Protection against fludarabine neurotoxicity in leukemic mice by the nucleoside transport inhibitor nitrobenzylthioinosine.

Abstract

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.

• Authors: A A Adjei, L Dagnino, M M Wong, A R Paterson
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 31 Issue 1 Pg. 71-5 ( 1992) ISSN: 0344-5704 [Print] Germany
• PMID: 1458562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prodrugs
• Thionucleotides
• Thioinosine
• nitrobenzylthioinosine 5'-monophosphate
• Vidarabine
• 4-nitrobenzylthioinosine
• fludarabine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Drug Synergism
• Female
• Hindlimb
• Leukemia L1210 (drug therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Neoplasm Transplantation
• Nervous System Diseases (chemically induced, prevention & control)
• Paralysis (chemically induced)
• Prodrugs (administration & dosage)
• Thioinosine (administration & dosage, analogs & derivatives, therapeutic use)
• Thionucleotides (administration & dosage)
• Vidarabine (analogs & derivatives, pharmacology, toxicity)