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Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties
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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.
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The long-established role for FP chemotherapy in CRC treatment holds promise for new FPs, including CF10, a polymeric fluoropyrimidine, to further advance the survival benefit of this important drug class in mCRC.
“The long-established role for FP chemotherapy in CRC treatment holds promise for new FPs, including CF10, a polymeric fluoropyrimidine [145], to further advance the survival benefit of this important drug class in mCRC.”
From Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment (2024) · cites this paper as [145]
The therapeutic benefit of TAS-102 in the third-line setting for mCRC is consistent with fluoropyrimidines with more DNA-directed mechanism having therapeutic potential, and the second-generation polymeric FP CF10 shows promising activity in preclinical studies.
“The therapeutic benefit of TAS-102 in the third-line setting for mCRC is consistent with FPs with more DNA-directed mechanism having therapeutic potential, and the second-generation polymeric FP CF10 shows promising activity in preclinical studies [145].”
From Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment (2024) · cites this paper as [145]
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Metadata
- Authors
- Gmeiner, W. H., Dominijanni, A., Haber, A. O., Ghiraldeli, L. P., Caudell, D. L., D’Agostino, R., Pasche, B. C., Smith, T. L., Deng, Z., Kiren, S., Mani, C., Palle, K., & Brody, J. R.
- Affiliations
- Wake Forest Baptist Comprehensive Cancer Center (US)
- Wake Forest University Health Sciences (US)
- Thomas Jefferson University (US)
- Winston-Salem State University (US)
- Texas Tech University (US)
- Oregon Health & Science University (US)
- Corresponding author
- Gmeiner, William H.
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2021-03-01
- Volume
- 20
- Issue
- 3
- Pages
- 553-563
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC8201368
- OpenAlex
- W3115299255
- Cited by
- 21
- References
- 43
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 1 · 2022: 1 · 2021: 5
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | NIH | National Cancer Institute (R21 CA218933, P30 CA012197, R01 CA212600, P30 CA056036, R01 CA219187)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- colorectal cancer, 5-fluorouracil, thymidylate synthase inhibition, topoisomerase I cleavage complexes, replication stress, anticancer activity, metastasis, pharmacokinetics, drug toxicity, nanoscale drug delivery
- MeSH terms
- Animals, Fluorouracil, Humans, Mice, Nude, Polymers, Colorectal Neoplasms, Mice
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