Cytarabine also possesses antiviral activity, and it has been used for the treatment of generalised herpesvirus infection. However, cytarabine is not very selective in this setting and causes bone 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 the nervous system to control the proliferation of glial cells in cultures, the amount of glial cells having an important impact on neurons.[citation needed]
When used in protocols designated as high dose, cytarabine can cause cerebral and cerebellar dysfunction, ocular toxicity, pulmonary toxicity, severe GI ulceration and peripheral 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.[9]
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.[10] 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[11] 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.[12]
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.[13] Cytarabine is transported into the cell primarily by hENT-1.[14] 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.[15] 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.[16] Cytarabine-5´-triphosphate is a substrate for SAMHD1.[17] Furthermore, SAMHD1 has been shown to limit the efficacy of cytarabine efficacy in patients.[18]
When used as an antiviral, cytarabine-5´-triphosphate functions by inhibiting viral DNA synthesis.[19] 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.[20] The blockage of memory consolidation was proposed to be due to the inhibition by Ara-CTP of the DNA non-homologous end joining pathway.[20] 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 sponge Cryptotheca crypta (now Tectitethya 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.[21] Cytarabine was first synthesized in 1959 by Richard Walwick, Walden Roberts, and Charles Dekker at the University of California, Berkeley.[22]
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Liliemark JO, Gahrton G, Paul CY, Peterson CO (June 1987). "ara-C in plasma and ara-CTP in leukemic cells after subcutaneous injection and continuous intravenous infusion of ara-C in patients with acute nonlymphoblastic leukemia". Seminars in Oncology. 14 (2 Suppl 1): 167–171. PMID3589691.
^Clarke ML, Mackey JR, Baldwin SA, Young JD, Cass CE (2002). "The Role of Membrane Transporters in Cellular Resistance to Anticancer Nucleoside Drugs". Clinically Relevant Resistance in Cancer Chemotherapy. Cancer Treatment and Research. Vol. 112. pp. 27–47. doi:10.1007/978-1-4615-1173-1_2. ISBN978-1-4613-5428-4. PMID12481710.
^Lemke TL, Williams DH, Foye WO (2002). Foye's principles of medicinal chemistry. Hagerstwon, MD: Lippincott Williams & Wilkins. p. 963. ISBN0-683-30737-1.
^Schwartsmann G, Brondani da Rocha A, Berlinck RG, Jimeno J (April 2001). "Marine organisms as a source of new anticancer agents". The Lancet. Oncology. 2 (4): 221–225. doi:10.1016/s1470-2045(00)00292-8. PMID11905767.
^Sneader W (2005). Drug discovery: a history. New York: Wiley. p. 258. ISBN0-471-89979-8.