Noble fosine

from Wikipedia, the free encyclopedia
Structural formula
Structure of noble fosine
General
Non-proprietary name Noble fosine
other names
  • ET-18-O-CH 3
  • 1-octadecyl-2- O- methyl-glycero-3-phosphocholine
Molecular formula C 27 H 58 NO 6 P 6
Brief description

White dust

External identifiers / databases
CAS number 70641-51-9
PubChem 1392
Wikidata Q3579094
Drug information
Drug class

Alkyl lysophospholipid (ALP)

properties
Molar mass 523.73 g · mol -1
solubility

soluble in dimethyl sulfoxide , chloroform , ethanol and water

safety instructions
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Edelfosine is a synthetic alkyl lysophospholipid (ALP). It is effective against different types of cancer cells.

Like all ALP, edelfosine is built into the cell membrane and does not affect the DNA . In many tumor cells it can trigger programmed cell death ( apoptosis ), whereby healthy cells are spared. Edelfosine can activate the Fas receptor / CD95 , a TNF receptor that triggers the death (apoptosis) of the cell in question after ligand binding . It can inhibit the mitogenic MAP kinase pathway and the protein kinase B signaling pathway . Apart from these effects on signal chains in the cytoplasm, it can influence the regulation of gene expression by influencing the formation and activity of transcription factors.

It has immunomodulating properties and crosses the blood-brain barrier . Edelfosine can thus influence diseases such as AIDS , parasitic infections, multiple sclerosis and autoimmune diseases. In combination with classic cytostatics such as cisplatin, edelfosine has a synergistic effect.

Edelfosine is an experimental drug and is suitable for oral, intraperitoneal (ip) and intravenous (iv) administration.

Edelfosine and other ALP can be used to remove remaining leukemia cells from stem cell transplants (purging).

It is structurally related to miltefosine and perifosine .

In vitro and in vivo results

The apoptosis-inducing properties of edelfosine have been studied in various types of cancer, including multiple myelomas and small and non-small cell lung cancer cell lines. In vivo activity against malignant gynecological tumors such as ovarian or breast cancer has been shown in the mouse model. In vivo studies on biological distribution showed a significantly increased accumulation of edelfosine in tumor cells compared to other examined tissues. It is only slowly degraded.

Clinical studies

Several clinical studies have been conducted, including a phase I study in solid tumors or leukemia and a phase II study in non-small cell lung cancer (NSCLC). In another phase II study of the treatment of leukemia with edelfosine and simultaneous bone marrow transplantation, the substance was shown to be safe and possibly effective. Another phase II study in brain tumors showed a stagnation of the tumor growth and an improvement in the quality of life of the patients. The phase II study in non-small cell lung cancer (NSCLC) resulted in a halt in tumor growth in 50% of patients.

toxicity

In animal studies, irritation of the digestive tract was the main side effect. There were no negative systemic disorders. It turned out that edelfosine can be given safely over a long period of time. Unlike many DNA-targeting drugs, no bone marrow toxicity has been observed in vivo . These results in animal models have been confirmed in clinical studies with over 1000 patients. No mutagenic or cytogenetic effects were observed.

history

In the 1960s Herbert Fischer and Paul Gerhard Munder in Freiburg discovered that 2- lysophosphatidylcholine (LPC) stimulates the phagocytic activity of macrophages . Since the biogenic LPC only has a short plasma half-life , Fischer, Otto Westphal, Hans Ulrich Weltzien and Paul Gerhard Munder tested synthetic LPC analogues. Some of these substances showed strong activity against tumor growth, especially edelfosine. It is therefore considered to be the “prototype” of synthetic anti-cancer lipids. In 1969, Edelfosine was synthesized for the first time by Kny in Freiburg.

