Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth
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 p...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116303663 |
| _version_ | 1830515200288096256 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sorah Yoon |
| collection | DOAJ |
| description | 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: aptamer-drug conjugates, ApDCs, nucleoside analog, cytotoxic agents, pancreatic cancer |
| first_indexed | 2024-12-22T03:17:49Z |
| format | Article |
| id | doaj.art-f010d89398944530bdf4cfe7473aa72b |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-22T03:17:49Z |
| publishDate | 2017-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-f010d89398944530bdf4cfe7473aa72b2022-12-21T18:40:47ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-03-0168088Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell GrowthSorah Yoon0Kai-Wen Huang1Vikash Reebye2Duncan Spalding3Teresa M. Przytycka4Yijie Wang5Piotr Swiderski6Lin Li7Brian Armstrong8Isabella Reccia9Dimitris Zacharoulis10Konstantinos Dimas11Tomokazu Kusano12John Shively13Nagy Habib14John J. Rossi15Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment 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, TaiwanDepartment of Surgery and Cancer, Imperial College London, London SW7 2AZ, UKDepartment of Surgery and Cancer, Imperial College London, London SW7 2AZ, UKNational Center of Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USANational Center of Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USADrug Discovery and Structural Biology Core-DNA/RNA Synthesis Laboratory, Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Molecular Immunology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USALight Microscopy Digital Imaging Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Surgery and Cancer, Imperial College London, London SW7 2AZ, UKDepartment of Surgery and Pharmacology, University Hospital of Larissa, Larissa 41110, GreeceDepartment of Surgery and Pharmacology, University Hospital of Larissa, Larissa 41110, GreeceDepartment of Surgery and Cancer, Imperial College London, London SW7 2AZ, UKDepartment of Molecular Immunology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Surgery and Cancer, Imperial College London, London SW7 2AZ, UKDepartment 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; Corresponding author: John J. Rossi, Beckman Research Institute of City of Hope, City of Hope, 1500 East Duarte Rd., Duarte, CA 91010, USA.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: aptamer-drug conjugates, ApDCs, nucleoside analog, cytotoxic agents, pancreatic cancerhttp://www.sciencedirect.com/science/article/pii/S2162253116303663 |
| spellingShingle | 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 Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth Molecular Therapy: Nucleic Acids |
| title | Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth |
| title_full | Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth |
| title_fullStr | Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth |
| title_full_unstemmed | Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth |
| title_short | Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth |
| title_sort | aptamer drug conjugates of active metabolites of nucleoside analogs and cytotoxic agents inhibit pancreatic tumor cell growth |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116303663 |
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