Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma.
Purine nucleoside phosphorylase (PNP) deficiency is a rare, inherited immunodeficiency disorder in which the specific molecular defect was identified. Clinically, a lack of PNP manifests as profound T-cell deficiency with minor or variable changes in the humoral system. Biochemically, the absence of PNP results in an increase in plasma deoxyguanosine (dGuo) and a T-cell-specific increase in intracellular deoxyguanosine triphosphate (dGTP). This observation has been the impetus for the search for either inhibitors of the enzyme or PNP-resistant dGuo analogues as potential anti-T-cell-lineage agents over the past 30 years. Forodesine (an inhibitor of PNP) and nelarabine (a PNP-resistant dGuo analogue) proved to be T-cell selective when tested in clinic. This review summarises the preclinical, clinical and pharmacokinetic investigations with these novel agents.
Ravandi
Farhad
F
University of Texas MD Anderson Cancer Center, Department of Leukaemia, Unit 428, 1515 Holcombe Boulevad, Houston, TX 77030, USA. fravandi@mdanderson.org
Gandhi
Varsha
V
D000328:Adult; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003849:Deoxyguanosine / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology
D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D015507:Drugs, Investigational; D009363:Neoplasm Proteins; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; C113101:forodesine; C104457:nelarabine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine