Ara-C: cellular and molecular pharmacology.
The antimetabolite cytosine arabinoside (ara-C) represents a prototype of the nucleoside analog class of antineoplastic agents and remains one of the most effective drugs used in the treatment of acute leukemia as well as other hematopoietic malignancies. The ability of ara-C to kill neoplastic cells is regulated at three distinct but interrelated levels. First, the activity of ara-C depends on conversion to its lethal triphosphate derivative, ara-CTP, a process that is influenced by multiple factors, including nucleoside transport, phosphorylation, deamination, and levels of competing metabolites, particularly dCTP. Second, the antiproliferative and lethal effects of ara-C are linked to the ability of ara-CTP to interfere with one or more DNA polymerases as well as the degree to which it is incorporated into elongating DNA strands, leading to DNA fragmentation and chain termination. Finally, the fate of the cell is ultimately determined by whether a threshold level of ara-C-mediated DNA damage is exceeded, thereby inducing apoptosis, or programmed cell death. The latter process is influenced by components of various signal transduction pathways (e.g., PKC) and expression of oncogenes (e.g., bcl-2, c-Jun), perturbations in which may significantly alter ara-C sensitivity. A better understanding of these factors could eventually lead to the development of novel therapeutic strategies capable of overcoming ara-C resistance and improving therapeutic efficacy.
Grant
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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D009857:Oncogenes; D015398:Signal Transduction / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D003115:Colony-Stimulating Factors; D008563:Membrane Lipids; D003561:Cytarabine