Toxicity nitrogen mustards

There is no antidote for nitrogen mustard toxicity, and decontamination of potentially exposed persons must be done within minutes to avoid tissue damage. Victims should be moved out of the hot zone, administered oxygen and/or assisted ventilation, and seek medical attention at once. The nitrogen mustards are delayed chemical agents, and may delay for up to twenty-four hours to show symptoms. They are poisons, and contact with vapor or liquids can be fatal. Do not eat, drink, or smoke during response to a nitrogen mustard incident or criminal event. 

Caution There is no antidote for nitrogen mustard toxicity decontamination of all potentially exposed areas within minutes after exposure is the only effective method to decrease tissue damage. Other than that, treatment is mainly supportive. 

Medical management of nitrogen mustard exposure is similar to that for sulfur mustard and involves prevention of exposure and, where exposure has occurred, decontamination and support therapy. The use of antioxidants in the treatment of nitrogen mustard toxicity is currently under investigation (Hardej and Billack, 2006). 

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). 

HN-2 has the greatest blistering power of the nitrogen mustards in vapor form but is intermediate as a liquid blistering agent. It produces toxic eye effects more rapidly than does HD. 

Very reactive nitrogen mustards and aziridine-containing molecules are usually too toxic for general therapeutic use, but find use in neoplastic disease. Benzodepa (182) is such an agent. Treatment of ethyl carbamate with phosphorous pentachloride leads to cyanate 180 which readily adds benzyl alcohol to produce carbamate 181. Displacement of the active... 

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. 

Since the formation of the ethyleniminium ion is crucial for the cytotoxic activity of the nitrogen mustards, it is not surprising that stable ethylenimine derivatives have antitumor activity. Thiophospho-ramide or thiotepa is the best known compound of this type that has been used clinically. Both thiotepa and its primary metabolite, triethylenephos-phoramide (TEPA), to which it is rapidly converted by hepatic mixed-function oxygenases form crosslinks with DNA. It is mainly used as an intravesicu-lar agent in bladder cancer. Thiotepa produces little toxicity other than myelosuppression. 

Bone marrow toxicity is the major side effect of chlorambucil. Nausea is uncommon or mUd, and hair loss does not occur. Chlorambucil shares the immunosuppressive, teratogenic, and carcinogenic properties of the nitrogen mustards. 

L B. Although all of the compounds are nitrogen mustards and have the same basic mechanism of action, differences in the toxicity profile, duration of action, metabolism, and distribution within the body... 

Cyclophosphamide (72) was made as a latent form of nitrogen mustard with fairly low toxicity. It undergoes oxidation by microsomes in the liver and then breaks down to give much more reactive derivatives of 2,2 -dichlorodiethylamine (Scheme 3). Several aziridines are used as alkylating agents. They include triethylenemelamine (73), triaziquone (74), TEPA (triethylenephosphoramide) (75 X = O) and thio-TEPA (75 X = S). Ethylene oxide... 

Chlorambucil (Leukeran) is the least toxic nitrogen mustard, and is used as the drug of choice in the treatment of chronic lymphocytic leukemia. It is absorbed orally, is slow in its onset of action, and may cause bone marrow depression. 

In some instances, researchers are able to develop separate Hansch equations for both activity and toxicity of a drug. Differing parameters between the activity and toxicity QSAR equations allow researchers to optimize properties that boost desired activity and minimize toxicity. The following two QSAR equations give the activity (12.d) and toxicity (12.e) for a series of nitrogen mustard antitumor compounds (see Chapter 6). Based on these equations, is it likely that a nontoxic nitrogen mustard will be developed Explain. 

Fleer R, Brendel M. 1982. Toxicity, interstrand cross-links and DNA fragmentation induced by activated cyclophosphamide in yeast Comparative studies on 4-hydroxyperoxy-cyclophosphamide, its monofunctional analogue, acrolein, phosphoramide mustard, and nor-nitrogen mustard. Chem Biol Interact 39 1-15. 

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