Melphalan

Not to be confused with Melphalan flufenamide.
Melphalan
Names
Trade namesAlkeran, Evomela, others
Other names(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid
IUPAC name
  • 4-[bis(2-Chloroethyl)amino]-L-phenylalanine
Clinical data
Drug classAlkylating agent[1]
Main usesMultiple myeloma, ovarian cancer, melanoma, amyloidosis[1]
Side effectsNausea, bone marrow suppression[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth (tablets), intravenous
Defined daily dosenot established[2]
External links
AHFS/Drugs.comMonograph
MedlinePlusa682220
Legal
License data
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability25–89% (By mouth)
MetabolismHydrolysis to inactive metabolites
Elimination half-life1.5 ± 0.8 hours
ExcretionKidney (IV: 5.8–21.3%)
Chemical and physical data
FormulaC13H18Cl2N2O2
Molar mass305.20 g·mol−1
3D model (JSmol)
SMILES
  • c1cc(ccc1C[C@@H](C(=O)O)N)N(CCCl)CCCl
InChI
  • InChI=1S/C13H18Cl2N2O2/c14-5-7-17(8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19/h1-4,12H,5-9,16H2,(H,18,19)/t12-/m0/s1 checkY
  • Key:SGDBTWWWUNNDEQ-LBPRGKRZSA-N checkY

Melphalan, sold under the trade name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma, ovarian cancer, melanoma, and amyloidosis.[1] It is used by mouth or by injection into a vein.[1]

Common side effects include nausea and bone marrow suppression.[1] Other severe side effects may include anaphylaxis and the development of other cancers.[1] Use during pregnancy may result in harm to the baby.[3] Melphalan belongs to the class of nitrogen mustard alkylating agents.[1] It works by interfering with the creation of DNA and RNA.[1]

Melphalan was approved for medical use in the United States in 1964.[1] It is on the World Health Organization's List of Essential Medicines.[4] It is available as a generic medication.[5] In the United Kingdom it costs the NHS £137 per 50 mg vial.[5] In the United States the cost of this amount is US$257.[6]

Medical uses

It is used to treat multiple myeloma,[7] ovarian cancer, AL amyloidosis, and occasionally malignant melanoma.

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:

Melphalan is currently being used to treat ocular retinoblastoma, a pediatric solid tumor. This is accomplished via transarterial catheter based slow pulsed infusion into the ophthalmic artery.[9]

Dosage

The defined daily dose is not established.[2]

Side effects

Common side effects include:[1]

Less common side effects include:

Mechanism of action

Melphalan chemically alters the DNA nucleotide guanine through alkylation, and causes linkages between strands of DNA. This chemical alteration inhibits DNA synthesis and RNA synthesis, functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing tumor cells.[10]

Synthesis

Another amino acid-like drug is the antineoplastic agent melphalan. Tumor cells 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.

Syntheses:[11][12][13] U.S. Patent 3,032,584; U.S. Patent 3,032,585 (both 1962 to NRDC).

4-Nitro-L-phenylalanine (1) was converted to its phthalimide by heating with phthalic anhydride, and this was converted to its ethyl ester (2). Catalytic hydrogenation produced the corresponding aniline. Heating in acid with oxirane, followed by treatment with phosphorus oxychloride provided the bischloride, and removal of the protecting groups by heating in hydrochloric acid gave melphalan (3).

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Melphalan Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 17 August 2019. Retrieved 9 October 2019.
  2. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 28 July 2020. Retrieved 11 September 2020.
  3. ↑ "Melphalan Use During Pregnancy". Drugs.com. Archived from the original on 9 October 2019. Retrieved 9 October 2019.
  4. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 873–874. ISBN 9780857113382.
  6. ↑ "Melphalan Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 27 October 2019. Retrieved 27 October 2019.
  7. ↑ Facon T, Mary JY, Hulin C, et al. (October 2007). "Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial". Lancet. 370 (9594): 1209–18. doi:10.1016/S0140-6736(07)61537-2. PMID 17920916.
  8. ↑ "Evomela (melphalan) for Injection, for Intravenous Use. Full Prescribing Information". Spectrum Pharmaceuticals, Inc. Irvine, CA 92618. Archived from the original on 18 March 2016. Retrieved 17 March 2016.
  9. ↑ Gobin YP, Dunkel IJ, Marr BP, et al. (June 2011). "Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience". Arch Ophthalmol. 129 (6): 732–7. doi:10.1001/archophthalmol.2011.5. PMID 21320950.
  10. ↑ "Melphalan". National Cancer Institute. Archived from the original on 8 August 2014. Retrieved 4 August 2014.
  11. ↑ Bergel, F.; Stock, J. A. (1954). "Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines". Journal of the Chemical Society (Resumed): 2409. doi:10.1039/JR9540002409.
  12. ↑ Bergel, F.; Burnop, V. C. E.; Stock, J. A. (1955). "Cyto-active amino-acids and peptides. Part II. Resolution of para-substituted phenylalanines and synthesis of p-di-(2-chloroethyl)amino-DL-phenyl[?-14C]alanine". Journal of the Chemical Society (Resumed): 1223–1230. doi:10.1039/JR9550001223.
  13. ↑ Larionov LF, Khokhlov AS, Shkodinskaja EN, Vasina OS, Troosheikina VI, Novikova MA (1955). "Studies on the anti-tumour activity of p-di-(2-chloroethyl) aminophenylalanine (sarcolysine)". Lancet. 266 (6882): 169–71. doi:10.1016/S0140-6736(55)92736-7. PMID 13243678.
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