Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties
| Autor: | Komaraiah Palle, Ralph B. D'Agostino, Jonathan R. Brody, Lais P. Ghiraldeli, David L. Caudell, Thomas L. Smith, Sezgin Kiren, Alex Haber, William H. Gmeiner, Anthony Dominijanni, Chinnadurai Mani, Boris Pasche, Zhiyong Deng |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Polymers Colorectal cancer medicine.medical_treatment Mice Nude Thymidylate synthase Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo medicine Animals Humans Chemotherapy biology Cytidine medicine.disease 030104 developmental biology Oncology chemistry Blood chemistry Cell culture 030220 oncology & carcinogenesis Cancer research biology.protein Fluorouracil Colorectal Neoplasms Thymidine |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-20-0516 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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