literature

  • VA Selivanov et al .: Edelfosine-induced metabolic changes in cancer cells that precede the overproduction of reactive oxygen species and apoptosis. In: BMC systems biology. Volume 4, 2010, p. 135, doi : 10.1186 / 1752-0509-4-135 . PMID 20925932 . PMC 2984393 (free full text).
  • S. Harguindey et al .: Edelfosine, apoptosis, MDR and Na + / H + exchanger: induction mechanisms and treatment implications. In: Apoptosis. Volume 5, Number 1, February 2000, pp. 87-89, PMID 11227496 .
  • RM Santa-Rita et al .: Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis. In: Journal of Antimicrobial Chemotherapy . Volume 54, Number 4, October 2004, pp. 704-710, doi : 10.1093 / jac / dkh380 . PMID 15329361 .
  • C. Gajate, F. Mollinedo: Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. In: Blood . Volume 109, Number 2, January 2007, pp. 711-719, doi : 10.1182 / blood-2006-04-016824 . PMID 17003375 .
  • F. Mollinedo et al .: Novel anti-inflammatory action of edelfosine lacking toxicity with protective effect in experimental colitis. In: Journal of Pharmacology and Experimental Therapeutics . Volume 329, Number 2, May 2009, pp. 439-449, doi : 10.1124 / jpet.108.148254 . PMID 19244550 .
  • BA Wagner et al: Sensitivity of K562 and HL-60 cells to edelfosine, an ether lipid drug, correlates with production of reactive oxygen species. In: Cancer Research . Volume 58, Number 13, July 1998, pp. 2809-2816, PMID 9661895 .

