Impaired transport as a mechanism of resistance to thiopurines in human T-lymphoblastic leukemia cells.
In order to better understand the mechanisms of resistance to thiopurines, we studied two sublines of the MOLT4 T-lymphoblastic leukemia cell line, resistant to 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We found that the underlying mechanism of resistance in both resistant cell lines was a markedly reduction in initial transport of 6-MP (3- and 5-fold, respectively, in 6-MP- and 6-TG-resistant cells). No significant alteration of activities of hypoxanthine-guanine phosphoribosyl transferase, thiopurine methyltransferase or inosine monophosphate dehydrogenase, the key enzymes involved in the metabolism of thiopurines was detected. We conclude that defected initial transport of thiopurines by cells may very well explain their resistance to these drugs.
Fotoohi
A K
AK
Department of Oncology and Pathology, Cancer Center Karolinska (CCK), Karolinska Hospital, Stockholm, Sweden. Alan.fotoohi@ki.se
Lindqvist
M
M
Peterson
C
C
Albertioni
F
F
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000096:biosynthesis; D007168:IMP Dehydrogenase / Q000096:biosynthesis; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D015122:Mercaptopurine / Q000494:pharmacology; D008780:Methyltransferases / Q000096:biosynthesis; D013866:Thioguanine / Q000494:pharmacology; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D007168:IMP Dehydrogenase; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine