Edelfosine Explained

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.^[5] Aside from these plasma-level effects, edelfosine also affects gene expression by modulating the expression and activity of transcription factors.

It has immune modulating properties.^[6] These characteristics cause edelfosine also to affect HIV,^[7] parasitic,^[8] and autoimmune diseases.^[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.^{[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, 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.^{[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). 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.^[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.^[21]

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

Notes and 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 . dead . https://web.archive.org/web/20110811144708/http://apjcn.nhri.org.tw/server/APJCN/Volume17/vol17suppl.1/204-207S12-1.pdf . 2011-08-11 .
2. 9844614 . 16 . 8 . The anticancer drug edelfosine is a potent inhibitor of neovascularization in vivo . 1998 . 549–53 . Cancer Invest. . 10.3109/07357909809032884. Vogler . William R. . Liu . Jianguo . Volpert . Olga . Ades . Edwin W. . Bouck . Noel .
3. Gajate. C. Mollinedo F. 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. 2002. 5. 3. 491–525. 10.2174/1389200023337225. 12369895. 10261/59536. free.
4. Mollinedo. F . Gajate C . Martín-Santamaria S . Gago F. ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas/CD95 death receptor.. Current Medicinal Chemistry. 2004. 11. 24. 3163–84. 15579006. 10.2174/0929867043363703.
5. Ruiter. GA. Zerp SF . Bartelink H . Blitterswijk WJ van . Verheij M . Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway.. Anti-Cancer Drugs. 2003. 14. 2. 167–73. 12569304. 10.1097/00001813-200302000-00011. 42468599.
6. Munder. PG. Modolell M . Andreesen R . Weltzien HU . Westphal O . Lysophosphatidylcholine (Lysolecithin) and its Synthetic Analogues. Immunemodulating and Other Biologic Effects . Springer Seminars in Immunopathology. 1979. 203. 2. 187–203 . 10.1007/bf01891668. 42907729.
7. Lucas. A. Kim Y . Rivera-Pabon O . Targeting the PI3K/Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds.. PLOS ONE. 2010. 5. 9. e13121. 20927348. 10.1371/journal.pone.0013121 . 2948033. 2010PLoSO...513121L. etal. free.
8. Azzouz. S . Maache M . Garcia RG . Osuna A. activity of edelfosine, miltefosine and ilmofosine.. Basic & Clinical Pharmacology & Toxicology. 2005. 96. 1. 60–5. 15667597. 10.1111/j.1742-7843.2005.pto960109.x. free.
9. Klein-Franke. A. Munder PG. Alkyllysophospholipid prevents induction of experimental allergic encephalomyelitis.. Journal of Autoimmunity. 1992. 5. 1. 83–91. 1373062. 10.1016/s0896-8411(05)80053-8.
10. Noseda. A. Berens ME . White JG . Modest EJ . In vitro antiproliferative activity of combinations of ether lipid analogues and DNA-interactive agents against human tumor cells.. Cancer Research. 1988. 48. 7. 1788–91. 3349458.
11. Berdel. WE. Ether lipids and derivatives as investigational anticancer drugs. A brief review.. Onkologie. 1990. 13. 4. 245–50. 10.1159/000216771. 2234777.
12. Vogler. WR. Berdel WE. Autologous bone marrow transplantation with alkyl-lysophospholipid-purged marrow.. Journal of Hematotherapy. 1993. 2. 1. 93–102. 10.1089/scd.1.1993.2.93. 7921970.
13. Mollinedo. PG. Iglesia-Vicente J de la . Gajate C . Lipid raft-targeted therapy in multiple myeloma.. Oncogene. 2010. 29. 26. 3748–3757. 20418917. 10.1038/onc.2010.131. etal. free.
14. Shafer. SH. Williams CL. 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. 2003. 23. 2. 389–400. 10.3892/ijo.23.2.389. 12851688.
15. Estella-Hermoso de Moendoza. A. Campanero M a . Iglesi-Vincente J de la . Antitumor alkyl ether lipid edelfosine: tissue distribution and pharmacokinetic behavior in healthy and tumor-bearing immunosuppressed mice.. Clinical Cancer Research. 2009. 15. 3. 858–64. 19188156. 10.1158/1078-0432.CCR-08-1654. etal. free.
16. Arnold. B. Reuther R . Weltzien HU . Distribution and metabolism of synthetic alkyl analogs of lysophosphatidylcholine in mice.. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1978. 530. 1. 47–55. 10.1016/0005-2760(78)90125-x. 687654.
17. Web site: A Phase I/II trial of edelfosine purging of autologous bone marrow transplantation (ABMT) in acute leukemia (Meeting abstract). . 1996 . 2011-02-28 . 2012-03-08 . https://web.archive.org/web/20120308092256/http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=29&abstractID=8944 . dead .
18. Web site: United States Patent 6514519 . Edelfosin for the treatment of brain tumors . 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 . dead . 14 December 2012 . 11 May 2011 .
19. Drings. P. Günther I . Gatzmeier U . ulbrich F . Final Evaluation of a Phase II Study on the Effect of Edelfosine (an Ether Lipid) in Advanced Non-Small-Cell Bronchogenic Carcinoma.. Onkologie. 1992. 15. 5. 375–382. 10.1159/000217391. etal.
20. Houlihan. WJ. Lohmeyer M . Workman P . Cheon SH . Phospholipid antitumor agents.. Medicinal Research Reviews. 1995. 15. 3. 157–223. 7658750. 10.1002/med.2610150302. 6997551.
21. Munder. PG. Ferber E . Modolell M . Fischer H. . The influence of various adjuvants on the metabolism of phospholipids in macrophages.. International Archives of Allergy and Applied Immunology. 1969. 36. 1. 117–28. 10.1159/000230731. 4980286.