|Oral (tablets), intravenous|
|Metabolism||Hydrolysis to inactive metabolites|
|Elimination half-life||1.5 ± 0.8 hours|
|Excretion||Renal (IV: 5.8–21.3%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||305.2 g/mol g·mol−1|
|3D model (JSmol)|
An alkylating agent adds an alkyl group (CnH2n+1) to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring.
Mechanism of actionEdit
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.
The agent was first investigated as a possible drug for use in melanoma, it was not found to be effective.
On March 15, 2016 it was approved by the U.S. FDA under the trade name Evomela 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
Oral or intravenous; dosing varies by purpose and route of administration as well as patient weight.
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Common side effects include:
- Nausea and vomiting, and oral ulceration.
- Bone marrow suppression, including
Less common side effects include:
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.
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).
- "Melphalan". National Cancer Institute. Retrieved 4 August 2014.
- 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.
- "Evomela (melphalan) for Injection, for Intravenous Use. Full Prescribing Information". Spectrum Pharmaceuticals, Inc. Irvine, CA 92618. Retrieved 17 March 2016.
- Gobin YP, Dunkel IJ, Marr BP, et al. (Jun 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.
- 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.
- 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. doi:10.1039/JR9550001223.
- Larionov, L.F.; Khokhlov, A.S.; Shkodinskaja, E.N.; Vasina, O.S.; Troosheikina, V.I.; Novikova, M.A. (1955). "STUDIES ON THE ANTI-TUMOUR ACTIVITY OF p-DI-(2-CHLOROETHYL) AMINOPHENYLALANINE (SARCOLYSINE)". The Lancet. 266 (6882): 169. doi:10.1016/S0140-6736(55)92736-7.