Influence of serum levels on leukemic cell destruction by the ether lipid ET-18-OCH3

Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia: enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl‐lysophospholipid ET‐18‐OCH3

“…As shown in Fig 2A, the threshold for cytotoxicity on these subsets was achieved at an ET-18-OCH 3 dose of 50 mg/ml when cells were incubated for 4 h at 378C in the presence of 10% serum. It has been reported that serum may interfere with the cytotoxic effects of ET-18-OCH 3 (Heesbeen et al, 1995). Therefore, serum levels were modulated and its influence on cytotoxicity was determined at doses of 25 mg/ml and 50 mg/ml ET-18-OCH 3 respectively.…”

“…The current study is the first in which the effects of ET-18-OCH 3 on both the haematopoietic progenitor cell (STRA) and the primitive haematopoietic stem cell (LTRA) were analysed in comparison with a leukaemia-initiating stem cell (LISC). Initially, the incubations were performed in the presence 10% FCS, analogous to most studies on the cytotoxic effects of ET-18-OCH 3 (Okamoto et al, 1987;Heesbeen et al, 1995;Zimmer et al, 1995;Koenigsmann et al, 1996). Under these conditions, no effect on STRA cells was observed at ET-18-OCH 3 concentrations up to 50 mg/ml (Fig 2), confirming previous studies (Okamoto et al, 1987;Heesbeen et al, 1995).…”

“…Initially, the incubations were performed in the presence 10% FCS, analogous to most studies on the cytotoxic effects of ET-18-OCH 3 (Okamoto et al, 1987;Heesbeen et al, 1995;Zimmer et al, 1995;Koenigsmann et al, 1996). Under these conditions, no effect on STRA cells was observed at ET-18-OCH 3 concentrations up to 50 mg/ml (Fig 2), confirming previous studies (Okamoto et al, 1987;Heesbeen et al, 1995). However, by decreasing the serum levels during the incubation, an increase in the cytotoxic effect on the leukaemic cells was noticed without affecting normal STRA cells, confirming the selectivity of ET-18-OCH 3 towards leukaemic cells (Fig 3).…”

“…There is some evidence that a preferential accumulation of the alkyl-lysophospholipid occurs in leukaemic cells owing to the lack of alkyl-cleavage enzymes in these cells. The accumulation of alkyl-lysophospholipids might disturb the normal phospholipid metabolism and, subsequently, result in a disrupted plasma membrane (Andreesen et al, 1978;Chabot et al, 1989;Heesbeen et al, 1995). The cytotoxic effect of alkyl-lysophospholipids is known to be temperaturedependent (Andreesen et al, 1983) and, therefore, it may be anticipated that the combination of ET-18-OCH 3 and hyperthermia will be even more effective in eliminating leukaemic cells from an autograft than ET-18-OCH 3 or hyperthermia as singular purging agents.…”

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

“…Because ET-18-OCH 3 binds strongly to serum proteins, primarily albumin and high density lipoprotein (HDL) [50], the action of ET-18-OCH 3 is very dependent on the amount of serum present in the assay. Increasing amounts of serum inhibit the cytotoxic effects of ET-18-OCH 3 in a concentration-dependent manner [50][51][52](Gajate, C. and Mollinedo, F., unpublished data). The specific action of ET-18-OCH 3 and other ATLs on apoptosis should be separated from their non-specific lytic effect on membranes (detergent-like action) shown by ATLs at elevated doses.…”