Mechlorethamine

Mechlorethamine (nitrogen mustard) In vivo each chloroethylamine group undergoes intramolecular cy-clization with release of a chloride ion. The so formed highly reactive ethylen-immonium derivative alkylates DNA and other biomolecules and causes the cytotoxic effect. 

Nitrogen mustard is clinically used for the treatment of lymphomas and some forms of lung cancer. The major indication for mechlorethamine is Hodgkin s disease as a part of the MOPP regimen (mechlorethamine + vincristine (oncovin) + procarbazine + prednisone). The usual dose consists of 6 mg/m2 on days 1 and 8. This drug has pronounced hematological toxicity (myelo-suppression). 

More recently, a German study compared a dose-escalated regimen of BEACOPP (with filgrastim support) with standard-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, gemcitabine (BEACOPP) and COPP alternating with ABVD (C—cyclophosphamide instead of mechlorethamine for MOPP).18 The escalated BEACOPP was... 

Anthracycline, mechlorethamine, and vinca alkaloid extravasations typically cause immediate pain. 

Mechlorethamine Cold packs Sodium thiosulfate Prepare 1/6 M solution by adding 4 mL of 10% solution to 6 mL sterile water inject 2 mL for each mg of mechlorethamine. Follow with 1 mL SQ (0.1 mL doses clockwise around area) may repeat every 3-4 hours if needed. Sodium thiosulfate must be diluted prior to administration. 

The antidote of choice for mechlorethamine extravasations is sodium thiosulfate. This agent binds alkylating agents, resulting in neutralization to inactive compounds that are then excreted. Sodium thiosulfate also may be effective for high-concentration cisplatin or dacarbazine extravasations. 

The reactivity of the agent mechlorethamine (11.31, R = Me, Fig. 11.5) was investigated in buffer solution by means of NMR to monitor the formation of primary, secondary, and tertiary products [66], The reactive aziridin-ium derivative (11.32) mentioned above and resulting from intramolecular nucleophilic substitution was indeed observed and underwent hydrolysis first to the 2-hydroxyethyl derivative and then to A-methyl-2,2 -iminodi-ethanol. 

The reactivity of mechlorethamine was also examined in the presence of reduced glutathione (L-glutamyl-L-cysteinylglycine), a major cytoprotective compound present throughout the body in physiologically high concentra-... 

Fig. 11.5. Mechanism of hydrolytic dechlorination of mechlorethamine (11.31, R = Me) and other antitumor nitrogen mustards [65] [66]. Also shown is the mechanism of the nonenzymat-ic conjugation with reduced glutathione (GSH, L-glutamyl-L-cysteinylglycine).

That the metabolism of melphalan occurs by the same reaction mechanism as that of mechlorethamine has been demonstrated in in vitro studies [65]. Under physiological conditions of temperature and pH, formation of the first and second aziridinium intermediates en route to the bis(hydroxyethyl) metabolite occurred with rate constants of ca. 0.017 and 0.041 min-1, respectively. After 60 min, ca. 2/3 of the drug had been converted to the monohydroxy and dihydroxy products in comparable amounts. In the presence of a phosphate buffer, competition between hydrolysis and phosphatolysis was seen, such that at completion of the reaction (4 h) the two major products were the dihydroxy and the hydroxy/phosphate metabolites, with the dihydroxy derivative produced in small amounts. Similar hydrolytic dehalogena-tion has also been observed for ifosfamide in acidic aqueous solution [69]. 

Alkyl sulfonates busulfan treosulfan aziridines ThioTEPA and TEPA methylmelamine altretamine N-mustards mechlorethamine, chlorambucil, phenylacetic acid mustard, melphalan, prednimustine, estramustine nitrosoureas tallimustine, tauromustine, lomustine/carmustine dacarbazine, temozolomide and mitozolomide... 

Zackheim HS, Smuckler EA Tumorigenic effect of topical mechlorethamine, BCNU and CCNU in mice. Experientia 36 1211-1212, 1980... 

Epstein JH Nitrogen mustard (mechlorethamine) and UVB photocarcinogenesis a dose response effect. J Invest Dermatol 83 320-322, 1984... 

The schematic mechanism of the action of alkylating drags, mechlorethamine for example, the most simple of them all, can be explained by the following scheme. 

Mechlorethamine Mechlorethamine, bis-(2-chloroethyl)methylamine (30.2.1.2), is made by reacting methylamine with ethylene oxide, forming bis-(2-hydroxyethyl)methylamine (30.2.1.1), which npon reaction with thionyl chloride tnms into the desired mechlorethamine [39 1]. 

Mechlorethamine is widely used intravenonsly in combination with other drugs to treat Hodgkin s disease, lymphosarcoma, lenkemia, and bronchogenic carcinoma. Synonyms of this drug are azotoyperit, chlorethamine, chlorethazide, mustine, and many others. 

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