Purging leukemic cells from simulated human remission marrow with alkyl- lysophospholipid

Abstract

Alkyl-lysophospholipids (ALP) are analogues of 2- lysophosphatidylcholine that have been reported to have selective antitumor activity. These compounds could potentially be useful in purging bone marrow of leukemic cells in autologous marrow transplantation in acute leukemia. To determine the efficacy of pharmacological purging by ALP, we have designed a human assay system to mimic the conditions expected in the clinical setting of autotransplantation using remission marrow. A simulated remission marrow (SRM) was prepared by mixing normal marrow cells and HL60 cells in a ratio of 1,000:1. The effect of cryopreservation on ALP-treated normal, HL60, and SRM cells was examined. In separate experiments, ALP significantly reduced the number of clonogenic HL60 cells with no effect on normal marrow progenitors. The effect of ALP was more apparent after cryopreservation. Incubation of HL60 cells with 50 micrograms/mL ALP for four hours followed by cryopreservation resulted approximately in a 3 log reduction of clonogenic HL60 cells. ALP also selectively purged the small number of leukemic cells from SRM. In SRM, the data suggested that ALP had indirect cytotoxic activity on leukemic cells by enhancing the cytotoxic activity of monocytes in addition to its direct effect. We found no evidence that clonogenic HL60 cells decreased because of induction of differentiation by ALP. These data indicated that treatment of marrow cells with ALP offers an efficient means to eliminate leukemic cells from the graft.

The ether lipid 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine induces expression of fos and jun proto-oncogenes and activates AP-1 transcription factor in human leukaemic cells

“…Synthetic ether phospholipids seem to constitute a novel class of anti-tumour agents [1]. The ether lipid 1-octadecyl-2-methyl-racglycero-3-phosphocholine (ET-1 8-OCH3) is a synthetic analogue of 2-lysophosphatidylcholine and acts as an strong anti-tumour agent [2][3][4]. It has been recently reported that the ether lipid ET-18-OCH3 promotes apoptosis in human myeloid leukaemic cells [5,6].…”

Dissociation of the effects of the antitumour ether lipid ET‐18‐OCH3 on cytosolic calcium and on apoptosis

“…Several synthetic ether lipid analogues of platelet‐activating factor (1‐ O ‐alkyl‐2‐ O ‐acetyl‐ sn ‐glycero‐3‐phosphocholine, PAF) have been found to be selectively cytotoxic to tumour cells (Andreesen et al , 1978; Okamoto et al , 1987). One of them, 1‐octadecyl‐2‐methyl‐ rac ‐glycero‐3‐phosphocholine (ET‐18‐OCH 3 ), has been used to purge leukaemic cells from remission marrows in acute leukaemia (Vogler et al , 1992) and behaves as a promising anticancer drug (Dietzfelbinger et al , 1993; Houlihan et al , 1995).…”