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

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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
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 Mechlorethamine, but not the other nitrogen mustards, will produce a severe necrosis if extravasated on the skin during administration. If extravasation occurs, the area should be infiltrated with isotonic sodium thiosulfite which reacts with the electrophilic drug derivatives. Busulfan has few pharmacological effects other than myelosuppression. This property is important in both its therapeutic use and toxicity. Busulfan is an atypical alkylating agent, although it is converted to a bifunctional alkylator. Its action is limited mainly to the myeloid cells. It is useful for the treatment of chronic myelocytic leukemia (CML) during the chronic phase of this disease. Its toxicity is mainly on the bone marrow where it is toxic mainly to the granulocytes. At high doses it does affect platelets and red blood cells and in some patients a severe pancytopenia will result. Also at high doses pulmonary fibrosis can occur. The nitrosourea class of alkylating agents appear to function as bifunctional alkylating agents but differ in both pharmacological and toxicological properties from the other alkylating agents. The nitrosoureas are converted non-enzymatically into a carbonium ion and an isothiocyanate molecule. The carbonium ion acts as a typical alkylating agent and is probably responsible for the cytotoxic action of the nitrosoureas. The isothiocyanate may interact with proteins and account for some of the toxic effects of these drugs. Of the nitrosoureas used currently, carmustine must be administered parenterally while lomustine and semustine can be given orally. All of them have short plasma half-lives. All of the nitrosoureas are very lipophilic and have very good penetration into brain tissue. This allows good therapeutic utility in various CNS neoplasms. They are used mainly for the treatment of Hodgkin's disease, meningeal leukemia and brain tumors. Occasionally they are used in the treatment of solid tumors such as lung, gastrointestinal and breast carcinomas in combination with other anticancer agents. The usual dose limiting toxicity is a delayed bone marrow suppression. They also produce acute nausea and vomiting. Carmustine can produce an unusual interstitial pulmonary fibrosis. Several other alkylating agents have been available over the years. Most of them are quite toxic and have been used only in special circumstances. Among them are dacarbazine, hydroxymethylmelamine, thiotepa and mitomycin C. Dacarbazine is probably the most widely used of the miscellaneous agents. It functions as a methylating agent after metabolic activation in the liver. It is employed in combination regimens for the treatment of malignant melanomas, Hodgkin’s disease and adult sarcomas. Antimetabolites Antimetabolites are structural analogs of naturally occurring compounds. They interfere with the production of nucleic acids, working through a variety of mechanisms including competition for binding sites on enzymes and incorporation into nucleic acids. Their are three categories of antimetabolites – antifolates, purine analogs and pyrimidine antimetabolites. The importance of folates in tumor cell growth was demonstrated in 1948 by Farber and colleagues when aminopterin was shown to produce remissions in leukemia. Antifolates produced both the first striking remissions in leukemia and the first cure of a solid tumor, choriocarcinoma. Although aminopterin was the first clinically useful folate, methotrexate was soon introduced in therapy and it has become the major folate used in cancer therapy. Trimetrexate is a recent introduction. Folic acid is an essential growth factor from which is derived a series of tetrahydrofolate cofactors that provide single carbon groups for the synthesis of RNA and DNA precursors such as thymidylate and purines. Folic acid must be reduced in two successive steps by the enzyme dihydrofolate reductase (DHFR) before it can function as a coenzyme. The fully reduced form is the one that picks up and delivers single carbon units in various metabolic processes. DHFR is the primary target of action of most folate analogs such as methotrexate. Inhibition of this enzyme leads to toxicity through partial depletion of cofactors required for the synthesis of purines and thymidylate. Methotrexate is a strong inhibitor of DHFR. It has a high affinity for the tumor cell enzyme blocking the formation of tetrahydrofolate needed for thymidylate and purine synthesis. Cell death probably results from inhibition of DNA synthesis. As with most antimetabolites methotrexate is only partially selective for tumor cells and is toxic to all rapidly dividing normal cells such as those of the gastrointestinal epithelium and bone marrow. Several factors influence the effectiveness of methotrexate treatment. Included among them are factors that concentrate the drug intracellularly such as transport and conversion to the higher molecular weight polyglutamates that are preferentially retained within the cell. Also important are changes in the amount and structure DHFR. Changes in the latter will influence methotrexate binding and determine how well the drug is able to inhibit nucleotide synthesis. The major mechanisms of resistance are decreased drug uptake, Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 9
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