Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth

Sorah Yoon; Kai-Wen Huang; Vikash Reebye; Duncan Spalding; Teresa M Przytycka; Yijie Wang; Piotr Swiderski; Lin Li; Brian Armstrong; Isabella Reccia; Dimitris Zacharoulis; Konstantinos Dimas; Tomokazu Kusano; John Shively; Nagy Habib; John J Rossi

doi:10.1016/j.omtn.2016.11.008

Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth

Mol Ther Nucleic Acids. 2017 Mar 17:6:80-88. doi: 10.1016/j.omtn.2016.11.008. Epub 2016 Dec 10.

Authors

Affiliations

¹ Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
² Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, College of Medicine, Taipei 10051, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
³ Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
⁴ National Center of Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA.
⁵ Drug Discovery and Structural Biology Core-DNA/RNA Synthesis Laboratory, Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
⁶ Department of Molecular Immunology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
⁷ Light Microscopy Digital Imaging Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
⁸ Department of Surgery and Pharmacology, University Hospital of Larissa, Larissa 41110, Greece.
⁹ Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, City of Hope, 1500 East Duarte Rd., Duarte, CA 91010, USA. Electronic address: jrossi@coh.org.

Abstract

Aptamer-drug conjugates (ApDCs) have the potential to improve the therapeutic index of traditional chemotherapeutic agents due to their ability to deliver cytotoxic drugs specifically to cancer cells while sparing normal cells. This study reports on the conjugation of cytotoxic drugs to an aptamer previously described by our group, the pancreatic cancer RNA aptamer P19. To this end, P19 was incorporated with gemcitabine and 5-fluorouracil (5-FU), or conjugated to monomethyl auristatin E (MMAE) and derivative of maytansine 1 (DM1). The ApDCs P19-dFdCMP and P19-5FdUMP were shown to induce the phosphorylation of histone H2AX on Ser139 (γ-H2AX) and significantly inhibited cell proliferation by 51%-53% in PANC-1 and by 54%-34% in the gemcitabine-resistant pancreatic cancer cell line AsPC-1 (p ≤ 0.0001). P19-MMAE and P19-DM1 caused mitotic G2/M phase arrest and inhibited cell proliferation by up to 56% in a dose-dependent manner when compared to the control group (p ≤ 0.001). In addition, the cytotoxicity of P19-MMAE and P19-DM1 in normal cells and the control human breast cancer cell line MCF7 was minimal. These results suggest that this approach may be useful in decreasing cytotoxic side effects in non-tumoral tissue.

Keywords: ApDCs; aptamer-drug conjugates; cytotoxic agents; nucleoside analog; pancreatic cancer.

Abstract

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