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Molecular Cancer Therapeutics
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Large Molecule Therapeutics

Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties

William H. Gmeiner, Anthony Dominijanni, Alex O. Haber, Lais P. Ghiraldeli, David L. Caudell, Ralph D’Agostino Jr, Boris C. Pasche, Thomas L. Smith, Zhiyong Deng, Sezgin Kiren, Chinnadurai Mani, Komaraiah Palle and Jonathan R. Brody
William H. Gmeiner
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
2Comprehensive Cancer Center Wake Forest School of Medicine, Winston-Salem, North Carolina.
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  • For correspondence: bgmeiner@wfubmc.edu
Anthony Dominijanni
3Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Alex O. Haber
4Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Lais P. Ghiraldeli
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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David L. Caudell
5Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Ralph D’Agostino Jr
6Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Boris C. Pasche
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
2Comprehensive Cancer Center Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Thomas L. Smith
7Department of Orthopedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Zhiyong Deng
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Sezgin Kiren
8Department of Chemistry, Winston-Salem State University, Winston-Salem, North Carolina.
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Chinnadurai Mani
9Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Centre, Lubbock, Texas.
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Komaraiah Palle
9Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Centre, Lubbock, Texas.
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Jonathan R. Brody
10Brenden Colson Center for Pancreatic Care, Departments of Surgery and Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
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DOI: 10.1158/1535-7163.MCT-20-0516 Published March 2021
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Abstract

Chemotherapy regimens that include 5-fluorouracil (5-FU) are central to colorectal cancer treatment; however, risk/benefit concerns limit 5-FU’s use, necessitating development of improved fluoropyrimidine (FP) drugs. In our study, we evaluated a second-generation nanoscale FP polymer, CF10, for improved antitumor activity. CF10 was more potent than the prototype FP polymer F10 and much more potent than 5-FU in multiple colorectal cancer cell lines including HCT-116, LS174T, SW480, and T84D. CF10 displayed improved stability to exonuclease degradation relative to F10 and reduced susceptibility to thymidine antagonism due to extension of the polymer with arabinosyl cytidine. In colorectal cancer cells, CF10 strongly inhibited thymidylate synthase (TS), induced Top1 cleavage complex formation and caused replication stress, while similar concentrations of 5-FU were ineffective. CF10 was well tolerated in vivo and invoked a reduced inflammatory response relative to 5-FU. Blood chemistry parameters in CF10-treated mice were within normal limits. In vivo, CF10 displayed antitumor activity in several colorectal cancer flank tumor models including HCT-116, HT-29, and CT-26. CF10’s antitumor activity was associated with increased plasma levels of FP deoxynucleotide metabolites relative to 5-FU. CF10 significantly reduced tumor growth and improved survival (84.5 days vs. 32 days; P < 0.0001) relative to 5-FU in an orthotopic HCT-116-luc colorectal cancer model that spontaneously metastasized to liver. Improved survival in the orthotopic model correlated with localization of a fluorescent CF10 conjugate to tumor. Together, our preclinical data support an early-phase clinical trial of CF10 for treatment of colorectal cancer.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:553–63

  • Received June 19, 2020.
  • Revision received October 26, 2020.
  • Accepted December 16, 2020.
  • Published first December 23, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (3)
March 2021
Volume 20, Issue 3
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Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties
William H. Gmeiner, Anthony Dominijanni, Alex O. Haber, Lais P. Ghiraldeli, David L. Caudell, Ralph D’Agostino Jr, Boris C. Pasche, Thomas L. Smith, Zhiyong Deng, Sezgin Kiren, Chinnadurai Mani, Komaraiah Palle and Jonathan R. Brody
Mol Cancer Ther March 1 2021 (20) (3) 553-563; DOI: 10.1158/1535-7163.MCT-20-0516

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Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties
William H. Gmeiner, Anthony Dominijanni, Alex O. Haber, Lais P. Ghiraldeli, David L. Caudell, Ralph D’Agostino Jr, Boris C. Pasche, Thomas L. Smith, Zhiyong Deng, Sezgin Kiren, Chinnadurai Mani, Komaraiah Palle and Jonathan R. Brody
Mol Cancer Ther March 1 2021 (20) (3) 553-563; DOI: 10.1158/1535-7163.MCT-20-0516
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Molecular Cancer Therapeutics
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