Nucleoside analogues: mechanisms of drug resistance and reversal strategies.
Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.
Galmarini
C M
CM
Unité INSERM 453, Laboratoire de Cytologie Analytique, Faculté de Médécine Rockefeller, Lyon, France.
Mackey
J R
JR
Dumontet
C
C
D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015720:5'-Nucleotidase / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001087:Arabinonucleosides / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D003561:Cytarabine / Q000737:chemistry / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003839:Deoxyadenosines / Q000737:chemistry / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004148:Dioxolanes / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy; D008232:Lymphoproliferative Disorders / Q000188:drug therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009705:Nucleosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D012074:Remission Induction; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D002352:Carrier Proteins; D003839:Deoxyadenosines; D004148:Dioxolanes; D016298:Hematopoietic Cell Growth Factors; D009705:Nucleosides; D003561:Cytarabine; D003841:Deoxycytidine; D015762:2-Chloroadenosine; C028771:9-arabinofuranosylguanine; C074908:troxacitabine; D003596:Cytosine; D012264:Ribonucleotide Reductases; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase; D003842:Deoxycytidine Kinase; D004259:DNA-Directed DNA Polymerase; D015720:5'-Nucleotidase; D003564:Cytidine Deaminase; D014740:Vidarabine; C055994:2-chloro-3'-deoxyadenosine; C024352:fludarabine; D000093542:Gemcitabine