Hatse S, De Clercq E, Balzarini J
Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Mol Pharmacol. 1996 Nov;50(5):1231-42.
The acyclic nucleoside phosphonate derivative 9-(2-phosphonylmethoxyethyl) adenine (PMEA) is a strong inducer of differentiation in several tumor cell lines, including human erythroleukemia K562 cells. A PMEA-resistant K562 cell line (designated K562/PMEA-1) was selected in the presence of escalating PMEA concentrations. This cell line proved to be insensitive to the induction of erythroid differentiation by PMEA. It also was 108-fold resistant to the cytostatic effects of PMEA. The K562/PMEA-1 cells showed reduced sensitivity to the differentiation-inducing capacity and cytostatic activity of several closely related PMEA analogs. Furthermore, the mutant cells exhibited a decreased sensitivity to the differentiation-inducing activity of a wide variety of structurally nonrelated antimetabolites targeted at different enzymes of nucleotide biosynthesis. A 5-25-fold higher concentration of each of these compounds was required to obtain the same level of differentiation in the K562/PMEA-1 cells as in the wild-type cells. However, unlike the PMEA derivatives, the antimetabolites remained equally cytostatic for the mutant K562 cells and for the wild-type cells. Our results reveal two unique features of the K562/PMEA-1 cells: (i) specific resistance to both the differentiation-inducing and cytostatic effects of several acyclic nucleoside phosphonate analogs (which can be accounted for by a diminished cellular uptake and subsequent metabolism of the compounds) and (ii) nonspecific resistance to antimetabolites with regard to their differentiation-inducing, but not cytostatic, properties (which must reside in an unspecified alteration of a common site of the differentiation process that is shared by all of these antimetabolites).
无环核苷膦酸酯衍生物9-(2-膦酰甲氧基乙基)腺嘌呤（PMEA）是几种肿瘤细胞系（包括人红白血病K562细胞）中分化的强诱导剂。在逐步增加的PMEA浓度存在下，选择了一株对PMEA耐药的K562细胞系（命名为K562/PMEA-1）。该细胞系被证明对PMEA诱导的红系分化不敏感。它对PMEA的细胞生长抑制作用也具有108倍的抗性。K562/PMEA-1细胞对几种密切相关的PMEA类似物的分化诱导能力和细胞生长抑制活性的敏感性降低。此外，突变细胞对多种结构上不相关的抗代谢物针对核苷酸生物合成不同酶的分化诱导活性的敏感性降低。在K562/PMEA-1细胞中，需要比野生型细胞高5 - 25倍的这些化合物浓度才能获得相同水平的分化。然而，与PMEA衍生物不同，抗代谢物对突变的K562细胞和野生型细胞的细胞生长抑制作用保持相同。我们的结果揭示了K562/PMEA-1细胞的两个独特特征：（i）对几种无环核苷膦酸酯类似物的分化诱导和细胞生长抑制作用具有特异性抗性（这可以通过细胞对这些化合物的摄取减少和随后的代谢来解释），以及（ii）对具有分化诱导但不具有细胞生长抑制特性的抗代谢物具有非特异性抗性（这一定存在于所有这些抗代谢物共有的分化过程共同位点的未明确改变中）。
