The nitrogen mustards are compounds that are chemically similar to sulfur mustard or mustard gas developed and used in World War I. The term "mustard" comes from the similarity in the blisters produced by the compound and those seen upon exposure to the oil of black mustard seeds. Investigation of sulfur mustard revealed that it possessed an-tineoplastic properties but because the compound existed as a gas at room temperature, handling and administration of the material were difficult. Conversion of the sulfide to a tertiary amine allowed for the formation of salts, which exist as solids at room temperature allowing for easier handling and dosing. The term mustard was then extended to the nitrogen analogs (nitrogen mustards) given their chemical similarity.
Mustards such as mechlorethamine are classified as di-alkylating agents in that one mustard molecule can alkylate two nucleophiles.5 The initial acid-base reaction is necessary to release the lone pair of electrons on nitrogen, which subsequently displaces chloride to give the highly reactive aziri-dinium cation (Scheme 10.3). Nucleophilic attack can then occur at the aziridinium carbon to relieve the small ring strain and neutralize the charge on nitrogen. This process can then be repeated provided a second leaving group is present.6
Mechlorethamine is highly reactive, in fact, too reactive and therefore nonselective, making it unsuitable for oral
Scheme 10.3 • Alkylation of nucleophilic species by nitrogen mustards.
administration and necessitating direct injection into the tumor. In cases of extravasation (drug escapes from the tumor into the underlying tissue), the antidote sodium thiosulfate (Na2S2O3), a strong nucleophile, may be administered. It is capable of reacting with electrophilic sites on the mustard, and once reaction has occurred, the resulting adduct has increased water solubility and may be readily eliminated (Scheme 10.4). Cancer patients are at an increased risk of extravasation because of the fragility of their veins resulting from radiation, previous chemotherapy treatments, or malnutrition.
The lack of selectivity of mechlorethamine led to attempts to improve on the agent. One rationale was to reduce the reactivity by reducing the nucleophilicity of nitrogen, thereby slowing aziridinium cation formation. This could be accomplished by replacement of the weakly electron-donating methyl group with groups that were electron withdrawing (-I). This is seen in the case of chlorambucil and melphalan by attachment of nitrogen to a phenyl ring (Fig. 10.3).7 Reactivity was reduced such that these compounds could be administered orally. In the case of melphalan, attachment of the mustard functionality to a phenylalanine moiety was not only an attempt to reduce reactivity but also an attempt to increase entry into cancer cells by utilization of carrier-mediated uptake.8 Melphalan was found to utilize active transport to gain entry into cells, but selective uptake by cancer cells has not been demonstrated. 9
Attachment of more highly electron-withdrawing functionalities was utilized in the case of cyclophosphamide and ifosfamide (Fig. 10.4). In these cases, aziridinium cation formation is not possible until the electron-withdrawing function has been altered. In the case of cyclophosphamide, it was initially believed that the drug could be selectively activated in cancer cells because they were believed to contain high levels of phosphoramidase enzymes. This would remove the electron-withdrawing phosphoryl function and allow aziridine formation to occur. However, it turned out that the drug was activated by cytochrome P450 (CYP) isozymes CYP2B6 and CYP3A4/5 to give a carbinolamine that could undergo ring opening to give the aldehyde.10,11 The increased acidity of the aldehyde a-hydrogen facilitates a retro-Michael decomposition (Scheme 10.5). The ionized phosphoramide is now electron-releasing via induction and allows aziridinium cation formation to proceed. Acrolein is also formed as a result of this process, which may itself act as an electrophile that has been associated with bladder toxicity. Alternatively, the agent may be inactivated by alcohol dehydrogenase-mediated oxidation of the carbinolamine to give the amide or by further oxidation of the aldehyde intermediate to give the acid by aldehyde dehydrogenase.
To decrease the incidence of kidney and bladder toxicity, the sulfhydryl (—SH) containing agent mesna may be administered and functions to react with the electrophilic species that may be present in the kidney. The sulfonic acid functionality serves to help concentrate the material in the urine, and the nucleophilic sulfhydryl group may react with the carbinol-amine, aziridinium cation, the chloro substituents of cy-clophosphamide, or via conjugate addition with acrolein (Scheme 10.6). This inactivation and detoxification may also be accomplished by other thiol-containing proteins such as
Figure 10.4 • Structures of cyclophosphamide and ifosfamide.
Figure 10.4 • Structures of cyclophosphamide and ifosfamide.
glutathione. Increased levels of these proteins may occur as cancer cells become resistant to these alkylating agents.
Ifosfamide contains similar functionality and also requires activation by CYP2B6 and CYP3A4/5 (Scheme 10.7). Although the agents are similar, there are differences in the metabolism and activity of the agents.12,13 Both are administered as racemic mixtures as a result of the presence of a chi-ral phosphorus atom. There appears to be little difference in the metabolic fate of the R- and S-isomers of cyclophosphamide, but in the case of ifosfamide, the R-isomer is converted to the required 4-hydroxy-ifosfamide 2 to 3 times faster than the S-isomer.14 The S-isomer undergoes preferential oxidation of the side chain to give N-dechloroethylation, which removes the ability of the agent to cross-link DNA and also produces the neurotoxic and urotoxic chloroacetalde-hyde. An additional difference between cyclophosphamide and ifosfamide is the larger alkylating species that ultimately results after metabolic activation of ifosfamide. This results in the reactive form of ifosfamide having a higher affinity for DNA than the analogous form of cyclophosphamide and differences in the interstrand and intrastrand links that ultimately result. The differential metabolism also results in increased formation of the urotoxic chloroacetaldehyde in the case of ifosfamide such that bladder toxicity that normally presents as hemorrhagic cystitis becomes dose limiting with this agent.
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