Inactivation of deoxycytidine kinase and overexpression of P-glycoprotein in AraC and daunorubicin double resistant leukemic cell lines.
AraC resistance in vitro is explained by inactivation of dCK, while resistance to DNR is described by overexpression of multidrug efflux pumps like Pgp or MRP. Thus far, no correlation between resistance mechanisms in vitro and in patients with AML has been documented. We generated AraC and DNR double resistant cell lines to investigate resistance mechanisms of both agents. In these cell lines involvement of dCK was extensively investigated and Pgp expression and activity was determined. Our data implicate that similar resistance mechanisms like inactivation of dCK coincided by alternatively spliced dCK forms and overexpression of Pgp are induced in single-as well as in double resistant leukemic cell lines.
Veuger
Marjan J T
MJ
Laboratory of Experimental Hematology, C2-R, Leiden University Medical Center, Department of Hematology, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Honders
M Willy
MW
Spoelder
Hananja E
HE
Willemze
Roel
R
Barge
Renée M Y
RM
D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D003630:Daunorubicin / Q000494:pharmacology*; D000077209:Decitabine; D003839:Deoxyadenosines / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005978:Glutathione / Q000037:antagonists & inhibitors; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D008727:Methotrexate / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D004273:DNA, Neoplasm; D003839:Deoxyadenosines; D009363:Neoplasm Proteins; D003561:Cytarabine; D015762:2-Chloroadenosine; D019328:Buthionine Sulfoximine; D000077209:Decitabine; D014700:Verapamil; D003842:Deoxycytidine Kinase; D005978:Glutathione; C055994:2-chloro-3'-deoxyadenosine; D001374:Azacitidine; D008727:Methotrexate; D015255:Idarubicin; D003630:Daunorubicin