On H

5-Fluorouracil figure 2.6. Metabolic activation of capecitabine (5'-DFCR, 5'-deoxy-5-fluorocytidine; 5'-DFUR, 5'-deoxy-5-fluorouridine).

Cytosine Arabinoside

Cytosine arabinoside (Ara-C) is one of the cornerstone agents in AML therapy. It was originally extracted from the sponge Cryptothethya crypta. This cytidine analogue differs from the native cytidine by the substitution of the sugar moiety ara-binose for ribose. It is intracellularly activated after phosphorylation by different kinases into its triphosphate form (Ara-CTP) such as deoxycytidine kinase, deoxycytidine monophosphate kinase, and nucleoside dephosphate kinase. Deoxycytidine kinase activity is highest during the S phase of the cell cycle and is the rate-limiting step in the anabolic conversion of various other nucleoside analogues. Ara-CTP then competes with and depletes the dCTP pool and reversibly inhibits DNA polymerase. More importantly, the degree of incorporation of ara-CTP into DNA, leading to chain termination and inhibition of DNA synthesis, correlates with cytotoxicity.76 It also inhibits ribonucleotide reductase, the enzyme that catalyzes the synthesis of other deoxynucleoside triphosphates. Likewise, ara-C inhibits the formation of CDP-choline integral to the synthesis of membrane glycoproteins and glycolipids. Balancing these are deaminating reactions, catalyzed by cytidine deaminase and dCMP deaminase, that degrade the active ara-C metabolites. Cytidine deaminase is widely distributed in normal cells, including the liver, GI mucosa, and mature granulocytes.

Ara-C enters cells by a saturable carrier-mediated transport system in common with physiologic nucleosides. It has been shown that the transport system is the rate-limiting factor in the formation ara-CTP.88 At drug levels above 10 mmol/L, passive diffusion occurs and the ability to accumulate ara-CTP becomes saturated. Thus, high-dose regimens may overcome resistance in some cases associated with deficiencies in the transport system. In spite of its water solubility, ara-C penetrates the CNS quite effectively, 20% to 40% of plasma levels at steady state, to reach threshold cytotoxic levels for leukemia cells in the CSF at conventional doses. Because of the high concentrations of cytidine deaminase in the GI tract, oral administration yields significantly lower plasma levels, and therefore this route is precluded. Myelosuppression and GI toxicities are the major adverse effects of ara-C. Diarrhea and mucositis occur frequently. High-dose ara-C intensifies the severity of these toxicities. Moreover, certain syndromes unique to high-dose therapy are notable. Neurotoxicity in the form of cerebral-cerebellar dysfunction manifested as ataxia, dementia, slurred speech, and coma may lead to permanent disability in up to 40% of affected patients. An irreversible acute respiratory distress syndrome can occur in association with a high incidence of Streptococcus viridans pneumonia, especially in children. Steroid-responsive conjunctivitis is a frequent side effect. An unusual febrile state in conjunction with cutaneous eruption of plaques of nodules, termed neutrophilic eccrine hydradeni-tis, is also associated with high-dose therapy.


Gemcitabine (2,2-difluorodeoxycytidine, dFdC) is the most important cytidine analogue currently in use for solid tumors. Cellular influx also occurs via the nucleoside transport system. Intracellular activation by deoxycytidine kinase is the rate-limiting step necessary for antitumor activity. The diphosphate form (dFdCDP) inhibits ribonucleotide reductase more effectively than ara-C,89 whereas the triphosphate dFdCTP not only inhibits DNA polymerase but also leads to DNA strand termination upon its incorporation into the elongating DNA strand. Similar to ara-C, cytidine deaminase catalyzes the major catabolic pathway in degrading gemcitabine to difluorodeoxyuridine (dFdU). Deamination requires activation by dCTP, whose level in turn is reduced upon inhibition of ribonucleotide reductase by dFdCDP. Moreover, dFdCTP directly inhibits cytidine deaminase. The preclinical finding that prolonged exposure to gemcitabine leads to dramatically greater antitumor effect is consistent with the concept of self-potentiation leading to prolonged intracellular concentrations of its primary cytotoxic metabolite, dFdCTP. Affinity of gem-citabine for deoxycytidine kinase and cytidine deaminase is much lower than deoxycytidine itself. Nevertheless, gem-citabine is a better substrate for the nucleoside transporter of tumor cells and has greater affinity for deoxycytidine kinase than ara-C. DFdCTP has a longer half-life than ara-CTP. Moreover, dFdCDP is a more potent inhibitor of ribonu-cleotide reductase than ara-CTP. Gemcitabine enhances the formation of DNA adducts, and thus cytotoxicity, by cisplatin. It also potently sensitizes cells to ionizing radiation. This radiosensitization is dose- and time-dependent and is maximal when radiation follows gemcitabine exposure. Because dFdCTP is present intracellularly for several days after drug administration, gemcitabine is able to radiosensi-tize cells for several days after bolus administration. However, this also underlies the unwanted side effect of increased treatment-related morbidity and, in some cases, mortality.90 Gemcitabine is currently used in pancreatic and non-small cell lung cancers and is active in breast, bladder, and ovarian cancers, lymphomas, and head and neck

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