Comparative effects of cladribine, fludarabine and pentostatin on nucleotide metabolism in T- and B-cell lines.
OBJECTIVE
the purine nucleoside analogues cladribine (CdA), fludarabine (F-Ara-AMP) and pentostatin (dCf), are effective therapy for a range of T- and B-cell lymphoid malignancies. The effects upon nucleotide metabolism in human CCRF-CEM T-cell leukaemia and Raji B-cell lymphoma cell lines of these drugs have been compared to assess possible mechanisms of cytotoxicity.


METHODS
Leukaemia cells were exposed to a purine nucleoside analogue and perchloric acid extracts were analysed by HPLC for 2'-deoxynucleoside-5'-triphosphates (dNTPs), nucleoside-5'-triphosphates (NTPs) and drug metabolites.


RESULTS
After addition of a purine nucleoside analogue, CdA-TP and F-Ara-ATP accumulate in cells while the levels of dCf-TP formed were not detectable by ultra-violet absorbance. In response to accumulating concentrations of drug triphosphate, the cellular levels of dNTPs initially decrease (0-4 h), then accumulate above their initial levels (4-10 h) before slowly declining beyond 10 h. NTPs also accumulate during the period 4-10 h before declining at later times.


CONCLUSIONS
The temporal effects on the levels of dNTPs and NTPs of the 3 purine nucleoside analogues are similar against CCRF-CEM and Raji cells. However, CdA induces major depletions of dTTP, dGTP and dATP in CCRF-CEM cells and F-Ara-A induces a major accumulation of dATP in Raji cells.
Department of Biochemistry, University of Sydney, NSW, Australia.
P K
PK
Wilson
E
E
Szabados
S P
SP
Mulligan
R I
RI
Christopherson
D058892:Adenosine Deaminase Inhibitors; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D017338:Cladribine / Q000378:metabolism / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D015649:Pentostatin / Q000378:metabolism / Q000494:pharmacology*; D012265:Ribonucleotides / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D003854:Deoxyribonucleotides; D004791:Enzyme Inhibitors; D012265:Ribonucleotides; D015649:Pentostatin; D017338:Cladribine; D014740:Vidarabine; C024352:fludarabine