THERAPY OF MOUSE LEUKEMIA-L1210 WITH COMBINATIONS OF NEBULARINE AND NITROBENZYLTHIOINOSINE 5'-MONOPHOSPHATE

Abstract

In the presence of nitrobenzylthioinosine (NBMPR), a potent, tightly bound inhibitor of nucleoside transport, cells proliferating in culture are protected against a number of cytotoxic nucleosides; mice are protected against potentially lethal dosages of nebularine (and other toxic nucleosides) by coadministration of NBMPR. Nitrobenzylthio-IMP (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 .apprx. 4 h. In chemotherapy experiments, mice bearing transplanted neoplasms were treated with high dosages of nebularine together with protecting doses of NBMPR-P. When mice bearing [mouse] leukemia L1210 cells were treated with a potentially lethal regimen of nebularine administered 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.