title: Selective toxicity of purine nucleosides to human leukaemic cells.
abstract: The in vitro cytotoxicity of various purine nucleosides and purine enzyme inhibitors, alone or in combination, and of the alkylating agent mafosfamide (Asta Z7557), incubated for 4 and 24 h have been studied in 17 leukaemic cell lines and normal bone marrow (BM). The purine nucleosides and their analogues included: 2'chlorodeoxyadenosine (CdA), 2'deoxyadenosine (AdR), 3'deoxyadenosine (3'AdR) (cordycepin), adenosine (AR), adenine arabinoside (Ara-A), deoxyguanosine (GdR) and guanine arabinoside (Ara-G). Purine enzyme inhibitors included 2-deoxycoformycin (dCF) and 8-aminoguanosine (8-AG). Cytotoxicity was based on inhibition of (i) incorporation of 3H-leucine into cell proteins and (ii) colony forming units--granulocytic/monocytic (CFU-GM) and for mixed cell colonies (CFU-GEMM). Marked and selective inhibition of T-cell growth was shown by the combinations dCF with either AdR or Ara-A, 8-AG and GdR and by CdA or Ara-G alone; these compounds even at high concentrations produced only partial inhibition of the growth of normal bone marrow CFU-GM and CFU-GEMM except for CdA which completely inhibited the formation of CFU-GEMM colonies. The combination dCF + cordycepin and alkylating agent mafosfamide were, however, toxic to all the cell lines at the concentrations employed, as well as to CFU-GM and CFU-GEMM. The high therapeutic index of some of the purine nucleosides with a relatively short exposure time makes them candidates for selective in vitro removal of residual neoplastic cells in autologous bone marrow transplantation (ABMT) for T-ALL.
authors.affiliation: Academic Department of Hematology, Royal Free Hospital School of Medicine, London.
authors.forename: A
authors.initials: A
authors.lastname: Piga
authors.forename: K
authors.initials: K
authors.lastname: Ganeshaguru
authors.forename: E S
authors.initials: ES
authors.lastname: Green
authors.forename: B
authors.initials: B
authors.lastname: Sheridan
authors.forename: A V
authors.initials: AV
authors.lastname: Hoffbrand
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D015649:Pentostatin / Q000494:pharmacology*; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D011684:Purine Nucleosides / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D058892:Adenosine Deaminase Inhibitors; D011684:Purine Nucleosides; D006151:Guanosine; C032533:8-aminoguanosine; D015649:Pentostatin; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D009700:Nucleoside Deaminases