Deletion mutants of human deoxycytidine kinase mRNA in cells resistant to antitumor cytosine nucleosides.
We studied mutational events in deoxycytidine (dCyd) kinase mRNA expression, focusing on aberrant dCyd kinase mRNA, which has been frequently observed in established cell lines resistant to antitumor dCyd nucleoside analogues such as 1-beta-D-arabinofuranosyl cytosine (Ara-C), gemcitabine (dFdC) and 2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine (CNDAC). We describe here the expression of aberrant dCyd kinase mRNAs identified as splicing mutants. These mutants included deletions of the fifth exon in CNDAC-resistant cells (originating from HT-1080 cells), of the third exon in Ara-C-resistant cells (originating from SK-MEL-28 cells) and of the fourth exon in 2'-deoxy-2'-methylidenecytidine (DMDC)-resistant cells (originating from SK-MEL-28 cells). Various nucleoside-resistant cells originating from the same parental HT-1080 cells were established. The resulting cells expressed the same mRNA with deletion of the fifth exon, and the location of splicing was independent of the type of nucleosides used for the establishment of resistant cells. The deletion of the fifth exon in dCyd kinase seems to be a target for acquisition of resistance to antitumor cytosine nucleosides. However, distinct mutations in the dCyd kinase gene seem to be associated with acquisition of resistance to different antitumor cytosine nucleosides.
Obata
T
T
Department of Experimental Therapeutics, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan. takuma@kenroku.kanazawa-u.ac.jp
Endo
Y
Y
Tanaka
M
M
Uchida
H
H
Matsuda
A
A
Sasaki
T
T
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D003561:Cytarabine; D003841:Deoxycytidine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine; D003842:Deoxycytidine Kinase; C056034:2'-deoxy-2'-methylenecytidine