{{chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 457477026 | ImageFile = Edelfosine.svg | ImageClass = skin-invert-image | ImageSize = 250px | SystematicName = 2-Methoxy-3-(octadecyloxy)propyl 2-(trimethylazaniumyl)ethyl phosphate | OtherNames = ET-18-O-CH3; 1-octadecyl-2-''O''-methyl-glycero-3-phosphocholine |Section1={{Chembox Identifiers | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 1Y6SNA8L5S | CASNo = 70641-51-9 | CASNo_Ref = {{cascite|changed|??}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C27H58NO6P/c1-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-23-32-25-27(31-5)26-34-35(29,30)33-24-22-28(2,3)4/h27H,6-26H2,1-5H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = MHFRGQHAERHWKZ-UHFFFAOYSA-N | PubChem = 1392 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 1350 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 78649 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 107514 | SMILES = [O-]P(=O)(OCC(OC)COCCCCCCCCCCCCCCCCCC)OCC[N+](C)(C)C | InChI = InChI=1S/C27H58NO6P/c1-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-23-32-25-27(31-5)26-34-35(29,30)33-24-22-28(2,3)4/h27H,6-26H2,1-5H3 }} |Section2={{Chembox Properties | C=27 | H=58 | N=1 | O=6 | P=1 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = }} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} |Section5={{Chembox Pharmacology | AdminRoutes = | Bioavail = | Metabolism = | HalfLife = | ProteinBound = | Excretion = | Legal_status = | Legal_US = | Legal_UK = | Legal_AU = | Legal_CA = | PregCat = | PregCat_AU = | PregCat_US = }} }}

'''Edelfosine''' (ET-18-O-CH3; 1-octadecyl-2-''O''-methyl-glycero-3-phosphocholine)<ref name=R2008>{{cite journal|url=http://apjcn.nhri.org.tw/server/APJCN/Volume17/vol17suppl.1/204-207S12-1.pdf |title=The antitumor ether lipid Edelfosine (ET-18-O-CH3) induces apoptosis in H-ras transformed human breast epithelial cells: by blocking ERK1/2 and p38 mitogenactivated protein kinases as potential targets |year=2008 |archive-url=https://web.archive.org/web/20110811144708/http://apjcn.nhri.org.tw/server/APJCN/Volume17/vol17suppl.1/204-207S12-1.pdf |archive-date=2011-08-11 }}</ref> is a synthetic alkyl-lysophospholipid (ALP). It has antineoplastic (anti-cancer) effects.<ref>{{cite journal | pmid = 9844614 | volume=16 | issue=8 | title=The anticancer drug edelfosine is a potent inhibitor of neovascularization in vivo | year=1998 | pages=549–53 | journal=Cancer Invest. | doi=10.3109/07357909809032884| last1=Vogler | first1=William R. | last2=Liu | first2=Jianguo | last3=Volpert | first3=Olga | last4=Ades | first4=Edwin W. | last5=Bouck | first5=Noel }}</ref>

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.<ref name=Mollinedo-2002>{{cite journal|last=Gajate|first=C|author2=Mollinedo F|title=Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells.|journal=Current Drug Metabolism|year=2002|volume=5|issue=3|pages=491–525|doi=10.2174/1389200023337225|pmid=12369895|hdl=10261/59536|hdl-access=free}}</ref> Edelfosine can activate the Fas/CD95 cell death receptor,<ref name=Mollindeo-2004>{{cite journal|last=Mollinedo|first=F |author2=Gajate C |author3=Martín-Santamaria S |author4=Gago F|title=ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas/CD95 death receptor.|journal=Current Medicinal Chemistry|year=2004|volume=11|issue=24|pages=3163–84|pmid=15579006|doi=10.2174/0929867043363703}}</ref> can inhibit the MAPK/ERK mitogenic pathway and the Akt/protein kinase B (PKB) survival pathway.<ref name=Mollinedo-2002 /><ref name=Ruiter-2003>{{cite journal|last=Ruiter|first=GA|author2=Zerp SF |author3=Bartelink H |author4=Blitterswijk WJ van |author5= Verheij M |title=Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway.|journal=Anti-Cancer Drugs|year=2003|volume=14|issue=2|pages=167–73|pmid=12569304|doi=10.1097/00001813-200302000-00011|s2cid=42468599}}</ref> Aside from these plasma-level effects, edelfosine also affects gene expression by modulating the expression and activity of transcription factors.<ref name=Mollinedo-2002 /><ref name=Mollindeo-2004 />

