Cytosine arabinoside combines a
cytosine base with an
arabinose sugar. It is an
antimetabolic agent with the chemical name of
1β-arabinofuranosylcytosine. Certain
sponges, where similar compounds were originally found, use arabinoside sugars for chemical defense. Cytosine arabinoside is similar enough to human deoxycytosine to be incorporated into human DNA, but different enough that it kills the cell. Cytosine arabinoside interferes with the synthesis of DNA. Its mode of action is due to its rapid conversion into
cytosine arabinoside triphosphate, which damages
DNA when the
cell cycle holds in the
S phase (synthesis of DNA). Rapidly dividing cells, which require DNA replication for
mitosis, are therefore most affected. Cytosine arabinoside also inhibits both
DNA and
RNA polymerases and
nucleotide reductase enzymes needed for DNA synthesis. Cytarabine is the first of a series of cancer drugs that altered the sugar component of
nucleosides. Other cancer drugs modify the base. Cytarabine is often given by continuous intravenous infusion, which follows a biphasic elimination – initial fast clearance rate followed by a slower rate of the analog. Cytarabine is transported into the cell primarily by hENT-1. It is then monophosphorylated by deoxycytidine kinase and eventually cytarabine-5'-triphosphate, which is the active metabolite being incorporated into DNA during DNA synthesis. Several mechanisms of resistance have been reported. Cytarabine is rapidly deaminated by cytidine deaminase in the serum into the inactive uracil derivative. Cytarabine-5'-monophosphate is deaminated by deoxycytidylate deaminase, leading to the inactive uridine-5'-monophosphate analog. Cytarabine-5'-triphosphate is a substrate for
SAMHD1. Furthermore, SAMHD1 has been shown to limit the efficacy of cytarabine efficacy in patients. When used as an
antiviral, cytarabine-5'-triphosphate functions by inhibiting viral DNA synthesis. Cytarabine is able to inhibit herpesvirus and vaccinia virus replication in cells during tissue culture. However, cytarabine treatment was only effective for herpesvirus infection in a murine model. In mice, Ara-CTP (cytarabine-5'-triphosphate) blocks memory consolidation, but not short-term memory, of a context fear conditioning event. The blockage of memory consolidation was proposed to be due to the inhibition by Ara-CTP of the DNA
non-homologous end joining pathway. Thus transient DNA breakage followed by non-homologous end joining appear to be necessary steps in the formation of a long-term memory of an event. ==History==