However, the addition of an "extremely low" dosage of 0.1 mg/day DES to cyproterone acetate has been found to result in a synergistic antigonadotropic effect and to suppress testosterone levels into the castrate range in men. DES at 3 mg/day has similar testosterone suppression to a dose of 300 mg/day, suggesting that suppression of testosterone levels is maximal by 3 mg/day. Other activities
In addition to the ERs, an in vitro study found that DES also possesses activity, albeit relatively weak, at a variety of other steroid hormone receptors. Whereas the study found EC50 values of 0.18 nM and 0.06 nM of DES for the ERα and ERβ, respectively, the medication showed significant glucocorticoid activity at a concentration of 1 μM that surpassed that of 0.1 nM dexamethasone, as well as significant antagonism of the androgen, progesterone, and mineralocorticoid receptors (75%, 85%, and 50% inhibition of positive control stimulation, respectively, all at a concentration of 1 μM). It also showed approximately 25% inhibition of the activation of PPARγ and LXRα at a concentration of 10 μM. The researchers stated that, to the best of their knowledge, they were the first to report such actions of DES, and hypothesized that these actions could be involved in the clinical effects of DES, for instance, in prostate cancer (notably in which particularly high dosages of DES are employed).
Side effects
Common side effects include:
Nausea
Bone marrow suppression, including
Decreased white blood cell count causing increased risk of infection
Decreased platelet count causing increased risk of bleedingLess common side effects include:

Severe allergic reactions
Pulmonary fibrosis (scarring of lung tissue) including fatal outcomes (usually only with prolonged use)
Hair loss
Interstitial pneumonitis
Rash
Itching
Irreversible bone marrow failure due to melphalan not being withdrawn early enough
Cardiac arrest

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. 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. Synthesis
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). Society and culture
Legal status
On 17 September 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for melphalan.