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 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 Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 12
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 inhibition versus incorporation into DNA has been studied for several years now. The evidence indicates that synthesis inhibition is secondary to analog incorporation. However, the precise cause of cellular death by ara-C is not known. Cytarabine is very poorly absorbed after oral administration in humans. It is routinely given IV by continuous infusion, sometimes in high dose regimens. Intrathecal administration is also used for meningeal leukemia and lymphoma. Ara-C reaches the CNS reasonable well with CSF levels as high as 40% of the plasma levels. It has a very short plasma half-life due to cytidine deaminase activity in liver and elsewhere, and its metabolites are renally excreted. Metabolism accounts for 70-90% of the Ara-C eliminated with most of the drug being excreted as ara-U. Ara-C is used primarily for the treatment of acute myeloid leukemia (AML) due to its potent myelosuppressive action. It is the single most effective agent for induction of remission in this disease and it is used primarily in combination with daunorubicin. It has occasionally been used to treat ALL and, in high doses, it has been used for non-Hodgkin’s lymphoma and CML. It is not active against solid tumors. Toxicity: The principal toxicity is bone marrow depression manifested as granulocytopenia and thrombocytopenia. Other toxicities include oral ulceration, nausea, vomiting and diarrhea, and peripheral neurotoxicity with high doses. Extra caution is needed when hepatic function is decreased. Fludarabine is a new nucleoside analog that has modifications in both the base and sugar moieties. Like ara-C it is metabolized to the nucleotide triphosphate by sequential action of several kinases. It then interferes with DNA synthesis by DNA polymerase inhibition and by incorporation into nascent DNA. Unlike ara-C this compound is much more likely to act as a chain terminator. It also apparently acts as an inhibitor of the proofreading exonuclease activity of DNA polymerase epsilon. Fludarabine has been shown to be very effective against CLL. It gives a response rate exceeding 80% in previously untreated patients. Moderate to severe myelosuppression occurs at therapeutic doses, while neurologic toxicity occurs especially at higher doses. Antitumor antibiotics (non-covalent DNA-binding drugs) These drugs interact with DNA in a variety of different ways including intercalation, DNA strand breakage and inhibition of the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and are antibiotics. However, they lack the specificity of clinically used antimicrobial antibiotics and thus produce significant toxicity. Actinomycin D (Dactinomycin) is the only actinomycin used clinically. This compound contains a phenoxasone ring and two cyclic pentapeptides as part of its structure. The phenoxasone ring is the chromophore moiety which imparts a red color to the drug. At low concentrations dactinomycin inhibits DNA directed RNA synthesis and at higher concentrations DNA synthesis is also inhibited. All types of RNA are affected, but ribosomal RNA is more sensitive. Dactinomycin binds to double stranded DNA, permitting RNA chain initiation but blocking chain elongation. Binding to the DNA depends on the presence of guanine. X-ray crystallography studies show that in the dactinomycin-DNA complex the phenoxasone ring lies between two deoxyguanosine molecules and strong hydrogen bonds connect the 2-amino group of guanine and the threonine residues in the polypeptide side chains of the drug. There is a very tight binding of the drug with the DNA and thus a very slow dissociation. This apparently reflects the intermolecular hydrogen bonds. Apparently the tight binding of the dactinomycin prevents unwinding of the DNA to facilitate its interaction with RNA polymerase. This prevents the synthesis of RNA by the DNA dependent RNA polymerase and this blockade is responsible for the cytotoxic effect. The exact mechanism of the cytotoxicity is not clear but in some cells apoptosis is initiated. Dactinomycin is cytotoxic to cells in any phase of the cell cycle and it is probably equally toxic to exponentially growing cells and stationary cells. Dactinomycin is usually given IV and can cause severe local necrosis if extravasation occurs. Therefore, it should be administered into the tubing of a rapidly flowing IV infusion. The plasma half-life is very short, but tissue half-life is long (48 h) due to DNA binding. Only a small amount of the drug is known to be metabolized. Urinary and fecal excretion of the drug is prolonged. In humans it does not appear to enter into the CNS . Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 13
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