Huber K R, Rosenfeld H, Roberts J
Department of Basic Pharmaceutical Sciences, University of South Carolina, Columbia 29208.
Int J Cancer. 1988 May 15;41(5):752-5. doi: 10.1002/ijc.2910410519.
The uptake system for 6-diazo-5-oxo-L-norleucine (DON) was studied in mouse P388 leukemia cells. The DON transport system was found to resemble that of another glutamine antimetabolite, Acivicin, in its strong temperature dependence, utilization of the "L" transport system, inhibition by glutamine but not by glutamate, potent inhibition by p-chloromercuribenzene sulfonate, Na+, and only minimal inhibition by various energy poisons. A Km of approximately 70 microM and a Vmax of 3.4 nmoles/10(6) cells/min was calculated for this cell line. The accumulated DON was not metabolized by P388 cells and moderate efflux occurred at 37 degrees C. The DON transport characteristics of a DON-resistant P388 cell line (100 times ID50 of parent line) were similar to those of the DON-sensitive parent line, indicating that altered drug transport may not be involved in development of resistance to this antimetabolite. The finding that an Acivicin-resistant subline of P388 cells which exhibited good transport of DON showed negligible transport of Acivicin suggests different modes of resistance towards the two glutamine antimetabolites.
在小鼠P388白血病细胞中研究了6-重氮-5-氧代-L-正亮氨酸（DON）的摄取系统。发现DON转运系统在其对温度的强烈依赖性、对“L”转运系统的利用、被谷氨酰胺而非谷氨酸抑制、被对氯汞苯磺酸盐、Na + 强烈抑制以及仅被各种能量毒物轻微抑制方面，类似于另一种谷氨酰胺抗代谢物阿西维辛的转运系统。计算出该细胞系的Km约为70 microM，Vmax为3.4纳摩尔/10(6)个细胞/分钟。积累的DON未被P388细胞代谢，并且在37℃时发生适度的外排。对DON耐药的P388细胞系（亲本系ID50的100倍）的DON转运特性与对DON敏感的亲本系相似，表明药物转运的改变可能与对这种抗代谢物的耐药性发展无关。P388细胞的阿西维辛耐药亚系表现出良好的DON转运但阿西维辛转运可忽略不计这一发现表明对这两种谷氨酰胺抗代谢物存在不同的耐药模式。
