Lynch T P, Paran J H, Paterson A R
Cancer Res. 1981 Feb;41(2):560-5.
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.
(a) 在存在硝基苄硫代肌苷（NBMPR）（一种强效、紧密结合的核苷转运抑制剂）的情况下，培养中增殖的细胞可免受多种细胞毒性核苷的影响；(b) 通过同时给予NBMPR，小鼠可免受潜在致死剂量的杀腺癌菌素（及其他有毒核苷）的影响。本研究使用了硝基苄硫代肌苷5'-磷酸酯（NBMPR-P），它是NBMPR的一种易溶“前药”形式，扩展了体内保护研究，并表明保护作用的半衰期约为4小时。在化疗实验中，用高剂量的杀腺癌菌素以及保护剂量的NBMPR-P对患有移植性肿瘤的小鼠进行治疗。当用与NBMPR-P联合给药的潜在致死方案治疗患有白血病L1010的小鼠时，导致大量白血病细胞被杀死（一些小鼠成为长期存活者）。在保护剂剂量水平超过非白血病小鼠免受所用致死剂量杀腺癌菌素影响所需的剂量时，治疗效果最佳，这表明治疗效果是由于NBMPR-P的一种代谢产物和杀腺癌菌素共同存在于白血病细胞中；NBMPR-P对白血病宿主免受杀腺癌菌素致死性的保护对于表现出治疗效果是必要的。
