Edelfosine

''In vitro'' and ''in vivo'' results

Edelfosine apoptosis-inducing abilities were studied with several types of cancer, among them multiple myeloma and non-small and small cell lung carcinoma cell lines. In vivo activity against human solid tumors in mice was shown against malignant gynecological tumor cells,

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'. A phase II trial for the treatment of brain cancers was also reported. 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.

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.

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.

References

References

1. (2008). "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".
2. (1998). "The anticancer drug edelfosine is a potent inhibitor of neovascularization in vivo". Cancer Invest..
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4. Mollinedo, F. (2004). "ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas/CD95 death receptor.". Current Medicinal Chemistry.
5. Ruiter, GA. (2003). "Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway.". Anti-Cancer Drugs.
6. Munder, PG. (1979). "Lysophosphatidylcholine ( Lysolecithin ) and its Synthetic Analogues. Immunemodulating and Other Biologic Effects". Springer Seminars in Immunopathology.
7. Lucas, A. (2010). "Targeting the PI3K/Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds.". PLOS ONE.
8. Azzouz, S. (2005). "activity of edelfosine, miltefosine and ilmofosine.". Basic & Clinical Pharmacology & Toxicology.
9. Noseda, A. (1988). "In vitro antiproliferative activity of combinations of ether lipid analogues and DNA-interactive agents against human tumor cells.". Cancer Research.
10. Vogler, WR. (1993). "Autologous bone marrow transplantation with alkyl-lysophospholipid-purged marrow.". Journal of Hematotherapy.
11. Mollinedo, PG. (2010). "Lipid raft-targeted therapy in multiple myeloma.". Oncogene.
12. Shafer, SH. (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.
13. Arnold, B. (1978). "Distribution and metabolism of synthetic alkyl analogs of lysophosphatidylcholine in mice.". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism.
14. (1996). "A Phase I/II trial of edelfosine purging of autologous bone marrow transplantation (ABMT) in acute leukemia (Meeting abstract).".
15. United States Patent 6514519. "Edelfosin for the treatment of brain tumors".
16. Drings, P. (1992). "Final Evaluation of a Phase II Study on the Effect of Edelfosine (an Ether Lipid) in Advanced Non-Small-Cell Bronchogenic Carcinoma.". Onkologie.
17. Munder, PG. (1969). "The influence of various adjuvants on the metabolism of phospholipids in macrophages.". International Archives of Allergy and Applied Immunology.