Cytosine arabinoside, metabolism

Hunt, C. A., Rustum, Y. M., Mayhew, E., and Papahadjopoulos, D. (1979). Retention of cytosine arabinoside in mouse lung following intravenous administration in liposomes of different size, Drug Metabol. Dispos., 7, 124-128. 

Cytarabine (cytosine arabinoside, ara-C) is an S phase-specific antimetabolite that is converted by deoxycytidine kinase to the 5 -mononucleotide (AraCMP). AraCMP is further metabolized to the triphosphate (AraCTP), which competitively inhibits DNA polymerase and results in blockade of DNA synthesis. Cytarabine is also incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized... 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-5], interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabolites, interfering with complex metabolic pathways in the cell, include methotrexate [59-05-2], 5-fluorouracil [51-21-8], and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxorubicin [23214-92-8] have been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Figure 13.14. Cytosine arabinoside Stracture (a), inhibition of DNA polymerase (b), and metabolism (c).

The introduction of an azido substituent on the C-2 position of cytosine arabinoside (ara-C) (149) or adenosine arabinoside (ara-A) (154) has been found to confer favourable properties to these antimetabolites. Ara-C, one of the most effective drugs for the treatment of human acute myeloblastic leukaemia [176], is subject to rapid metabolic deamination, by deoxycytid-ine deaminase, to the inactive uridine derivative ara-U (152) Scheme 3.5), and the drug has a half-life of approximately 12 minutes in man [177]. Efforts to circumvent this problem by modifying the 2 -arah/ o-position led... 

Macrocytic anemias are divided into megaloblastic and nonmega-loblastic anemias. Macrocytosis, as seen in megaloblastic anemias, is due to abnormalities in DNA metabolism resulting from a deficiency in vitamin Bi2 or folate, as well as due to various drugs such as hydroxyurea, zidovudine, cytosine arabinoside, methotrexate, azathioprine, 6-mercaptopurine, or cladribine. 

Figure 1. Transport and metabolism of cytosine arabinoside in humans...

Examples of teratogenic compounds which interfere with nucleic acid metabolism are cytosine arabinoside, which inhibits DNA polymerase, mitomycin C, which causes cross-linking, and 6-... 

S ATP + deoxyadenosine <1, 3, 5, 6> (<1> involved in biosynthesis of nucleoside monophosphates from preformed deoxyribonucleosides [4] <3> key anaboHc enzyme for activation of purine and pyrimidine deoxyriho-nucleosides as weU as cytosine arabinoside and other anti-tumour drugs [9] <5> involved in nucleoside metabolism [11] <6> dGK/dAK plays an essential role in generating the dexyribonucleotide precursors, dGTP and dATP, for DNA metabolism [12]) (Reversibility <1, 3, 5, 6> [4, 9, 11, 12]) [4, 9, 11, 12]... 

The comparative rates of metabolism of cytosine arabinoside have been studied by Camiener and Smith [113] and by Mulligan and Mellett [114]. Serum levels in various species are shown in Fig. 6. 

After administration of 50 mg/kg, drug serum levels are depleted in an apparently haphazard fashion in relation to body size. The monkey and man metabolize the drug at a rate greater than any other species studied. However, in this instance there is a reasonable explanation for this deviation. Cytosine arabinoside is metabolized to uracil arabinoside under control of a pyrimidine nucleoside deaminase. The enzyme has a unique distribution in tissues and animal... 

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