Chemistry:Edelfosine

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Edelfosine
Edelfosine.svg
Names
Systematic IUPAC name
2-Methoxy-3-(octadecyloxy)propyl 2-(trimethylazaniumyl)ethyl phosphate
Other names
ET-18-O-CH3; 1-octadecyl-2-O-methyl-glycero-3-phosphocholine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
UNII
Properties
C27H58NO6P
Molar mass 523.736 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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.

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-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.[20][21]

References

  1. ↑ 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. 2008. Archived from the original on 2011-08-11. https://web.archive.org/web/20110811144708/http://apjcn.nhri.org.tw/server/APJCN/Volume17/vol17suppl.1/204-207S12-1.pdf. 
  2. ↑ Vogler, William R.; Liu, Jianguo; Volpert, Olga; Ades, Edwin W.; Bouck, Noel (1998). "The anticancer drug edelfosine is a potent inhibitor of neovascularization in vivo". Cancer Invest. 16 (8): 549–53. doi:10.3109/07357909809032884. PMID 9844614. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Gajate, C; Mollinedo F (2002). "Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells.". Current Drug Metabolism 5 (3): 491–525. doi:10.2174/1389200023337225. PMID 12369895. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Mollinedo, F; Gajate C; Martín-Santamaria S; Gago F (2004). "ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas/CD95 death receptor.". Current Medicinal Chemistry 11 (24): 3163–84. doi:10.2174/0929867043363703. PMID 15579006. 
  5. ↑ Ruiter, GA; Zerp SF; Bartelink H; Blitterswijk WJ van; Verheij M (2003). "Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway.". Anti-Cancer Drugs 14 (2): 167–73. doi:10.1097/00001813-200302000-00011. PMID 12569304. 
  6. ↑ Munder, PG; Modolell M; Andreesen R; Weltzien HU; Westphal O (1979). "Lysophosphatidylcholine ( Lysolecithin ) and its Synthetic Analogues. Immunemodulating and Other Biologic Effects". Springer Seminars in Immunopathology 203 (2): 187–203. doi:10.1007/bf01891668. 
  7. ↑ Lucas, A et al. (2010). "Targeting the PI3K/Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds.". PLOS ONE 5 (9): e13121. doi:10.1371/journal.pone.0013121. PMID 20927348. Bibcode: 2010PLoSO...513121L. 
  8. ↑ Azzouz, S; Maache M; Garcia RG; Osuna A (2005). "activity of edelfosine, miltefosine and ilmofosine.". Basic & Clinical Pharmacology & Toxicology 96 (1): 60–5. doi:10.1111/j.1742-7843.2005.pto960109.x. PMID 15667597. 
  9. ↑ Klein-Franke, A; Munder PG (1992). "Alkyllysophospholipid prevents induction of experimental allergic encephalomyelitis.". Journal of Autoimmunity 5 (1): 83–91. doi:10.1016/s0896-8411(05)80053-8. PMID 1373062. 
  10. ↑ Noseda, A; Berens ME; White JG; Modest EJ (1988). "In vitro antiproliferative activity of combinations of ether lipid analogues and DNA-interactive agents against human tumor cells.". Cancer Research 48 (7): 1788–91. PMID 3349458. 
  11. ↑ Berdel, WE (1990). "Ether lipids and derivatives as investigational anticancer drugs. A brief review.". Onkologie 13 (4): 245–50. doi:10.1159/000216771. PMID 2234777. 
  12. ↑ Vogler, WR; Berdel WE (1993). "Autologous bone marrow transplantation with alkyl-lysophospholipid-purged marrow.". Journal of Hematotherapy 2 (1): 93–102. doi:10.1089/scd.1.1993.2.93. PMID 7921970. 
  13. ↑ Mollinedo, PG et al. (2010). "Lipid raft-targeted therapy in multiple myeloma.". Oncogene 29 (26): 3748–3757. doi:10.1038/onc.2010.131. PMID 20418917. 
  14. ↑ Shafer, SH; Williams CL (2003). "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.". International Journal of Oncology 23 (2): 389–400. doi:10.3892/ijo.23.2.389. PMID 12851688. 
  15. ↑ Estella-Hermoso de Moendoza, A et al. (2009). "Antitumor alkyl ether lipid edelfosine: tissue distribution and pharmacokinetic behavior in healthy and tumor-bearing immunosuppressed mice.". Clinical Cancer Research 15 (3): 858–64. doi:10.1158/1078-0432.CCR-08-1654. PMID 19188156. 
  16. ↑ Arnold, B; Reuther R; Weltzien HU (1978). "Distribution and metabolism of synthetic alkyl analogs of lysophosphatidylcholine in mice.". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 530 (1): 47–55. doi:10.1016/0005-2760(78)90125-x. PMID 687654. 
  17. ↑ 17.0 17.1 "A Phase I/II trial of edelfosine purging of autologous bone marrow transplantation (ABMT) in acute leukemia (Meeting abstract).". 1996. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=29&abstractID=8944. 
  18. ↑ United States Patent 6514519. "Edelfosin for the treatment of brain tumors". 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. Retrieved 11 May 2011. 
  19. ↑ Drings, P et al. (1992). "Final Evaluation of a Phase II Study on the Effect of Edelfosine (an Ether Lipid) in Advanced Non-Small-Cell Bronchogenic Carcinoma.". Onkologie 15 (5): 375–382. doi:10.1159/000217391. 
  20. ↑ 20.0 20.1 Houlihan, WJ; Lohmeyer M; Workman P; Cheon SH (1995). "Phospholipid antitumor agents.". Medicinal Research Reviews 15 (3): 157–223. doi:10.1002/med.2610150302. PMID 7658750. 
  21. ↑ Munder, PG; Ferber E; Modolell M; Fischer H. (1969). "The influence of various adjuvants on the metabolism of phospholipids in macrophages.". International Archives of Allergy and Applied Immunology. 36 (1): 117–28. doi:10.1159/000230731. PMID 4980286. 

Further reading



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