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Evidence for distinction of the differentiation-inducing activities and cytostatic properties of 9-(2-phosphonylmethoxyethyl)adenine and a variety of differentiation-inducing agents in human erythroleukemia K562 cells

S Hatse, E De Clercq and J Balzarini

Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

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).

Volume 50, Issue 5, pp. 1231-1242, 11/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




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S. Hatse, E. De Clercq, and J. Balzarini
Enhanced 9-(2-Phosphonylmethoxyethyl)adenine Secretion by a Specific, Indomethacin-Sensitive Efflux Pump in a Mutant 9-(2-Phosphonylmethoxyethyl)adenine-Resistant Human Erythroleukemia K562 Cell Line
Mol. Pharmacol., November 1, 1998; 54(5): 907 - 917.
[Abstract] [Full Text]


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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics