Edelfosine
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Names | |
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IUPAC name
2-Methoxy-3-(octadecyloxy)propyl 2-(trimethylammonio)ethyl phosphate
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Other names
ET-18-O-CH3 ; 1-Ooctadecyl-2-O-methyl-glycero-3-phosphocholine
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Identifiers | |
70641-51-9 ![]() |
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ChEBI | CHEBI:78649 ![]() |
ChEMBL | ChEMBL107514 ![]() |
ChemSpider | 1350 ![]() |
Jmol 3D model | Interactive image |
PubChem | 1392 |
UNII | 1Y6SNA8L5S ![]() |
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Properties | |
C27H58NO6P | |
Molar mass | 523.74 g·mol−1 |
Vapor pressure | {{{value}}} |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references | |
Edelfosine (ET-18-O-CH3 ; 1-octadecyl-2-O-methyl-glycero-3-phosphocholine)[1] is a synthetic alkyl-lysophospholipid (ALP). It has antineoplastic (anti-cancer) effects.[2]
Like all ALPs, it incorporates into the cell membrane and does not target the DNA. In many tumor cells, it causes selective apoptosis, sparing healthy cells.[3] Edelfosine can activate the Fas/CD95 cell death receptor,[4] can inhibit the MAPK/ERK mitogenic pathway and the Akt/protein kinase B (PKB) survival pathway.[3][5] Aside from these plasma-level effects, edelfosine also affects gene expression by modulating the expression and activity of transcription factors.[3][4]
It has immune modulating properties.[6] These characteristics cause edelfosine also to affect HIV,[7] parasitic,[4][8] and autoimmune diseases.[4][9]
It can complement classic anti-cancer drugs such as cisplatin.[10]
It can be administered orally, intraperitoneally (IP) and intravenously (IV).
Edelfosine and other ALPs can be used for purging residual leukemic cells from bone marrow transplants.[4][11][12]
It is an analog of miltefosine and perifosine.
Contents
In vitro and in vivo results
Edelfosine apoptosis-inducing abilities were studied with several types of cancer, among them multiple myeloma[13] and non-small and small cell lung carcinoma cell lines.[14] In vivo activity against human solid tumors in mice was shown against malignant gynecological tumor cells,[3] like ovarian cancer, and against breast cancer. In vivo biodistribution studies demonstrated a “considerably higher” accumulation of Edelfosine in tumor cells than in other analyzed organs. It remained undergraded for a long time.[3][15][16]
Clinical trials
Several clinical trials were conducted. Among them a phase I trials with solid tumors or leukemias and phase II with non-small-cell lung carcinomas (NSCLC).[3] In a Phase II clinical trial for use of Edelfosine in treating leukemia with bone marrow transplants, it was found to be safe and 'possibly effective'.[17] A phase II trial for the treatment of brain cancers was also reported.[18] It showed encouraging results in stopping the growth of the tumor and a considerable improvement in the “quality of life” of the patients. A phase II trial on the effect of Edelfosine on advanced non-small-cell bronchogenic carcinoma had a “remarkable” “high proportion of patients with stationary tumor status” as result, stable disease after initial progression in 50% of the patients.[17] [19]
Toxicity
In animal tests the main toxic effect was gastrointestinal irritation. There were no significant negative systemic side effects observed. It showed that edelfosine can be given over a long period safely. Most important, in contrast to many DNA-directed anti-cancer drugs, no bone marrow toxicity was in vivo observed. Those findings in animals were confirmed in clinical trials. No mutagenic or cytogenetic effects were observed.[3][20]
History
In the 1960s Herbert Fischer and Paul Gerhard in Freiburg, Germany, found that lysolecitin (2-lysophosphhatidylcholine, LPC) increases the phagocytotic activity of macrophages. Since LPC had a short half-life, synthetic LPC-analogues were tested by Fischer, Otto Westphal, Hans Ulrich Weltzien and Paul Gerhard Munder. Unexpectedly, some of the substances showed strong anti-tumor activity and among them Edelfosine was the most effective. It is therefore considered to be the prototype of synthetic anti-cancer lipids.[20][21]
References
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Further reading
- Edelfosine-induced metabolic changes in cancer cells that precede the overproduction of reactive oxygen species and apoptosis. 2010
- Edelfosine, apoptosis, MDR and Na+/H+ exchanger: Induction mechanisms and treatment implications.
- Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis.
- Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts
- Novel Anti-Inflammatory Action of Edelfosine Lacking Toxicity with Protective Effect in Experimental Colitis
- Sensitivity of K562 and HL-60 Cells to Edelfosine, an Ether Lipid Drug, Correlates with Production of Reactive Oxygen Species