Lynch T P, Jakobs E S, Paran J H, Paterson A R
Cancer Res. 1981 Aug;41(8):3200-4.
Previous studies from this laboratory demonstrated that a potent inhibitor of nucleoside transport, nitrobenzylthioinosine (NBMPR), protected cultured cells against cytotoxic nucleosides (nebularine, tubercidin, and toyocamycin). NBMPR and its 5'-monophosphate (NBMPR-P) also protected mice against potentially lethal dosage of these agents. This report describes protection of mice from potentially lethal dosages of tubercidin by administration of NBMPR-P and the use of combinations of these agents in treatments of mice bearing transplanted neoplasms. Treatment of mice bearing i.p. implants of the Ehrlich ascites carcinoma, leukemia L1210/TG8, and colon carcinoma 26 with potentially lethal dosages of tubercidin administered together with host-protecting dosages of NBMPR-P resulted in substantial kill of neoplastic cells and long-term survivors. In these experiments, therapeutic effects were achieved at optimal dosages of NBMPR-P, which protected host vital tissues but did not protect neoplastic cells in ascitic fluids (Ehrlich ascites carcinoma cells and leukemia L1210/TG8 cells). However, at supraoptimal dosages of NBMPR-P, the occurrence of therapeutic failures which were neoplastic deaths indicated that NBMPR-P also protected the neoplastic ascites cells against tubercidin cytotoxicity. Thus, the selectivity of tubercidin toxicity toward cells of the Ehrlich ascites carcinoma and leukemia L1210/TG8 was modified by NBMPR-P dosage.
本实验室先前的研究表明，核苷转运的强效抑制剂硝基苄硫肌苷（NBMPR）可保护培养细胞免受细胞毒性核苷（喷司他丁、杀结核菌素和丰加霉素）的侵害。NBMPR及其5'-单磷酸酯（NBMPR-P）还可保护小鼠免受这些药物的潜在致死剂量的影响。本报告描述了通过给予NBMPR-P保护小鼠免受杀结核菌素的潜在致死剂量的影响，以及这些药物组合在治疗移植性肿瘤小鼠中的应用。用潜在致死剂量的杀结核菌素联合宿主保护剂量的NBMPR-P治疗腹腔植入艾氏腹水癌、白血病L1210/TG8和结肠癌26的小鼠，可导致大量肿瘤细胞死亡并产生长期存活者。在这些实验中，在NBMPR-P的最佳剂量下可实现治疗效果，该剂量可保护宿主重要组织，但不能保护腹水（艾氏腹水癌细胞和白血病L1210/TG8细胞）中的肿瘤细胞。然而，在NBMPR-P的超最佳剂量下，出现的治疗失败（即肿瘤死亡）表明NBMPR-P也保护肿瘤腹水细胞免受杀结核菌素的细胞毒性作用。因此，NBMPR-P的剂量改变了杀结核菌素对艾氏腹水癌和白血病L1210/TG8细胞毒性的选择性。
