Earlier reports from this laboratory showed that: (a) in the presence of nitrobenzylthioinosine (
NBMPR), a potent, tightly bound inhibitor of
nucleoside transport, cells proliferating in culture were protected against a number of cytotoxic
nucleosides; and (b) mice were protected against potentially lethal dosages of
nebularine (and other toxic
nucleosides) by coadministration of
NBMPR. The present study, which used nitrobenzylthioinosine 5'-phosphate (
NBMPR-P), a readily soluble "
prodrug" form of
NBMPR, extended the in vivo protection studies and showed that the half-life of the protection effect was about 4 hr. In
chemotherapy experiments, mice bearing transplanted
neoplasms were treated with high dosages of
nebularine together with protecting doses of
NBMPR-P. When mice bearing
leukemia L1010 were treated with a potentially lethal regimen of
nebularine administered together with
NBMPR-P, a substantial kill of leukemic cells resulted (some mice were long-term survivors). The
therapeutic effect was optimal at dosage levels of the protecting agent in excess of those required in nonleukemic mice for protection against the lethal
nebularine dosages used, suggesting that the
therapeutic effect was due to the joint presence in the leukemic cells of a metabolite of
NBMPR-P and
nebularine;
NBMPR-P protection of the leukemic host against
nebularine lethality was necessary for the
therapeutic effect to be manifested.