Micro-array analysis of resistance for gemcitabine results in increased expression of ribonucleotide reductase subunits.
To study in detail the relation between gene expression and resistance against gemcitabine, a cell line was isolated from a tumor for which gemcitabine resistance was induced in vivo. Similar to the in vivo tumor, resistance in this cell line, C 26-G, was not related to deficiency of deoxycytidine kinase (dCK). Micro-array analysis showed increased expression of ribonucleotide reductase (RR) subunits M1 and M2 as confirmed by real time PCR analysis (28- and 2.7-fold, respectively). In cell culture, moderate cross-resistance (about 2-fold) was observed to 1-ss-D-arabinofuranosylcytosine (ara-C), 2-chloro-2'deoxyadenosine (CdA), LY231514 (ALIMTA), and cisplatin (CDDP), and pronounced cross-resistance (>23-fold) to 2',2'-difluorodeoxyuridine (dFdU) and 2',2'-difluorodeoxyguanosine (dFdG). Culture in the absence of gemcitabine reduced resistance as well as RRM1 RNA expression, demonstrating a direct relationship of RRM1 RNA expression with acquired resistance to gemcitabine.
Smid
K
K
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Bergman
A M
AM
Eijk
P P
PP
Veerman
G
G
van Haperen
V W T Ruiz
VW
van den Ijssel
P
P
Ylstra
B
B
Peters
G J
GJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D017338:Cladribine / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D020411:Oligonucleotide Array Sequence Analysis; D000068437:Pemetrexed; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012264:Ribonucleotide Reductases / Q000096:biosynthesis* / Q000737:chemistry; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D005971:Glutamates; D003561:Cytarabine; D000068437:Pemetrexed; D003841:Deoxycytidine; D017338:Cladribine; D006147:Guanine; D012264:Ribonucleotide Reductases; D002945:Cisplatin; D000093542:Gemcitabine