It has immune modulating properties.<ref>{{cite journal|last=Munder|first=PG|author2=Modolell M |author3=Andreesen R |author4=Weltzien HU |author5= Westphal O |title=Lysophosphatidylcholine ( Lysolecithin ) and its Synthetic Analogues. Immunemodulating and Other Biologic Effects |journal=Springer Seminars in Immunopathology|year=1979|volume=203|issue=2|pages=187–203 |doi=10.1007/bf01891668|s2cid=42907729}}</ref> These characteristics cause edelfosine also to affect HIV,<ref name=Lucas-2010>{{cite journal|last=Lucas|first=A|author2=Kim Y |author3=Rivera-Pabon O |title=Targeting the PI3K/Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds.|journal=PLOS ONE|year=2010|volume=5|issue=9|article-number=e13121|pmid=20927348|doi=10.1371/journal.pone.0013121 |pmc=2948033|bibcode=2010PLoSO...513121L|display-authors=etal|doi-access=free}}</ref> parasitic,<ref name=Mollindeo-2004 /><ref name=Azzouz-2005>{{cite journal|last=Azzouz|first=S |author2=Maache M |author3=Garcia RG |author4=Osuna A|title=activity of edelfosine, miltefosine and ilmofosine.|journal=Basic & Clinical Pharmacology & Toxicology|year=2005|volume=96|issue=1|pages=60–5|pmid=15667597|doi=10.1111/j.1742-7843.2005.pto960109.x|doi-access=free}}</ref> and autoimmune diseases.<ref name=Mollindeo-2004 /><ref name=KF-1992>{{cite journal|last=Klein-Franke|first=A|author2=Munder PG|title=Alkyllysophospholipid prevents induction of experimental allergic encephalomyelitis.|journal=Journal of Autoimmunity|year=1992|volume=5|issue=1|pages=83–91|pmid=1373062|doi=10.1016/s0896-8411(05)80053-8}}</ref> <br /> It can complement classic anti-cancer drugs such as cisplatin.<ref name=noseda-1988>{{cite journal|last=Noseda|first=A|author2=Berens ME |author3=White JG |author4= Modest EJ |title=In vitro antiproliferative activity of combinations of ether lipid analogues and DNA-interactive agents against human tumor cells.|journal=Cancer Research|year=1988|volume=48|issue=7|pages=1788–91|pmid=3349458}}</ref>

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.<ref name=Mollindeo-2004 /><ref name=Berdel-1990>{{cite journal|last=Berdel|first=WE|title=Ether lipids and derivatives as investigational anticancer drugs. A brief review.|journal=Onkologie|year=1990|volume=13|issue=4|pages=245–50|doi=10.1159/000216771|pmid=2234777}}</ref><ref name=Vogler-1993>{{cite journal|last=Vogler|first=WR|author2=Berdel WE|title=Autologous bone marrow transplantation with alkyl-lysophospholipid-purged marrow.|journal=Journal of Hematotherapy|year=1993|volume=2|issue=1|pages=93–102|doi=10.1089/scd.1.1993.2.93|pmid=7921970}}</ref>

It is an analog of miltefosine and perifosine.

==''In vitro'' and ''in vivo'' results== Edelfosine apoptosis-inducing abilities were studied with several types of cancer, among them multiple myeloma<ref name=Mollinedo-2010>{{cite journal|last=Mollinedo|first=PG|author2=Iglesia-Vicente J de la |author3=Gajate C |title=Lipid raft-targeted therapy in multiple myeloma.|journal=Oncogene|year=2010|volume=29|issue=26|pages=3748–3757|pmid=20418917|doi=10.1038/onc.2010.131|display-authors=etal|doi-access=free}}</ref> and non-small and small cell lung carcinoma cell lines.<ref name=Shafer-2003>{{cite journal|last=Shafer|first=SH|author2=Williams CL|title=Non-small and small cell lung carcinoma cell lines exhibit cell type-specific sensitivity to edelfosine-induced cell death and different cell line-specific responses to edelfosine treatment.|journal=International Journal of Oncology|year=2003|volume=23|issue=2|pages=389–400|doi=10.3892/ijo.23.2.389|pmid=12851688}}</ref> ''In vivo'' activity against human solid tumors in mice was shown against malignant gynecological tumor cells,<ref name=Mollinedo-2002 /> 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.<ref name=Mollinedo-2002 /><ref name=Estella-2009>{{cite journal|last=Estella-Hermoso de Moendoza|first=A|author2=Campanero M a |author3=Iglesi-Vincente J de la |title=Antitumor alkyl ether lipid edelfosine: tissue distribution and pharmacokinetic behavior in healthy and tumor-bearing immunosuppressed mice.|journal=Clinical Cancer Research|year=2009|volume=15|issue=3|pages=858–64|pmid=19188156|doi=10.1158/1078-0432.CCR-08-1654|display-authors=etal|doi-access=free}}</ref><ref name=Arnold-1978>{{cite journal|last=Arnold|first=B|author2=Reuther R |author3=Weltzien HU |title=Distribution and metabolism of synthetic alkyl analogs of lysophosphatidylcholine in mice.|journal=Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism|year=1978|volume=530|issue=1|pages=47–55|doi=10.1016/0005-2760(78)90125-x|pmid=687654}}</ref>

