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Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer

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Abstract

Purpose

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 (Χ 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.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Oncology, Catholic University, Campobasso, Italy

    Gabriella Ferrandina, Marco Petrillo & Giovanni Scambia

  2. Gynecologic Oncology Unit, Catholic University of the Sacred Heart, L.go A. Gemelli 8, 00168, Rome, Italy

    Gabriella Ferrandina & Cristiano Ferlini

  3. Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy

    Valentina Mey, Sara Nannizzi, Simona Ricciardi, Romano Danesi & Mario Del Tacca

Authors
  1. Gabriella Ferrandina
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  2. Valentina Mey
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  3. Sara Nannizzi
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  4. Simona Ricciardi
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  5. Marco Petrillo
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  6. Cristiano Ferlini
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  7. Romano Danesi
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  8. Giovanni Scambia
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Correspondence to Gabriella Ferrandina.

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Ferrandina, G., Mey, V., Nannizzi, S. et al. Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother Pharmacol 65, 679–686 (2010). https://doi.org/10.1007/s00280-009-1073-y

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