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Chapter: Modern Pharmacology with Clinical Applications: Antineoplastic Agents

Antimetabolites: Pyrimidine Analogues

Cytarabine (cytosine arabinoside, ara-C, Cytosar-U) is an analogue of the pyrimidine nucleosides cytidine and deoxycytidine.

Pyrimidine Analogues



Cytarabine (cytosine arabinoside, ara-C, Cytosar-U) is an analogue of the pyrimidine nucleosides cytidine and deoxycytidine. It is one of the most active agents avail-able for the treatment of acute myelogenous leukemia. Cytarabine kills cells in the S-phase of the cycle by com-petitively inhibiting DNA polymerase. The drug must

first be activated by pyrimidine nucleoside kinases to the triphosphate nucleotide ara-cytosine triphosphate (ara-CTP). The susceptibility of tumor cells to cytara-bine is thought to be a reflection of their ability to acti-vate the drug more rapidly (by kinases) than to inacti-vate it (by deaminases).


Cytarabine is rapidly metabolized in the liver, kid-ney, intestinal mucosa, and red blood cells and has a half-life in plasma of only 10 minutes after intravenous bolus injection. The major metabolite, uracil arabi-noside (ara-U), can be detected in the blood shortly af-ter cytarabine administration. About 80% of a given dose is excreted in the urine within 24 hours, with less than 10% appearing as cytarabine; the remainder is ara-U. When the drug is given by continuous infusion, cytarabine levels in CSF approach 40% of those in plasma.


Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with an anthracycline agent, thioguanine, or both. It is less use-ful in acute lymphoblastic leukemia and the lymphomas and has no known activity against other tumors. It has been used intrathecally in the treatment of meningeal leukemias and lymphomas as an alternative to meth-otrexate.


Myelosuppression is a major toxicity, as is severe bone marrow hypoplasia. Nausea and mucositis also may occur. Intrathecal administration occasionally pro-duces arachnoiditis or more severe neurological toxicity.




Fluorouracil (5-fluorouracil, 5-fluorouracil, Efudex, Adrucil) is a halogenated pyrimidine analogue that must be activated metabolically. The active metabolite that inhibits DNA synthesis is the deoxyribonucleotide 5-fluoro-2’ deoxyuridine-S -phosphate (FdUMP). 5-Fluorouracil is selectively toxic to proliferating rather than non-proliferating cells and is active in both the G1-and S-phases. The target enzyme inhibited by 5-fluo-rouracilfluorouracil is thymidylate synthetase, which catalyzes the following reaction:

The carbon-donating cofactor for this reaction is N5,N10 methylenetetrahydrofolate, which is converted to dihydrofolate. The reduced folate cofactor occupies an allosteric site on thymidylate synthetase, which al-lows for the covalent binding of 5-FdUMP to the active site of the enzyme.


Another action proposed for 5-fluorouracil may in-volve the incorporation of the nucleotide 5-fluorouri-dine triphosphate (5-FUTP) into RNA. The cytotoxic role of these “fraudulent” 5-fluorouracil-containing RNAs is not well understood.


Several possible mechanisms of resistance to 5-fluo-rouracil have been identified, including increased syn-thesis of the target enzyme, altered affinity of thymidy-late synthetase for FdUMP, depletion of enzymes (especially uridine kinase) that activate 5-fluorouracil to nucleotides, an increase in the pool of the normal metabolite deoxyuridylic acid (dUMP), and an increase in the rate of catabolism of 5-fluorouracil.


The drug has been administered orally, but absorp-tion by this route is erratic. The plasma half-life of 5-fluorouracil after intravenous injection is 10 to 20 min-utes. It readily enters CSF. Less than 20% of the parent compound is excreted into the urine, the rest being largely metabolized in the liver.


5-Fluorouracil is used in several combination regi-mens in the treatment of breast cancer. It also has pal-liative activity in gastrointestinal adenocarcinomas, in-cluding those originating in the stomach, pancreas, liver, colon, and rectum. Other tumors in which some antitu-mor effects have been reported include carcinomas of the ovary, cervix, oropharynx, bladder, and prostate. Topical 5-fluorouracil cream has been useful in the treatment of premalignant keratoses of the skin and su-perficial basal cell carcinomas, but it should not be used in invasive skin cancer.


Floxuridine (FUDR) is the nucleoside of 5-fluo-rouracil that is readily converted into 5-fluorouracil in vivo. It has similar pharmacological effects but is pre-ferred to 5-fluorouracil for hepatic arterial infusions be-cause it is more extensively metabolized in the liver than 5-fluorouracil, with less systemic toxicity.


The toxicities of 5-fluorouracil vary with the sched-ule and mode of administration. Nausea is usually mild if it occurs at all. Myelosuppression is most severe after intravenous bolus administration, with leukopenia and thrombocytopenia appearing 7 to 14 days after an in-jection. Daily injection or continuous infusion is most likely to produce oral mucositis, pharyngitis, diarrhea, and alopecia. Skin rashes and nail discoloration have been reported, as have photosensitivity and increased skin pigmentation on sun exposure. Neurological toxic-ity is manifested as acute cerebellar ataxia that may oc-cur within a few days of beginning treatment.


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