumor cell lines. Moreover, in combination with other (conventional) anticancer regimens, ALPs seem to cause an additive and sometimes synergistic cytotoxic effect. These biologic properties make ALPs attractive drugs for further clinical evaluation. The present review discusses recent insights into the mode(s) of action of ALPs, their interaction with ionizing radiation, and clinical application.
Ruiter
G A
GA
Division of Cellular Biochemistry, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), Amsterdam, The Netherlands.
Verheij
M
M
Zerp
S F
SF
van Blitterswijk
W J
WJ
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010742:Phospholipid Ethers / Q000627:therapeutic use*; D010743:Phospholipids / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D010726:Phosphodiesterase Inhibitors; D010742:Phospholipid Ethers; D010743:Phospholipids; D010767:Phosphorylcholine; C026659:edelfosine; C105905:perifosine; C039128:miltefosine