Cytosine arabinoside antimetabolite

Cytarabine is an effective antimetabolite in treating leukemia. Like other pyrimidine antimetabolites, cytarabine must be activated by initially transforming into the corresponding nucleotide. The active form of the drag is cytarabine triphosphate. Cytarabine is used for all types of leukemia. Synonyms of this drug are cytosine, arabinoside, and ara-C. 

Figure 1 Heterocycles as DNA antimetabolites a cytidine-guanosine base-pair from DNA is shown together with three heterocyclic antimetabolites, 8-azaguanine (90), 6-thioguanine (91) and cytosine arabinoside (92), making clear their similarity to the parent compounds...

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]. 

A nucleotide antimetabolite that carries the modification in the sugar rather than in the base is cytosine arabinoside (araC Figure 13.14). In this molecule, there is an OH group in position 2 of the ribose, pointing in the wrong direction (as compared to ribose). AraC gets incorporated into DNA but then apparently interferes with further DNA synthesis. This may affect different DNA polymerases to different extents in fact, araC reportedly inhibits DNA repair more strongly than DNA replication (the two processes involve different DNA polymerases). 

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... 

Resistance to purine and pyrimidine antimetabolites, such as adenosine arabinoside and cytosine arabinoside. by neoplastic cells that produce deaminases has stimulated a search... 

Antimetabolites Nephrotoxicity is generally not a major toxicity of antimetabolite therapy, except when these drugs are administered in high doses or in susceptible patients. Acute renal failure is the most common type of nephropathy induced by the antimetabolites with methotrexate treatment possessing the greatest risk. Acute renal failure has also been reported as a potential toxicity for 5-fluorouracil, 6-thioguanine, cytosine arabinoside, and 5-azacytidine. 

For various reasons, purine and pyrimidine drugs have not been routinely monitored outside of cfinical trials. Cytosine arabinoside 5-ftuorouracU 5-fluorodeoxyuridine and its monophosphate, 5-azacytidine and 2,2 difluorodeoxycyti-dine, which are all antimetabolites like methotrexate, have been extensively studied. Analytical methods have also been developed, but little relationship between circulating blood level and therapeutic efficacy has been found to justify... 

Mechanisms of action and resistance Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. The drug is activated by kinases to AraCTP, an inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the tumor cell cycle. Resistance to cytarabine can occur as a result of its decreased uptake or its decreased conversion to AraCTP. 

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