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| Trade names | Cytosar-U, Depocyt, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682222 |
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| Routes of administration | injectable (intravenous injection or infusion, intrathecal, or subcutaneously) |
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| Pharmacokinetic data | |
| Bioavailability | 20% by mouth |
| Protein binding | 13% |
| Metabolism | Liver |
| Eliminationhalf-life | biphasic: 10 min, 1–3 hr |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.005.188 |
| Chemical and physical data | |
| Formula | C9H13N3O5 |
| Molar mass | 243.219 g·mol−1 |
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Cytarabine, also known ascytosine arabinoside (ara-C), is achemotherapy medication used to treatacute myeloid leukemia (AML),acute lymphocytic leukemia (ALL),chronic myelogenous leukemia (CML), andnon-Hodgkin's lymphoma.[2] It is given byinjection into a vein,under the skin, or into thecerebrospinal fluid.[2] There is aliposomal formulation for which there is tentative evidence of better outcomes inlymphoma involving the meninges.[2]
Common side effects includebone marrow suppression, vomiting, diarrhea,liver problems, rash, ulcer formation in the mouth, and bleeding.[2] Other serious side effects includeloss of consciousness, lung disease, andallergic reactions.[2] Use duringpregnancy may harm the baby.[2] Cytarabine is in theantimetabolite andnucleoside analog families of medication.[3] It works by blocking the function ofDNA polymerase.[2]
Cytarabine was patented in 1960 and approved for medical use in 1969.[4] It is on theWorld Health Organization's List of Essential Medicines.[5]
Cytarabine is mainly used in the treatment ofacute myeloid leukaemia,acute lymphocytic leukaemia (ALL) and inlymphomas,[6] where it is the backbone ofinduction chemotherapy.
Cytarabine also possessesantiviral activity, and it has been used for the treatment of generalisedherpesvirus infection. However, cytarabine is not very selective in this setting and causesbone marrow suppression and other severe side effects. Therefore, ara-C is not a useful antiviral agent in humans because of its toxic profile.[7]
Cytarabine is also used in the study of thenervous system to control the proliferation ofglial cells in cultures, the amount of glial cells having an important impact onneurons.[citation needed] Recently, cytarabine was reported to promote robust and persistent neuronal differentiation in NSC-34 motor neuron-like cell line. Cytarabine is permissive, dispensable, and mostly irreversible in priming NSC-34 cells for neurite initiation and regeneration after mechanical dislodgement.[8]
One of the unique toxicities of cytarabine iscerebellar toxicity when given in high doses, which may lead toataxia. Cytarabine may causegranulocytopenia and other impaired body defenses, which may lead to infection, andthrombocytopenia, which may lead tohemorrhage.[citation needed]
Toxicity:pancreatitis,leukopenia, thrombocytopenia,anemia, GI disturbances,stomatitis,conjunctivitis,pneumonitis,fever, anddermatitis,palmar-plantar erythrodysesthesia. Rarely,myelopathy has been reported after high dose or frequentintrathecal Ara-C administration.[9]
When used in protocols designated as high dose, cytarabine can cause cerebral and cerebellar dysfunction, ocular toxicity, pulmonary toxicity, severe GI ulceration andperipheral neuropathy (rare).[citation needed]
To prevent the side effects and improve the therapeutic efficiency, various derivatives of these drugs (including amino acid, peptide, fatty acid and phosphates) have been evaluated, as well as different delivery systems.[10]
Cytosine arabinoside combines acytosine base with anarabinose sugar. It is anantimetabolic agent with the chemical name of1β-arabinofuranosylcytosine. Certainsponges, where similar compounds were originally found, use arabinoside sugars for chemical defense.[11] 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 intocytosine arabinoside triphosphate, which damagesDNA when thecell cycle holds in theS phase (synthesis of DNA). Rapidly dividing cells, which require DNA replication formitosis, are therefore most affected. Cytosine arabinoside also inhibits bothDNA[12] andRNA polymerases andnucleotide reductase enzymes needed for DNA synthesis. Cytarabine is the first of a series of cancer drugs that altered the sugar component ofnucleosides. Other cancer drugs modify the base.[13]
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.[14] Cytarabine is transported into the cell primarily by hENT-1.[15] It is then monophosphorylated by deoxycytidine kinase and eventually cytarabine-5´-triphosphate, which is the active metabolite being incorporated into DNA during DNA synthesis.[citation needed]
Several mechanisms of resistance have been reported.[16] 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.[17] Cytarabine-5´-triphosphate is a substrate forSAMHD1.[18] Furthermore, SAMHD1 has been shown to limit the efficacy of cytarabine efficacy in patients.[19]
When used as anantiviral, cytarabine-5´-triphosphate functions by inhibiting viral DNA synthesis.[20] 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.[citation needed]
In mice, Ara-CTP (cytarabine-5'-triphosphate) blocks memory consolidation, but not short-term memory, of a context fear conditioning event.[21] The blockage of memory consolidation was proposed to be due to the inhibition by Ara-CTP of the DNAnon-homologous end joining pathway.[21] 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.[citation needed]
Isolation of arabinose-containing nucleotides from the Caribbean spongeCryptotheca crypta (nowTectitethya crypta) together with the realization that these compounds could act as DNA synthesis chain terminators led to exploration of these novel nucleotides as potential anticancer therapeutics.[22] Cytarabine was first synthesized in 1959 by Richard Walwick, Walden Roberts, and Charles Dekker at theUniversity of California, Berkeley.[23]
It was approved by the United StatesFood and Drug Administration in June 1969, and was initially marketed in the US byUpjohn under the brand name Cytosar-U.[citation needed]
It is also known as ara-C (arabinofuranosyl cytidine).[24]
