Permeability of 5-fluorouracil and its prodrugs in Caco-2 cell monolayers: evidence for shift from paracellular to transcellular transport by prodrug formation

Imoto, Masumi; Azuma, Hidekazu; Yamamoto, Ikuo; Otagiri, Masaki; Imai, Teruko

doi:10.1016/s1773-2247(09)50005-6

Cited by 15 publications

(9 citation statements)

References 16 publications

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“…The results clearly showed that the free 5-FA is less toxic than the reference drug, 5-FU. A study by Imoto et al 53 revealed that 5-FU entered Caco-2 cells by passive diffusion. The terminal carboxyl group in 5-FA renders the molecule charged at physiological conditions, slightly more hydrophilic and higher polarity than 5-FU 54 .…”

Section: Discussionmentioning

confidence: 99%

Targeted delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells overexpressing epithelial growth factor receptor (EGFR) using virus-like nanoparticles

Gan

Rullah

Yong

et al. 2020

Sci Rep

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Chemotherapy is widely used in cancer treatments. However, non-specific distribution of chemotherapeutic agents to healthy tissues and normal cells in the human body always leads to adverse side effects and disappointing therapeutic outcomes. Therefore, the main aim of this study was to develop a targeted drug delivery system based on the hepatitis B virus-like nanoparticle (VLNP) for specific delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells expressing epithelial growth factor receptor (EGFR). 5-FA was synthesized from 5-fluorouracil (5-FU), and it was found to be less toxic than the latter in cancer cells expressing different levels of EGFR. The cytotoxicity of 5-FA increased significantly after being conjugated on the VLNP. A cell penetrating peptide (CPP) of EGFR was displayed on the VLNP via the nanoglue concept, for targeted delivery of 5-FA to A431, HT29 and HeLa cells. The results showed that the VLNP displaying the CPP and harboring 5-FA internalized the cancer cells and killed them in an EGFR-dependent manner. This study demonstrated that the VLNP can be used to deliver chemically modified 5-FU derivatives to cancer cells overexpressing EGFR, expanding the applications of the VLNP in targeted delivery of chemotherapeutic agents to cancer cells overexpressing this transmembrane receptor.

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Section: Discussionmentioning

confidence: 99%

Targeted delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells overexpressing epithelial growth factor receptor (EGFR) using virus-like nanoparticles

Gan

Rullah

Yong

et al. 2020

Sci Rep

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“…hOAT2 is highly expressed in the liver and kidney proximal tubules and may be responsible, at least in part, for the hepatic uptake of 5-FU ( 25–27 ). Finally, passive transport of 5-FU has also been demonstrated through paracellular and transcellular routes ( 28 ). Multidrug resistance-associated protein-5 (MRP-5) and MRP-8, two organic anion transporters ubiquitously expressed in tissues, mediate the efflux of 5-FU through the efflux of 5-FdUMP ( 29–31 ).…”

Section: Introductionmentioning

confidence: 99%

A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

et al. 2021

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5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.

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“…Since the P app of 5-FU across Caco-2 cell monolayers is dominated by passive diffusion (Imoto et al, 2009), a relatively rapid influx of free hydrophilic 5-FU was expected (Choi et al, 1996). Encapsulation of 5-FU into the CTS-Ca-ALG matrix produced significant retardation in the 5-FU passage, probably because of the time it took for the 5-FU to diffuse out of the matrix system (Wood et al, 2010), but also due to the controlled drug release and increased intracellular concentration of 5-FU when delivered from designed carrier system.…”

Section: Formulation Dependent Permeability and Cell-association Of 5mentioning

confidence: 99%

Wheat germ agglutinin-functionalised crosslinked polyelectrolyte microparticles for local colon delivery of 5-FU:in vitroefficacy andin vivogastrointestinal distribution

Dodov

Steffansen

Crcarevska

et al. 2013

Journal of Microencapsulation

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We have previously reported the development and characterisation of wheat germ agglutinin (WGA)-functionalised chitosan-Ca-alginate (CTS-Ca-ALG) microparticles (MPs) loaded with acid-resistant particles of 5-fluorouracil (5-FU). In the present work, our goal was to evaluate the potential of these carriers for efficient treatment of colon cancer by studying in vitro permeability and cell association of 5-FU and [methyl-³H]thymidine uptake in Caco-2 cells, as well as in vivo gastrointestinal distribution. The amount of 5-FU permeated through Caco-2 cells was 15.1, 7.7 and 6.5% for 5-FU solution, CTS-Ca-ALG MPs and WGA conjugates. The concentration of 5-FU associated with Caco-2 cells was significantly greater when delivered from MPs. By incorporation of 5-FU into MPs and further decoration with WGA, an increased [methyl-³H]thymidine uptake was observed few hours after continuous drug treatment followed by significantly reduced uptake after 6 h. Gastrointestinal distribution was in favour of increased localisation and concentration of the particles in colon region.

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Permeability of 5-fluorouracil and its prodrugs in Caco-2 cell monolayers: evidence for shift from paracellular to transcellular transport by prodrug formation

Cited by 15 publications

References 16 publications

Targeted delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells overexpressing epithelial growth factor receptor (EGFR) using virus-like nanoparticles

Targeted delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells overexpressing epithelial growth factor receptor (EGFR) using virus-like nanoparticles

A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

Wheat germ agglutinin-functionalised crosslinked polyelectrolyte microparticles for local colon delivery of 5-FU:in vitroefficacy andin vivogastrointestinal distribution

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