Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer.
OBJECTIVE
Gemcitabine (2',2'-difluorodeoxycytidine) (GEM) is one of the most actively investigated drugs in ovarian cancer. Many molecular mechanisms have been proposed to be involved in GEM sensitivity/resistance including the equilibrative nucleoside transporter-1 (hENT1), the concentrative nucleoside transporter-1 (hCNT1), and deoxycytidine kinase (dCK). The expression of the ribonucleotide reductase regulatory subunits M1 (RRM1) and M2 (RRM2), and the catabolic enzymes 5'nucleotidase (5'NT), and cytidine deaminase (CDA) play also an important role. The aim of the study is to investigate the potential clinical role of hENT1, hCNT1, dCK, RRM1, RRM2, CDA, and 5'NT in a single institutional series of 25 primary ovarian carcinomas.


METHODS
The expression levels of the target genes were assayed by means of real-time quantitative PCR. The clinical role of the expression levels of each parameter was analyzed by Kaplan and Meier method and the Cox's proportional hazards model.


RESULTS
hENT1, hCNT1, dCK, CDA, 5'NT, RRM1, and RRM2 gene expression was documented in all samples; undifferentiated and clear cell carcinoma exhibited higher levels of hENT1, dCK, 5'NT, and RRM1 compared to serous ovarian tumors. As of May 2009, the median follow-up was 32 months (range 10-80), and death of disease were observed in 17 cases (68.0%). A statistically significant direct association of RRM2 expression levels and the relative risk of death was observed (Chi (2) = 8.18, P = 0.0043). Moreover, cases with high RRM2 expression had a shorter OS (median OS = 19 months) than cases with low RRM2 levels (median OS = 36 months) (P = 0.0506).


CONCLUSIONS
We first reported that the most relevant genes involved in gemcitabine metabolism are expressed in ovarian carcinoma, and might be associated with more aggressive histotypes. The assessment of the expression levels of RRM2 as marker of clinical outcome deserves further investigation in a larger series of ovarian cancer patients.
Ferrandina
Gabriella
G
Department of Oncology, Catholic University, Campobasso, Italy. gabriella.ferrandina@libero.it
Mey
Valentina
V
Nannizzi
Sara
S
Ricciardi
Simona
S
Petrillo
Marco
M
Ferlini
Cristiano
C
Danesi
Romano
R
Scambia
Giovanni
G
Del Tacca
Mario
M
D015720:5'-Nucleotidase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D033703:Nucleoside Transport Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics*; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; C438649:SLC29A1 protein, human; D025521:Tumor Suppressor Proteins; C065171:cif nucleoside transporter; D003841:Deoxycytidine; C093713:ribonucleotide reductase M2; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase; D003564:Cytidine Deaminase; D000093542:Gemcitabine