**3.1 Uptake and absorption of alkylphospholipids**

Due to their amphiphilic nature alkylphospholipids are easily incorporated into cell membranes in substantial amounts and then spread among intracellular membrane compartments, where they accumulate and interfere with a wide variety of key enzymes (Unger et al., 1992; van Blitterswijk et al., 1987). At lower, clinically relevant concentrations alkylphospholipids interfere with phospholipid turnover and lipid-based signal transduction pathways. In mouse S49 lymphoma cells alkylphospholipids accumulate in detergent-resistant, sphingolipid- and cholesterol-enriched lipid raft domains and are rapidly internalized by clathrin-independent, raft-mediated endocytosis (van der Luit et al., 2007). Alkylphospholipid uptake in KB carcinoma cells, however, appears to be raftindependent and mediated by a yet unidentified ATP-dependent lipid transporter (Vink et al., 2007). In leukemic cells treatment with alkylphospholipids induces the formation of membrane raft aggregates containing Fas/CD95 death receptor and the adaptor molecule Fas-associated death domain-containing protein (FADD), which are critical in the triggering of apoptosis (Gajate et al., 2009). Miltefosine and other alkylphospholipids also alter intracellular cholesterol traffic and metabolism leading to an increased uptake, synthesis and accumulation of cholesterol in the cell (Carrasco et al., 2008; Jimenez-Lopez et al., 2006; Marco et al., 2009). As cholesterol and sphingomyelin content are critical for the integrity and functionality of membrane lipid rafts, the disturbance of the cholesterol/sphingomyelin ratio could alter signaling pathways associated with these membrane domains.