Individual evidence

  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.
  2. ↑ a b Data sheet ET-18-OCH 3 (PDF) from Calbiochem, accessed on December 9, 2015.
  3. ↑ Data sheet Edelfosine, ≥95% (HPLC) from Sigma-Aldrich , accessed on April 22, 2013 ( PDF ).
  4. ↑ The anticancer drug edelfosine is a potent inhibitor of neovascularization in vivo . In: Cancer Invest. tape 16 , no. 8 , 1998, pp. 549-553 , PMID 9844614 .
  5. ↑ a b c d e f g h C. Gajate, F. Mollinedo: Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells . In: Current Drug Metabolism . tape 5 , no. 3 , 2002, p. 491-525 , doi : 10.2174 / 1389200023337225 .
  6. ↑ a b c d e F. Mollinedo, C. Gajate, S. Martín-Santamaria, F. Gago: ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas / CD95 death receptor. In: Current Medicinal Chemistry . tape 11 , no. 24 , 2004, pp. 3163-3184 , PMID 15579006 .
  7. ↑ GA Ruiter, SF Zerp, H. Bartelink, WJ van Blitterswijk, M. Verheij: Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt / PKB survival pathway. In: Anti-Cancer Drugs . tape 14 , no. 2 , 2003, p. 167-173 , doi : 10.1097 / 01.cad.0000054974.31252.f7 , PMID 12569304 .
  8. ↑ PG Munder, M. Modolell, R. Andreesen, HU Weltzien, O. Westphal: Lysophosphatidylcholine (Lysolecithin) and its Synthetic Analogues. Immunemodulating and Other Biologic Effects . In: Seminars in Immunopathology . tape 203 , 1979, pp. 187-203 .
  9. ↑ A. Lucas, Y. Kim, O. Rivera-Pabon et al .: Targeting the PI3K / Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds . In: PLoS ONE . tape 5 , no. 9 , 2010, doi : 10.1371 / journal.pone.0013121 , PMID 20927348 .
  10. ↑ S. Azzouz, M. Maache, RG Garcia, A. Osuna: activity of edelfosine, miltefosine and ilmofosine . In: Basic & Clinical Pharmacology & Toxicology . tape 96 , no. 1 , 2005, p. 60-65 , doi : 10.1111 / j.1742-7843.2005.pto960109.x , PMID 15667597 .
  11. ↑ P. Munder, O. Westphal: Antitumoral and other biomedical activities of synthetic ether lysophospholipids . In: Chemical immunology . tape 127 , no. 49 , 1990, pp. 206-235 , PMID 2190582 .
  12. ↑ A. Klein-Franke, PG Munder: Alkyllysophospholipid prevents induction of experimental allergic encephalomyelitis . In: Journal of Autoimmunity . tape 5 , no. 1 , 1992, p. 83-91 , PMID 1373062 .
  13. ↑ C. Cabaner, C. Gajate, A. Macho et al .: Induction of apoptosis in human mitogen-activated peripheral blood T-lymphocytes by the ether phospholipid ET-18-OCH3: involvement of the Fas receptor / ligand system. In: British Journal of Pharmacology . tape 127 , no. 4 , 1999, p. 813-825 , PMID 10433487 .
  14. ↑ A. Noseda, ME Berens, JG White, EJ Modest: In vitro antiproliferative activity of combinations of ether lipid analogues and DNA-interactive agents against human tumor cells. In: Cancer Research . tape 48 , no. 7 , 1988, pp. 1788-1791 .
  15. ↑ Berdel: WE Ether lipids and derivatives as investigational anticancer drugs. A brief review . In: Oncology . tape 13 , no. 4 , 1990, pp. 245-250 .
  16. ^ WR Vogler, WE Berdel: Autologous bone marrow transplantation with alkyl-lysophospholipid-purged marrow . In: Journal of Hematotherapy . tape 2 , no. 1 , 1993, p. 93-102 .
  17. ^ PG Mollinedo, J. de la Iglesia-Vicente, C. Gajate et al .: Lipid raft-targeted therapy in multiple myeloma . In: Oncogene . tape 29 , 2010, p. 3748-3757 , doi : 10.1038 / onc.2010.131 , PMID 20418917 .
  18. ↑ SH Shafer, CL Williams: 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 . In: International Journal of Oncology . tape 23 , no. 2 , 2003, p. 389-400 .
  19. ↑ A. Estella-Hermoso de Moendoza, M. a Campanero, J. de la Iglesi-Vincente et al .: Antitumor alkyl ether lipid edelfosine: tissue distribution and pharmacokinetic behavior in healthy and tumor-bearing immunosuppressed mice . In: Clinical Cancer Research . tape 15 , no. 3 , 2009, p. 858-864 , doi : 10.1158 / 1078-0432.CCR-08-1654 , PMID 19188156 .
  20. ^ B. Arnold, R. Reuther, HU Weltzien: Distribution and metabolism of synthetic alkyl analogs of lysophosphatidylcholine in mice . In: Biochimica et Biophysica Acta . tape 530 , no. 1 , 1978, p. 47-55 .
  21. ↑ a b A Phase I / II trial of edelfosine purging of autologous bone marrow transplantation (ABMT) in acute leukemia (Meeting abstract). (No longer available online.) 1996, archived from the original on March 8, 2012 ; Retrieved September 20, 2013 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.asco.org
  22. ↑ United States Patent 6514519: Edelfosine for the treatment of brain tumors. Retrieved May 11, 2011 .
  23. ↑ P. Drings, I. Günther, U. Gatzmeier, F. Ulbrich et al .: Final Evaluation of a Phase II Study on the Effect of Edelfosine (an Ether Lipid) in Advanced Non-Small-Cell Bronchogenic Carcinoma . In: Oncology . tape 15 , 1992, pp. 375-382 .
  24. ↑ a b W. J. Houlihan, M. Lohmeyer, P. Workman, SH Cheon: Phospholipid antitumor agents . In: Medicinal Research Reviews . tape 15 , no. 3 , 1995, p. 157-223 , doi : 10.1002 / med . 2610150302 , PMID 7658750 .
  25. ↑ PG Munder, E. Ferber, M. Modolell, H. Fischer: The influence of various adjuvants on the metabolism of phospholipids in macrophages . In: International archives of allergy and applied immunology . tape 36 , no. 1 , 1969, p. 117-128 .