Melphalan, sold under the brand name Alkeran among others, is a

chemotherapy medication Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...

used to treat multiple myeloma,

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

, melanoma, and

AL amyloidosis Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis in the US. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein ...

. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

or by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...

. Common side effects include nausea and

bone marrow suppression Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity ( leukocytes), carrying oxygen ( erythrocytes), and/or those responsible for normal blood clotting ...

. Other severe side effects may include

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the foll ...

and the development of other

cancers Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

. Use during pregnancy may result in harm to the fetus. Melphalan belongs to the class of nitrogen mustard

alkylating agents Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting al ...

. It works by interfering with the creation of DNA and

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

. Melphalan was approved for medical use in the United States in 1964. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. It is available as a generic medication.

Medical uses

It is used to treat multiple myeloma,

, and occasionally

malignant melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ...

. The agent was first investigated as a possible drug for use in melanoma, it was not found to be effective. In 2016, it was approved in the U.S. for: * use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in multiple myeloma (MM) patients * the palliative treatment of MM patients for whom oral therapy is not appropriate Melphalan is used to treat ocular

retinoblastoma Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively fo ...

, a pediatric solid tumor. This is accomplished via transarterial catheter based slow pulsed infusion into the ophthalmic artery.

Side effects

Common side effects include: *

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

* Bone marrow suppression, including ** Decreased white blood cell count causing increased risk of

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...

** Decreased platelet count causing increased risk of bleeding Less common side effects include: * Severe

allergic reaction Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

s *

Pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...

(scarring of lung tissue) including fatal outcomes (usually only with prolonged use) *

Hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...

Interstitial pneumonitis Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue and space around the alveoli (air sacs)) of the lungs. It concerns alveolar epithelium, pu ...

Rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

Itching Itch (also known as pruritus) is a Wikt:sensation, sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of Sensory system, sensory experience. Itch has many similarities to pain, ...

* Irreversible bone marrow failure due to melphalan not being withdrawn early enough *

Cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and poss ...

Mechanism of action

Melphalan chemically alters the DNA nucleotide

guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is c ...

through

alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecti ...

, and causes linkages between strands of DNA. This chemical alteration inhibits

DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs ...

and

RNA synthesis Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...

, functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing tumor cells.

Tumor cells A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

spend less time in resting phases than normal cells so at any given time, they are more likely to be metabolically active than most normal host cells. The rationale behind incorporating an alkylating function in a molecule resembling a primary cellular metabolite was to get a greater safety margin by fooling tumor cells into taking up the toxin preferentially.

Synthesis

4-Nitro-L- phenylalanine (1) was converted to its

phthalimide Phthalimide is the organic compound with the formula C6H4(CO)2NH. It is the imide derivative of phthalic anhydride. It is a sublimable white solid that is slightly soluble in water but more so upon addition of base. It is used as a precursor ...

by heating with

phthalic anhydride Phthalic anhydride is the organic compound with the formula C6H4(CO)2O. It is the anhydride of phthalic acid. Phthalic anhydride is a principal commercial form of phthalic acid. It was the first anhydride of a dicarboxylic acid to be used commer ...

, and this was converted to its ethyl

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

(2). Catalytic hydrogenation produced the corresponding aniline. Heating in acid with

oxirane Ethylene oxide is an organic compound with the formula . It is a cyclic ether and the simplest epoxide: a three-membered ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless and flammable gas with a faintly swe ...

, followed by treatment with

phosphorus oxychloride Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from pho ...

provided the bischloride, and removal of the protecting groups by heating in hydrochloric acid gave melphalan (3).

Society and culture

Legal status

On 17 September 2020, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regardin ...

(CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for melphalan. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The applicant for this medicinal product is ADIENNE S.r.l. S.U. Melphalan was approved for medical use in the European Union in November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

References

External links

* {{Portal bar , Medicine Chloroethyl compounds IARC Group 1 carcinogens Nitrogen mustards Specialty drugs World Health Organization essential medicines Wikipedia medicine articles ready to translate