Genetic factors influencing cytarabine therapy.
The mainstay of acute myeloid leukemia chemotherapy is the nucleoside analog cytarabine (ara-C). Numerous studies suggest that the intracellular concentrations of the ara-C active metabolite, ara-CTP, vary widely among patients and, in turn, are associated with variability in clinical response to acute myeloid leukemia treatment. Thus, genetic variation in key genes in the ara-C metabolic pathway--specifically, deoxycytidine kinase (a rate-limiting activating enzyme), 5 nucleotidase, cytidine deaminase and deoxycytidylate deaminase (all three are inactivating enzymes), human equilibrative nucleoside transporter (ara-C uptake transporter) and ribonucleotide reductase (RRM1 and RRM2--enzymes regulating intracellular deoxycytidine triphosphate pools)--form the molecular basis of the interpatient variability observed in intracellular ara-CTP concentrations and response to ara-C. Understanding genetic variants in the key candidate genes involved in the metabolic activation of ara-C, as well as the pharmacodynamic targets of ara-C, will provide an opportunity to identify patients at an increased risk of adverse reactions or decreased likelihood of response, based upon their genetic profile, which in future could help in dose optimization to reduce drug toxicity without compromising efficacy. The pharmacogenetic studies on ara-C would also be equally applicable to other nucleoside analogs, such as gemcitabine, decitabine, clofarabine and so on, which are metabolized by the same pathway.
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. lamba004@umn.edu
Jatinder K
JK
Lamba
D015720:5'-Nucleotidase / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D003561:Cytarabine / Q000627:therapeutic use*; D003564:Cytidine Deaminase / Q000235:genetics; D003842:Deoxycytidine Kinase / Q000235:genetics; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics; D005544:Forecasting; D014644:Genetic Variation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D009700:Nucleoside Deaminases / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods; D012264:Ribonucleotide Reductases / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D012264:Ribonucleotide Reductases; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase