Monitoring of Suspected Adverse Drug Reactions in Oncology Unit ...

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
containing two reactive chloroethyl side chains) can undergo a second cyclization of the second side chain
and form a covalent bond with another nucleophilic group. The second group could be a 7-nitrogen of
another guanine or some other nucleophilic moiety. These bifunctional alkylating agents such as nitrogen
mustard react with another nucleophilic moiety resulting in the cross-linking of two nucleic acid chains or
the linking of a nucleic acid to a protein. This type of alteration could cause a major disruption in nucleic
acid function. Cytotoxicity of bifunctional alkylators correlates very closely with interstrand cross- linkage
of DNA. The ultimate cause of cell death related to DNA damage in not known. Some of the cellular
responses produced include cell-cycle arrest, DNA repair and apoptosis or programmed cell death. The
nucleophilic groups of proteins, RNA and many other molecules can also be subject to attack by the
alkylating agents, although the exact result of these interactions is not known.
The alkylating agents are generally considered to be cell cycle phase nonspecific. They also are known
to be most cytotoxic to rapidly proliferating cells. Thus although DNA alkylation can occur anytime in the
cell cycle, the biological consequences are most severe when this occurs during DNA synthesis. This is
because cells exposed to the alkylating agents earlier, such as in G 1 phase, would have enough time to
repair some of the DNA damage before the next DNA synthesis phase. Non-proliferating cells would have
an even greater period for DNA repair to occur before irreversible damage occurs. Thus the alkylating
agents are proliferation dependent but cell-cycle phase nonspecific.
All of the nitrogen mustards are chemically unstable but they vary greatly in their degree of instability
ranging from the highly unstable mechlorethamine to the highly stable chlorambucil and
cyclophosphamide. The original alkylating agents such as mechlorethamine were very unstable and had
to be administered rapidly to avoid breakdown. This, mechlorethamine must be given into a running
intravenous (IV) infusion.
Most of the current clinically useful alkylating agents have structural modifications that have produced
stable compounds that can be given orally as well as parenterally. For example, cyclophosphamide can be
administered orally or parenterally. However cyclophosphamide is unique in that it must be converted to an
active form by liver microsomal enzymes. Cyclophosphamide was originally designed so that it would be
preferentially activated in tumor tissue which is believed to contain high levels of enzymes that would
convert it to an active form. Although selectivity is now known not to be achieved, the drug undergoes
metabolic activation in the liver catalyzed by the cytochrome P 450 microsomal enzymes. One of the
metabolites formed is believed to be active a s a cytotoxic agent while another metabolite, acrolein, is
believed responsible for the cystitis produced by cyclophosphamide. Ifosphamide is a structural analog of
cyclophosphamide. It is metabolized by the cytochrome P 450 system and it undergoes the same metabolic
conversions as does cyclophosphamide. However, a smaller proportion of ifosphamide is converted to
cytotoxic compounds and larger doses are used clinically as compared to cyclophosphamide.
Therapeutic uses:
The nitrogen mustards can be used for treatment of a variety of tumors ranging from leukemias to solid
tumors. Mechlorethamine is used mainly to treat Hodgkin's disease (MOPP regimen). Chlorambucil is
used almost exclusively in the treatment of chronic lymphocytic leukemia (CLL). Occasionally it has been
used to treat certain lymphomas. Melphalan has been used principally to treat multiple myeloma. The most
commonly used alkylating agent is cyclophosphamide. It is an extremely versatile agent used in Hodgkin's
disease and other lymphomas. In addition it is useful to treat acute lymphocytic leukemia (ALL) and a
variety of solid tumors. It can be given in a variety of ways and dosages unlike many of the other nitrogen
mustards. The indications for ifosphamide are similar to cyclophosphamide. It is used almost exclusively
with mesna, a compound that inactivates the alkylating activity and helps prevent the cystitis associated
with this drug.
Toxicity:
The dose limiting toxicity of all the nitrogen mustards is bone marrow depression. This is usually of a
delayed nature. It is important to monitor leukocyte and platelet counts carefully during therapy with these
drugs. All of the nitrogen mustards produce acute nausea and vomiting, and with some, such as
mechlorethamine, the effect is quite severe. Cyclophosphamide frequently causes alopecia and a
hemorrhagic cystitis. As mentioned above, this cystitis is attributed to formation of acrolein during the
metabolism of cyclophosphamide. Its incidence can be reduced by ensuring good fluid intake and frequent
voiding and can be prevented by coadministration of sulfhydryl scavenging compounds such as N-
acetylcysteine or mesna. High dose cyclophosphamide is generally not used without mesna.
Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 8