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.
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).
Hatse
S
S
Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Clercq
E
E
Balzarini
J
J
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D009705:Nucleosides / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D010641:Phenotype; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009705:Nucleosides; D063065:Organophosphonates; D011687:Purines; D011743:Pyrimidines; D014316:Tritium; C053001:adefovir; D000225:Adenine