Mechlorethamine toxicity

Wormser, U., Nyska, A. (1991). Protective effect of O-phenan-throline against mechlorethamine toxicity in the rat liver slice system and in the guinea pig skin. Arch. Toxicol. 65 666-70. 

Pino, M.A., Pietka-Ottlik, M., Billack, B., 2014. Selected ebselen analogs reduce mechlorethamine toxicity in vitro. Cutan. Ocul. Toxicol. 33, 32-41. 

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). 

Mechlorethamine was the first nitrogen mustard. It is directly toxic. With its half-life of only a few minutes infusion directly into arteries supplying the tumor is the preferred mode of administration. Its spectrum of adverse effects is similar to that of cyclophosphamide. 

As a therapeutic agent, mechlorethamine has many toxic effects. Acutely, it causes nausea and vomiting, skin blistering, and ulceration. After a week or two, it causes leukopenia, lymphopenia, anemia, thrombocytopenia, diarrhea, oral ulcers, and hyperuricemia. It can cause sterility and after a few years, leukemia. The most susceptible tissues are those with renewable cell populations, bone marrow, lymphoid tissues, and gastrointestinal (GI) epithelium. The therapeutic dose of mechlorethamine and most of the cytotoxic chemotherapy drugs is very close to the toxic dose. The therapeutic index (ratio of beneficial effect to toxic effect) is small. 

M3. Marshall, W. H., Hoppe, E. T., and Stark, F., The effect of ambient oxygen tension on the toxicity and therapeutic effect of mechlorethamine (nitrogen mustard). Arch. Surg. 86, 932-939 (1963). 

Ever since MOPP therapy was created and the efficacy confirmed, researchers tried to modify the regimen in an attempt to improve efficacy and decrease toxicity. Some MOPP variations include MVPP (vinblastine substituted for vincristine), CVPP (cyclophosphamide substituted for mechlorethamine), and ChlVPP (chlorambucil substituted for mechlorethamine, and vinblastine substituted for vincristine) were attractive alternatives to MOPP because they offered equal efficacy and differing or less severe toxicities. The various combination chemotherapy regimens appear to produce initial complete response rates in over 80% of the patients treated, and result in a 55% to 65% cure rate for advanced Hodgkin s lymphoma. 

Significant improvements were achieved with the drugs chlorambucil (Leukeran, 1952) and melphalan (Alkeran, 1954), both developed at the Chester Beatty Laboratory in London. These drugs were more water-soluble (and hence available by mouth rather than intravenous infusion) and more easily taken up by cancer cells. They were also less toxic to bone-marrow cells and have been widely used over the intervening years for the treatment of various leukaemias and other tumours. An interesting combination of the female sex hormone oestradiol with mechlorethamine was invented in Romania in 1966, and was marketed under the trade-name Estracyte (estra-mustine) for the treatment of prostatic cancer. 

It is interesting to compare the relative toxicities of the two extreme types of nitrogen mustard. Over 90% of mechlorethamine is destroyed within... 

Dorr RT, Soble M and Alberts DS (1988). Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity in the mouse. Cancer Chemother Pharmacol, 22, 299-302. 

The major acute toxic manifestations of mechlorethamine are nausea and vomiting, lacrimation, and myelosuppression. Leukopenia and thrombocytopenia limit the amount of drug that can be given in a single course. 

Crystals from 80% ethanol, dec 239-241". [a]fl +18.46 (c = 1,81 in HjO). [Free base, crystals, dec 278".] Sol in water. Slightly sol in ethanol. Aq solns are mildly acid and stable at room temps. Claimed to be considerably less toxic than mechlorethamine. LD i.v. in rats 56 mg/kg (Scherf). 

Toxicity Gastrointestinal distress, myelosuppression, and alopecia are common. Mechlorethamine has marked vesicant actions. 

Mechlorethamine is the only aliphatic nitrogen mustard currently on the U.S. market (Fig. 42.3). Its use is limited by extremely high reactivity, which leads to rapid and nonspecific alkylation of cellular nucleophiles and excessive toxicity. It is a severe vesicant, and if accidental skin contact occurs, the drug must be inactivated with 2% sodium thiosulfate (Na2S203) solution. This reagent reacts with the mustard to create an inactive, highly ionized, and water-soluble thiosulfate ester that can be washed away (Fig. 42.4). The affected tissue also should be treated with an ice compress for 6 to 12 hours. 

This nitrogen mustard is also capable of alkylating DNA, causing cell death, but is less toxic lhan sulfur mustard. The discovery of mechlorethamine launched the field of chemotherapy, the use of chemical agents to treat cancer. 

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