Selective toxicity of purine nucleosides to human leukaemic cells.
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.
Piga
A
A
Academic Department of Hematology, Royal Free Hospital School of Medicine, London.
Ganeshaguru
K
K
Green
E S
ES
Sheridan
B
B
Hoffbrand
A V
AV
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
D058892:Adenosine Deaminase Inhibitors; D011684:Purine Nucleosides; D006151:Guanosine; C032533:8-aminoguanosine; D015649:Pentostatin; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D009700:Nucleoside Deaminases