Edelfosine (ET-18-O-CH3; 1-octadecyl-2-''O''-methyl-glycero-3-phosphocholine) is a synthetic alkyl-lysophospholipid (ALP). It has antineoplastic (anti-cancer) effects. Like all ALPs, it incorporates into the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

and does not target the

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. In many tumor cells, it causes selective

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

, sparing healthy cells. Edelfosine can activate the Fas/

CD95 The Fas receptor, also known as Fas, FasR, apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the ''FAS'' gene. Fas ...

cell death receptor, can inhibit the

MAPK/ERK The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling mo ...

mitogenic pathway and the Akt/

protein kinase B Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, trans ...

(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 The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...

, parasitic, and autoimmune diseases.
It can complement classic anti-cancer drugs such as

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

. 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 is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

transplants. It is an analog of

miltefosine Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat leishmaniasis and free-living amoeba infections such as '' Naegleria fowleri'' and '' Balamuthia mandrillaris''. This includes the three forms of ...

and

perifosine Perifosine (also KRX-0401) is a former drug candidate that was under development for a variety of cancer indications. It is an alkyl-phospholipid structurally related to miltefosine. Perifosine interrupts the PI3K/AKT/mTOR pathway by acting as an ...

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

Edelfosine apoptosis-inducing abilities were studied with several types of cancer, among them

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...

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 is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

. ''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.

Clinical trials

Several clinical trials were conducted. Among them a phase I trials with solid tumors or

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

s and phase II with

non-small-cell lung carcinoma Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

s (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 Lysophosphatidylcholines (LPC, lysoPC), also called lysolecithins, are a class of chemical compounds which are derived from phosphatidylcholines. Overview Lysophosphatidylcholines are produced within cells mainly by the enzyme phospholipase ...

(2-lysophosphatidylcholine, LPC) increases the phagocytotic activity of

macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

. 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

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

Clinical trials

Toxicity

History

References

Further reading