Metabolism of ether phospholipids and analogs in neoplastic cells

Fleer, E. A. M.; Unger, Clemens; Kim, D. J.; Eibl, Hansjörg

doi:10.1007/bf02535544

Cited by 73 publications

(22 citation statements)

References 15 publications

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“…This effect is currently under study for combination chemotherapy with DNA-interactive anti-HIV nucleoside analogs. Based on the hypothesis that degradation of certain ALP analogs by a phospholipase C is required for the generation of toxic metabolites (Fleer et al, 1987), Eibl and co-workers have synthesised derivatives of ether lipids such as a series of alkylphosphocholines (APC). One of the most active APC is hexadecylphosphocholine (D 18506, Asta-Werke, Germany), which is depicted in Figure 1.…”

Section: Development Of New Ether Lipidsmentioning

confidence: 99%

Membrane-interactive lipids as experimental anticancer drugs

Berdel¹

1991

Br J Cancer

109

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Section: Development Of New Ether Lipidsmentioning

confidence: 99%

Membrane-interactive lipids as experimental anticancer drugs

Berdel¹

1991

Br J Cancer

109

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“…Thus, it seems that there is not a marked enantiomer specificity in the ET-18-OCH 3 action that could suggest a lack of stereospecific interactions with a macromolecular target. It has been reported that ET-18-OCH 3 can be a substrate for a phospholipase C-like enzyme, able to split off or exchange the phosphocholine moiety, leading to the notion that the generation of 1-O-octadecyl-2-O-methyl-rac-glycerol could be responsible for the cytotoxic properties of ET-18-OCH 3 [65,66]. However, we found no apoptotic effect when HL-60 cells were treated with a number ET-18-OCH 3 -or ET-16-OCH 3 -derived diglycerides and analogues [15], indicating that the products generated by a phospholipase C-mediated degradation of ET-18-OCH 3 are unable to induce an apoptotic response.…”

Section: Structure-activity Relationship Studies In Et-18-och 3 -Indumentioning

confidence: 99%

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

Mollinedo¹,

Gajate²,

Martín‐Santamaría³

et al. 2004

CMC

122

103

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Synthetic ether-linked analogues of phosphatidylcholine and lysophosphatidylcholine, collectively named as antitumour lipids (ATLs), were initially synthesized in the late 60s, but have attracted a renewed interest since the finding that the ether lipid 1-O -octadecyl-2-O -methyl-rac-glycero-3-phosphocholine (ET-18-OCH 3 , edelfosine), a synthetic analogue of 2-lysophosphatidylcholine considered the ATL prototype, induces a selective apoptotic response in tumour cells, sparing normal cells. Unlike most chemotherapeutic agents currently used, ET-18-OCH 3 does not interact with DNA, but act at the cell membrane, and thereby its effects seem to be independent of the proliferative state of target cells. Each part of the molecular structure of ET-18-OCH 3 is important for its optimal proapoptotic activity. Recent progress has unveiled the molecular mechanism underlying the apoptotic action of ET-18-OCH 3 , involving membrane rafts and Fas/CD95 death receptor, and has led to the proposal of a two-step model for the ET-18-OCH 3 selective action on cancer cells, namely: a) ET-18-OCH 3 uptake into the tumour cell, but not in normal cells; b) intracellular activation of Fas/CD95 through its translocation and capping into membrane rafts. ET-18-OCH 3 constitutes the first antitumour drug acting through the intracellular activation of the Fas/CD95 death receptor. Computational docking studies have allowed us to propose a molecular model for the putative interaction of ET-18-OCH 3 with the intracellular Fas/CD95 death domain. This novel mechanism of action represents a new way to target tumour cells in cancer chemotherapy and can be of interest as a new framework in designing novel and more selective proapoptotic antitumour drugs.

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“…This may allow treatment with a few doses. Alkyl-PCs are slowly metabolized by phospholipases to form products such as choline and long-chain alcohols that are physiological metabolites and can be recycled into phospholipids (9). Although alkyl-PCs as pure substances are effective and may accumulate in the affected organs, they cause some side effects.…”

Section: Discussionmentioning

confidence: 99%

Effects of Miltefosine and Other Alkylphosphocholines on Human Intestinal Parasite Entamoeba histolytica

Seifert¹,

Duchêne²,

Wernsdorfer³

et al. 2001

Antimicrob Agents Chemother

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The protozoan parasite Entamoeba histolytica is the cause of amoebic dysentery and liver abscess. It is therefore responsible for significant morbidity and mortality in a number of countries. Infections with E. histolytica are treated with nitroimidazoles, primarily with metronidazole. At this time, there is a lack of useful alternative classes of substances for the treatment of invasive amoebiasis. Alkylphosphocholines (alkyl-PCs) such as hexadecyl-PC (miltefosine) were originally developed as antitumor agents, but recently they have been successfully used for the treatment of visceral leishmaniasis in humans. We examined hexadecyl-PC and several other alkyl-PCs with longer alkyl chains, with and without double bond(s), for their activity against two strains of E. histolytica. The compounds with the highest activity were oleyl-PC, octadecyl-PC, and nonadecenyl-PC, with 50% effective concentrations for 48 h of treatment between 15 and 21 M for strain SFL-3 and between 73 and 98 M for strain HM-1:IMSS. We also tested liposomal formulations of these alkyl-PCs and miltefosine. The alkyl-PC liposomes showed slightly lower activity, but are expected to be well tolerated. Liposomal formulations of oleyl-PC or closely related alkyl-PCs could be promising candidates for testing as broadspectrum antiprotozoal and antitumor agents in humans.

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Metabolism of ether phospholipids and analogs in neoplastic cells

Cited by 73 publications

References 15 publications

Membrane-interactive lipids as experimental anticancer drugs

Membrane-interactive lipids as experimental anticancer drugs

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

Effects of Miltefosine and Other Alkylphosphocholines on Human Intestinal Parasite Entamoeba histolytica

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