Edelfosine

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]

Edelfosine
Names
Preferred 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
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
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 Y
    Key: MHFRGQHAERHWKZ-UHFFFAOYSA-N Y
  • 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
SMILES
  • [O-]P(=O)(OCC(OC)COCCCCCCCCCCCCCCCCCC)OCC[N+](C)(C)C
Properties
Chemical formula
 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).
N verify (what is YN ?)
Infobox references

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" (PDF). 2008. Archived from the original (PDF) on 2011-08-11. {{cite journal}}: Cite journal requires |journal= (help)
  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. 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. hdl:10261/59536. PMID 12369895.
  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. S2CID 42468599.
  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. S2CID 42907729.
  7. Lucas, A; Kim Y; Rivera-Pabon O; 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. Bibcode:2010PLoSO...513121L. doi:10.1371/journal.pone.0013121. PMC 2948033. PMID 20927348.
  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; Iglesia-Vicente J de la; Gajate C; 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; Campanero M a; Iglesi-Vincente J de la; 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. "A Phase I/II trial of edelfosine purging of autologous bone marrow transplantation (ABMT) in acute leukemia (Meeting abstract)". 1996.
  18. United States Patent 6514519. "Edelfosin for the treatment of brain tumors". Archived from the original on 14 December 2012. Retrieved 11 May 2011.
  19. Drings, P; Günther I; Gatzmeier U; ulbrich F; 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. 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. S2CID 6997551.
  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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