==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).<ref name=Mollinedo-2002 /> 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'.<ref name="asco.org">{{cite web |url=http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=29&abstractID=8944 |title=A Phase I/II trial of edelfosine purging of autologous bone marrow transplantation (ABMT) in acute leukemia (Meeting abstract). |year=1996 |access-date=2011-02-28 |archive-date=2012-03-08 |archive-url=https://web.archive.org/web/20120308092256/http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=29&abstractID=8944 }}</ref> A phase II trial for the treatment of brain cancers was also reported.<ref name=USPAT6514519>{{cite web|last=United States Patent 6514519 |title=Edelfosin for the treatment of brain tumors |url=http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=6514519&OS=6514519&RS=6514519 |archive-url=https://archive.today/20121214202325/http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=6514519&OS=6514519&RS=6514519 |archive-date=14 December 2012 |access-date=11 May 2011 }}</ref> 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.<ref name="asco.org"/><ref name=Drings-1992>{{cite journal|last=Drings|first=P|author2=Günther I |author3=Gatzmeier U |author4=ulbrich F |title=Final Evaluation of a Phase II Study on the Effect of Edelfosine (an Ether Lipid) in Advanced Non-Small-Cell Bronchogenic Carcinoma.|journal=Onkologie|year=1992|volume=15|issue=5|pages=375–382|doi=10.1159/000217391|display-authors=etal}}</ref>

==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.<ref name=Mollinedo-2002 /><ref name=Houlihan-1995>{{cite journal|last=Houlihan|first=WJ|author2=Lohmeyer M |author3=Workman P |author4= Cheon SH |title=Phospholipid antitumor agents.|journal=Medicinal Research Reviews|year=1995|volume=15|issue=3|pages=157–223|pmid=7658750|doi=10.1002/med.2610150302|s2cid=6997551}}</ref>

==History== In the 1960s Herbert Fischer and Paul Gerhard in Freiburg, Germany, found that lysolecithin (2-lysophosphatidylcholine, 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.<ref name=Houlihan-1995 /><ref name=munder-1969>{{cite journal|last=Munder|first=PG|author2=Ferber E |author3=Modolell M |author4= Fischer H. |title=The influence of various adjuvants on the metabolism of phospholipids in macrophages.|journal=International Archives of Allergy and Applied Immunology|year=1969|volume=36|issue=1|pages=117–28|doi=10.1159/000230731|pmid=4980286}}</ref>

==References== {{reflist}}

==Further reading== *[http://www.biomedcentral.com/1752-0509/4/135 Edelfosine-induced metabolic changes in cancer cells that precede the overproduction of reactive oxygen species and apoptosis. 2010] *[https://doi.org/10.1023%2FA%3A1009645927931 Edelfosine, apoptosis, MDR and Na+/H+ exchanger: Induction mechanisms and treatment implications. ] *[https://archive.today/20130415160837/http://jac.oxfordjournals.org/content/54/4/704.full Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis. ] *[http://bloodjournal.hematologylibrary.org/cgi/content/short/blood-2006-04-016824v1 Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts ] *[http://jpet.aspetjournals.org/content/329/2/439.short Novel Anti-Inflammatory Action of Edelfosine Lacking Toxicity with Protective Effect in Experimental Colitis ] *[http://cancerres.aacrjournals.org/content/58/13/2809.full.pdf Sensitivity of K562 and HL-60 Cells to Edelfosine, an Ether Lipid Drug, Correlates with Production of Reactive Oxygen Species ]

Category:Quaternary ammonium compounds Category:Phospholipids Category:Zwitterions