Nitrogen-mustard

The management of cancer includes treatment with alkylating agents (nitrogen mustards and alkyl sulfonates), antimetabolites (methotrexate and purine analogues), natural products (vinca alkaloids and taxol), miscellaneous compounds (hydroxyurea, procarbazine, and m-platinum), hormones (estrogens and corticosteroids), and radioactive isotopes. 

The activity of nitrogen mustards depends on the presence of a Z /s-(2-chloroethyl) grouping  

This is present in mechlorethamine (Mustargen), which is used in patients with Hodgkin s disease and other lymphomas, usually in combination with other drugs, such as in MOPP therapy (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone). It may cause bone marrow depression. 

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. 

Cyclophosphamide (Cytoxan and Endoxan) is used in the treatment of Hodgkin s disease, lymphosarcoma, and other lymphomas. It is employed as a secondary drug in patients with acute leukemia and in combination with doxorubicin in women with breast cancer. A drug combination effective in the treatment of breast cancer is cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP). Cyclophosphamide is also an immunosuppressive agent. The toxicity of cyclophosphamide causes alopecia, bone marrow depression, nausea and vomiting, and hemorrhagic cystitis. 

HN-1 is a colorless liquid with a faint, fishy or musty odor. It is used as a delayed-action agent damage to skin begins to appear 12 or more hr after exposure. However, HD may act more quickly on the eyes than HD. The body does not detoxify HN-1, and it is a refractory agent. 

HN-2 may appear as a dark liquid with a fruity odor at high concentrations and a soft soap odor at low concentrations. Its toxicity is somewhat higher than HN-1. HN-2 has the highest blistering power of all nitrogen mustards when in vapor form. Skin effects for this compound are delayed, and it is highly unstable. 

a liquid with no odor in its pure form, is the most common nitrogen mustard and its blistering power is similar to that of HD. It is used as a delayed-action casualty agent — most symptoms may be delayed for 4 to 6 hr. The body does not detoxify HN-3 therefore, it accumulates in the body. Unlike HN-2, HN-3 is stable in storage. 

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Nitrogen fluoride Nitrogen heterocycles nitrogen implantation Nitrogen monoxide Nitrogen mustards Nitrogen oxide... 

Some hydantoias are very useful carriers of the nitrogen mustard moiety bis (P-chloroethyl)amine, and are useful ia several tumors and multiagent therapy regimens (128,129). Besides that, some 3-(2-chloro-ethyl)hydantoiQS (32) (130) and oxyranyLmethyUiydantoias, eg,... 

Properties. The physical properties of the mustards are summarized in Table 1. The sulfur mustards are only slightly soluble in water, whereas the nitrogen mustards are slightly soluble at neutral pH, but form water-soluble salts under acid conditions. Both sulfur and nitrogen mustards are extremely soluble in most organic solvents. 

Although sulfur and nitrogen mustards have limited solubiUty in water at neutral pH, the small quantity that dissolves is extremely reactive. The reaction proceeds via a cycHc sulfonium or imonium intermediate... 

With nitrogen mustards, the imonium ion, which apparendy forms even in the absence of any solvent, readily attacks another molecule to form a dimer. For this reason, the nitrogen mustards are less stable than sulfur mustards in long-term storage. 

Sulfur mustard reacts rapidly with chlorine or with bleach, and this reaction is a suitable means of decontamination. Nitrogen mustards, however, chlorinate extremely slowly thus chlorination is not suitable for their decontamination. The formation of water-soluble salts, such as by neutralization with sodium bisulfate, is the usual method for nitrogen mustard removal from contaminated surfaces. The mustard salts are much less vesicant than the corresponding free bases. 

Physiological Effects. The sulfur and nitrogen mustards act first as cell irritants and finally as a cell poison on all tissue surfaces contacted. The first symptoms usually appear in 4—6 h (4). The higher the concentration, the shorter the interval of time between the exposure to the agent and the first symptoms. Local action of the mustards results in conjunctivitis (inflammation of the eyes) erythema (redness of the skin), which may be followed by blistering or ulceration and an inflammatory reaction of the nose, throat, trachea, bronchi, and lung tissue. Injuries produced by mustard heal much more slowly and are much more Fable to infection than bums of similar intensity produced by physical means or by other chemicals. 

Uses The nitrogen mustards are used clinically in the treatment of certain neoplasms (14). They have been used in treatment of Hodgkin s disease, lymphosarcoma, and leukemia (see Chemotherapeutics, anticancer). 

NITROGEN FERTILIZER SOLUTION NITROGEN MUSTARD NITROGEN TETROXIDE NITROGEN TRIFLUORIDE NITROGEN TRIOXIDE... 

The adventitious discovery of the antitumor action of the nitrogen mustard poison war gases led to intensive investigation of the mode of action of these compounds. In brief, it has been fairly well established that these agents owe their effect to the presence of the highly reactive bis(2-chloroethyl)amine group. The cytotoxic activity of... 

Therapeutic Function Cancer chemotherapy Chemical Name 4-[bis(2-chloroethyl)amino]-L-phenylalanine Common Name Alanine nitrogen mustard L-sarcolysine Structural Formula... 

Classic (nitrogen mustards) Mechloretamine (nitrogen mustard)... 

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). 

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

Thiotepa is chemically less reactive than the nitrogen mustards. It has antineoplastic activity against ovarian and breast cancers as well as lymphomas. However, it has been largely supplanted by cyclophosphamide and other nitrogen mustards. 

The nitrogen mustards are cytotoxic chemotherapy agents which are chemically derived from mustard gas. Although their current use is medicinal, the predecessor of these compounds was also used for chemical warfare putposes. 

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