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ABSTRACT Ribonucleotide reductase is emerging as an important determinant of gemcitabine chemoresistance in human cancers. Activity of this enzyme, which catalyses conversion of

ribonucleotide 5′-diphosphates to their 2′-deoxynucleotides, is modulated by levels of its M2 subunit (RRM2). Here we show that RRM2 overexpression is associated with gemcitabine

chemoresistance in pancreatic adenocarcinoma cells, and that suppression of RRM2 expression using RNA interference mediated by small interfering RNA (siRNA) enhances gemcitabine-induced

cytotoxicity _in vitro_. We demonstrate the ability of systemically administered RRM2 siRNA to suppress tumoral RRM2 expression in an orthotopic xenograft model of pancreatic adenocarcinoma.

Synergism between RRM2 siRNA and gemcitabine results in markedly suppressed tumor growth, increased tumor apoptosis and inhibition of metastasis. Our findings confirm the importance of RRM2

in pancreatic adenocarcinoma gemcitabine chemoresistance. This is the first demonstration that systemic delivery of siRNA-based therapy can enhance the efficacy of an anticancer nucleoside

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support SIMILAR CONTENT BEING VIEWED BY OTHERS TAS1553, A SMALL MOLECULE SUBUNIT INTERACTION INHIBITOR OF RIBONUCLEOTIDE REDUCTASE, EXHIBITS ANTITUMOR ACTIVITY BY CAUSING DNA REPLICATION

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ANTIBODY-DRUG CONJUGATE INDUCES ROS-MEDIATED APOPTOSIS TO OVERCOME DRUG RESISTANCE IN KRAS MUTANT CANCER CELLS Article Open access 09 January 2025 CHANGE HISTORY * _ 16 FEBRUARY 2023 This

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This work was supported by The National Pancreas Foundation and departmental funds from the Department of Surgery, Brigham and Women's Hospital. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, USA Mark S Duxbury, Hiromichi Ito, Michael J

Zinner, Stanley W Ashley & Edward E Whang Authors * Mark S Duxbury View author publications You can also search for this author inPubMed Google Scholar * Hiromichi Ito View author

publications You can also search for this author inPubMed Google Scholar * Michael J Zinner View author publications You can also search for this author inPubMed Google Scholar * Stanley W

Ashley View author publications You can also search for this author inPubMed Google Scholar * Edward E Whang View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHOR Correspondence to Edward E Whang. ADDITIONAL INFORMATION This article has been retracted. Please see the retraction notice for more

detail:https://doi.org/10.1038/s41388-023-02625-6 ABOUT THIS ARTICLE CITE THIS ARTICLE Duxbury, M., Ito, H., Zinner, M. _et al._ RETRACTED ARTICLE: RNA interference targeting the M2 subunit

of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine. _Oncogene_ 23, 1539–1548 (2004). https://doi.org/10.1038/sj.onc.1207272 Download citation *

Received: 04 September 2003 * Revised: 03 October 2003 * Accepted: 06 October 2003 * Published: 08 December 2003 * Issue Date: 26 February 2004 * DOI: https://doi.org/10.1038/sj.onc.1207272

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clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * pancreatic adenocarcinoma * cancer * gemcitabine * ribonucleotide reductase * siRNA * RNA

interference