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

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
active as a cytotoxic agent. The nucleotide (5'-FUMP) can be formed by several different pathways. FUMP
can be incorporated into RNA and also can be converted to the deoxynucleotide (FdUMP). This latter
reaction is crucial to the cytotoxic effects of 5-FU. FdUMP may also be formed by the direct conversion of
FdUrd by thymidine kinase. FdUMP inhibits the enzyme thymidylate synthetase which leads to deletion of
thymidine triphosphate (TTP), a necessary constituent of DNA. Ordinarily, thymidylate synthetase
catalyzed the methylation of dUMP in a multistep process. When FdUMP is utilized, the process becomes
inhibited at an intermediate step. A complex between the enzyme, the pseudosubstrate and the folate
cofactor is formed. The complex dissociates very slowly and is sufficiently stable so that the enzyme no
longer can catalyze the reaction. DNA synthesis is inhibited until the drug is removed and new enzyme
synthesis occurs. Since FdUrd is converted to FdUMP directly in one step it is a more potent inhibitor of
TMP synthetase than is 5-FU. It is often effective in the nanomolar concentration range. On the other hand
5-FU will require micromolar concentrations to be effective and at such concentrations other active
metabolites are formed, such as FUTP, which can become incorporated into RNA in place of UTP.
Incorporation into RNA has resulted in observed effects on the function of both rRNA and mRNA.
Although incorporation into RNA is much higher than incorporation into DNA, recent studies have shown
this to occur also. However, the biological consequences of this are not known. It is most probable that the
cytotoxic action of these drugs is not the same in all cell lines and that this heterogeneity is the basis for the
wide variability in response to 5-FU.
The oral absorption of 5-FU is erratic, so it is usually given parenterally either by IV bolus or by
continuous infusion (IV or arterial). Administration by continuous infusion overcomes the problem of rapid
disappearance of 5-FU from the circulation. Since these drugs work best if they are present during the S
phase of the cell cycle their short time in the circulation would ordinarily present a problem as the plasma
levels would greatly fluctuate. Protocols using continuous infusion were developed to overcome this
potential problem. Metabolic degradation occurs particularly in the liver. 5-FU readily enters the CSF.
5-FU is used to treat several common solid tumors. It produces partial responses in up to about 1/3 of
patients with metastatic carcinomas of the breast and the gastrointestinal tract. Topically it has been used
for the treatment of basal cell carcinomas and premalignant skin keratoses. 5-FU is used in many different
combinations in order to enhance its activity. Some involve combination with other cytotoxic agents like
methotrexate while others involve combination with agents that by themselves lack toxicity but modulate
the cytotoxic effects of FU. Combination with leucovorin has been very successful as the leucovorin
enhances formation of the ternary complex. Floxuridine is primarily used by continuous infusion into the
hepatic artery for treatment of metastatic colon cancer.
Toxicity:
The toxicities of these two drugs are similar and somewhat dependent on the mode of administration.
Anorexia and nausea are among the earliest toxicities seen. These are followed by stomatitis and diarrhea
which are indicative of a sufficient dose being given. The frequency of effects varies with the treatment
schedule employed. Stomatitis and diarrhea are the most common dose-limiting toxicities when continuous
infusions are used. The major toxicity resulting from a bolus dose is bone marrow depression. This is
manifested by leukopenia and somewhat less often by thrombocytopenia and anemia. The lowest blood
counts occur at one to two weeks. Skin toxicity manifested by alopecia, thinning of the skin, nail changes,
dermatitis and photosensitivity can also occur. 5-FU also produces an acute cerebellar syndrome in less
than 1% of patients. This includes ataxia, nystagmus, slurred speech and dizziness.
Cytosine arabinoside (cytarabine or ara-C) is an analog of 2'-deoxycytidine with the 2'-hydroxyl in a
position trans to the 3'-hydroxyl of the sugar. The bases of polyarabinosides cannot stack normally as do
the bases of polydeoxynucleotides.
Ara-C is first converted to the monophosphate nucleotide (AraCMP) by deoxycytidine kinase. The
monophosphate can then react with appropriate kinases to form the di- and triphosphate nucleotides.
AraCTP is believed to be the key active component. Its accumulation causes potent inhibition of DNA
synthesis in many cells. This nucleotide is a competitive inhibitor of DNA polymerases. Also, the
triphosphate is a substrate for DNA polymerases and it is incorporated into the DNA. It apparently causes
inhibition of DNA chain elongation when ara-C in incorporated at the terminal position of a growing DNA
chain. Unlike most of the antimetabolites the effects of ara-C are directed almost exclusively towards DNA
and it has little or no effect on RNA synthesis or function. The relative biological impact of DNA synthesis
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