Cytosine arabinoside polymerase

When nucleoside analogs, such as cytosine arabinoside (AraC), azidothymidine (zidovudine orAZT), and dideoxyinosine (ddi), are converted into the corresponding nucleotides by salvage pathways, they can be Incorporated into nascent DNA strands by DNA polymerases. 

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 available for the treatment of acute myelogenous leukemia. Cytarabine kills cells in the S-phase of the cycle by competitively inhibiting DNA polymerase. The drug must... 

Cytarabine or cytosine arabinoside competitively inhibits DNA polymerase... 

Fluorouracil (chap. 3, Fig. 6), an inhibitor of thymidylate synthetase, and cytosine arabinoside, which inhibits DNA polymerase, are both teratogens, which have already been referred to. 

Cytosine arabinoside (Cytarabine, Cytosar, and Ara-C) is an analog of deoxycytidine, differing only in its substitution of sugar arabinose for deoxyribose. It is converted to Ara-CTP, and thereby inhibits DNA polymerase according to the following reactions ... 

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... 

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). 

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

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-... 

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. 

Perhaps best known of the nucleoside analogues are the arabinose compounds Ara(C) (cytosine arabinoside, l-jS-D-arabinofuranosylcytosine) and Ara(A) (adenine arabinoside, 9-j8-D-arabinofuranosyladenine). Both compounds are triphosphorylated [converted to Ara(CTP) and Ara(ATP) in vivol upon which they may exert a dual action on DNA polymerase. They may inhibit DNA polymerase (for example, Ara(CTP) inhibits DNA polymerase II and III) and they may be incorporated into newly synthesized DNA. In fact, Ara(C) but not Ara(A) is also incorporated into RNA. Such uptake into DNA is lethal since a subtle difference will develop in the DNA geometry as a result of the cytosine base adapting a new glycosidic bond angle due to steric hindrance from the 2 -hydroxyl function. 

Cytosine Arabinoside (1-B-D-arabinofuranosylcytosine, ara-C, cytara-bine) - Enzymatic phosphorylation studies confirm that ara-C and its phos-phorylated derivatives are deoxycytidine antagonists rather than cytidlne antagonists. 2 inhibition of DNA polymerase activity is considered more significant j-q antlneoplastic properties than either blocking the uptake of thymidine or the inhibition of the conversion of cytidlne diphosphate to deoxycytidine diphosphate. Ara-C rapidly kills S phase cells. It affects the passage rate of cells from S to G2 phase more than from Gl to Sl5. 

Within each category of DNA polymerases, member enzymes can be grouped into phylogenetic families based on sequence similarity, and then subdivided according to biological functions and sensitivity to inhibitors (e.g., aphidicolin, phosphonoacetic acid, and cytosine arabinoside). Yet DNA polymerases can differ significantly from one another in various physicochemical properties such as molecular size, thermal stability, template and primer preference, fidelity, process-ivity, optimal reaction conditions, and catalytic efficiency. Therefore, each polymerase deserves due attention to its specific properties. 

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