Edelfosine
Encyclopedia
Edelfosine is a synthetic alkyl-lisophospholipid
(ALP). It has antineoplastic (anti-cancer) effects.
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. Edelfosine can activate the Fas
/CD95 cell death receptor, can inhibit the MAPK/ERK mitogenic pathway and the Akt
/protein kinase B (PKB) survival pathway. 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.
These characteristics cause edelfosine also to affect HIV
, parasitic, and autoimmune diseases.
It can complement classic anti-cancer drugs such as cisplatin
.
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.
It is an analog of miltefosine
and perifosine
.
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, 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 undegraded for a long time.
s 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.
(2-lysophosphhatidylcholine, 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.
Alkyl-lysophospholipids
Alky-lysophospholipids are synthetic analogues of lysophosphatidylcholines , also called lysolecithins.They were synthesized by replacing the acyl-group within the LPC with an alkyl-group. They are in contrast to LPC metabolically very stable.,...
(ALP). It has antineoplastic (anti-cancer) effects.
Like all ALPs, it incorporates into the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
and does not target the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. In many tumor cells, it causes selective apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, sparing healthy cells. Edelfosine can activate the Fas
Fas receptor
The FAS receptor also known as apoptosis antigen 1 , cluster of differentiation 95 or tumor necrosis factor receptor superfamily member 6 is a protein that in humans is encoded by the TNFRSF6 gene....
/CD95 cell death receptor, can inhibit the MAPK/ERK mitogenic pathway and the Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
/protein kinase B (PKB) survival pathway. 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.
These characteristics cause edelfosine also to affect HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, parasitic, and autoimmune diseases.
It can complement classic anti-cancer drugs such as cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
.
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
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
transplants.
It is an analog of miltefosine
Miltefosine
Miltefosine is a phospholipid drug.Originally developed as an antineoplastic , it is finding use as an antiprotozoal drug...
and perifosine
Perifosine
Perifosine is a drug candidate being developed for a variety of cancer indications.It is an alkylphospholipid Perifosine is structurally related to miltefosine...
.
In vitro and in vivo results
Edelfosine apoptosis-inducing abilities were studied with several types of cancer, among them multiple myelomaMultiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
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, like ovarian cancer, and against breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. In vivo biodistribution studies demonstrated a “considerably higher” accumulation of Edelfosine in tumor cells than in other analyzed organs. It remained undegraded for a long time.
Clinical trials
Several clinical trials were conducted. Among them a phase I trials with solid tumors or leukemiaLeukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s 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 lysolecitinLysophosphatidylcholine
Lysophosphatidylcholines , also called lysolecithins, are a class of chemical compounds which are derived from phosphatidylcholines. They result from partial hydrolysis of phosphatidylcholines, which removes one of the fatty acid groups. The hydrolysis is generally the result of the enzymatic...
(2-lysophosphhatidylcholine, 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.
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