Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer
| Autor: | Ralf Buettner, Laleh G. Melstrom, Corey Morales, Thuy Phan, Don J. Diamond, Weiman Tsai, Vu H. Nguyen, Ziv Gil, Steven D. Rosen, Marcela d'Alincourt Salazar, Joshua D. Rabinowitz, Lifeng Yang, Paul Wong |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Antimetabolites
Antineoplastic Proliferation index endocrine system diseases T cell pancreatic cancer Apoptosis Applied Microbiology and Biotechnology Deoxycytidine chemistry.chemical_compound Mice In vivo Pancreatic cancer Cell Line Tumor medicine Tumor Microenvironment Animals de novo pyrimidine synthesis Molecular Biology Ecology Evolution Behavior and Systematics Cell Proliferation leflunomide Tumor microenvironment Cell growth Cell Biology medicine.disease Gemcitabine Mice Inbred C57BL Pancreatic Neoplasms Disease Models Animal medicine.anatomical_structure Ki-67 Antigen chemistry Tumor progression Cancer research Female Growth inhibition Immunocompetence Developmental Biology Research Paper |
| Zdroj: | International Journal of Biological Sciences |
| ISSN: | 1449-2288 |
| Popis: | Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis. De Novo pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer. Methods: MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells in vitro. An in vivo heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling. Results: Lef inhibits KPC cell growth and synergizes with Gem in vitro (P |
| Databáze: | OpenAIRE |
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