Protection against fludarabine neurotoxicity in leukemic mice by the nucleoside transport inhibitor nitrobenzylthioinosine.
Fludarabine phosphate (F-ara-AMP, Fludara) is rapidly converted in the circulation to fludarabine (F-ara-A) and is among the most effective single agents in the treatment of chronic lymphocytic leukemia. Although current treatment protocols are well tolerated, severe neurotoxicity was a consequence of high-dose F-ara-AMP regimens used in early phase I trials against adult acute leukemia. The present study showed that in mice implanted with leukemia L1210, fatal neurotoxicity, which initially manifested as hind-limb paralysis, was a consequence of high-dose F-ara-AMP treatment. However, the incidence of neurotoxicity was reduced by the coadministration of NBMPR-P, the 5'-phosphate of nitrobenzylthioinosine, a potent inhibitor of the es equilibrative nucleoside transport (NT) system. NBTGR-P, the 5'-phosphate of nitrobenzylthioguanosine (also a potent NT inhibitor) similarly prevented F-ara-AMP neurotoxicity in this experimental system. Treatment with F-ara-AMP/NBMPR-P combinations was more effective with respect to the fractional yield of "cured" mice than were the same treatment regimens without NBMPR-P.
Adjei
A A
AA
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Dagnino
L
L
Wong
M M
MM
Paterson
A R
AR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006614:Hindlimb; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D010243:Paralysis / Q000139:chemically induced; D011355:Prodrugs / Q000008:administration & dosage; D013868:Thioinosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013873:Thionucleotides / Q000008:administration & dosage; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity
D011355:Prodrugs; D013873:Thionucleotides; D013868:Thioinosine; C028318:nitrobenzylthioinosine 5'-monophosphate; D014740:Vidarabine; C001789:4-nitrobenzylthioinosine; C024352:fludarabine