Anticancer Drug 5-fluorouracil Research Articles

Sex-dependent liver cancer xenograft models for predicting clinical data in the evaluation of anticancer drugs

BackgroundThe incidence and mortality of liver cancer show a great difference between the sexes. We established sex-dependent liver cancer xenograft models and investigated whether such sex-dependent models could be used to simultaneously evaluate the therapeutic and adverse effects of anticancer drugs for drug screening.ResultsIn the in-vitro test, the cytotoxicity of anticancer drugs (cisplatin, 5-fluorouracil, and doxorubicin) was compared between male- and female-derived liver cancer cell lines. Cisplatin and 5-fluorouracil exhibited cytotoxicity without sex-difference, but doxorubicin showed dose-dependently significant cytotoxicity only in male-derived cells. Our results showed a strong correlation between preclinical and clinical data with the use of sex-dependent liver cancer xenograft models. Moreover, the male-derived Hep3B-derived xenograft model was more sensitive than the female-derived SNU-387-derived xenograft model against doxorubicin treatment. Doxorubicin showed more severe cardiotoxicity in the male xenograft model than in the female model. We investigated the occurrence frequency of doxorubicin-related cardiotoxicity using data obtained from the Korea Institute of Drug Safety & Risk Management Database, but no significant difference was observed between the sexes.ConclusionsOur results suggest that sex-dependent xenograft models are useful tools for evaluating the therapeutic and adverse effects of anticancer drugs, because sex is an important consideration in drug development.

Intrinsic and chemically-induced daughter number variations in cancer cell lines

ABSTRACT Multipolar mitosis was observed in cancer cells under mechanical stress or drug treatment. However, a comprehensive understanding of its basic properties and significance to cancer cell biology is lacking. In the present study, live-cell imaging was employed to investigate the division and nucleation patterns in four different cell lines. Multi-daughter divisions were observed in the three cancer cell lines HepG2, HeLa and A549, but not in the transformed non-cancer cell line RPE1. Multi-daughter mother cells displayed multi-nucleation, enlarged cell area, and prolonged division time. Under acidic pH or treatment with the anti-cancer drug 5-fluorouracil (5-FU) or the phytochemical compound wogonin, multi-daughter mitoses were increased to different extents in all three cancer cell lines, reaching as high as 16% of all mitoses. While less than 0.4% of the bi-daughter mitosis were followed by cell fusion events under the various treatment conditions, 50% or more of the multi-daughter mitoses were followed by fusion events at neutral, acidic or alkaline pH. These findings revealed a “Daughter Number Variation” (DNV) process in the cancer cells, with multi-daughter divisions in Stage 1 and cell fusions leading to the formation of cells containing up to five nuclei in Stage 2. The Stage 2-fusions were inhibited by 5-FU in A549 and HeLa, and by wogonin in A549, HeLa and HepG2. The parallel relationship between DNV frequency and malignancy among the different cell lines suggests that the inclusion of anti-fusion agents exemplified by wogonin and 5-FU could be beneficial in combinatory cancer chemotherapies.

Structural and functional remodeling of mitochondria as an adaptive response to energy deprivation

Cancer cells bioenergetics is more dependent on glycolysis than mitochondrial oxidative phosphorylation, a phenomenon known as the Warburg Effect. It has been proposed that inhibition of glycolysis may selectively affect cancer cells. However, the effects of glycolysis inhibition on mitochondrial function and structure in cancer cells are not completely understood. Here, we investigated the comparative effects of 2-deoxy-d-glucose (2-DG, a glucose analogue, which suppresses cellular glycolysis) on cellular bioenergetics in human colon cancer DLD-1 cells, smooth muscle cells, human umbilical vein endothelial cells and HL-1 cardiomyocytes. In all cells, 2-DG treatment resulted in significant ATP depletion, however, the cell viability remained unchanged. Also, we did not observe the synergistic effects of 2-DG with anticancer drugs doxorubicin and 5-fluorouracil. Instead, after 2-DG treatment and ATP depletion, mitochondrial respiration and membrane potential were significantly enhanced and mitochondrial morphology changed in the direction of more network organization. Analysis of protein expression demonstrated that 2-DG treatment induced an activation of AMPK (elevated pAMPK/AMPK ratio), increased mitochondrial fusion (mitofusins 1 and 2) and decreased fission (Drp1) proteins. In conclusion, this study suggests a strong link between respiratory function and structural organization of mitochondria in the cell. We propose that the functionality of the mitochondrial network is enhanced compared to disconnected mitochondria.

Green synthesis of Fe3O4 nanoparticles for hyperthermia, magnetic resonance imaging and 5-fluorouracil carrier in potential colorectal cancer treatment

Magnetite nanoparticles (Fe3O4 NPs) have received considerable attention in various biomedical applications due to their fascinating properties and multiple functionalities. In this multidisciplinary study, Fe3O4 NPs were produced by an inexpensive co-precipitation technique and using four different weight percentages of Punica granatum fruit peel extract as a green stabilizer. From the image of transmission electron microscopy, the NPs showed spherical shapes with an average size of 14.38 nm. Results of UV–VIS spectroscopy and bandgap indicated successful preparation of the Fe3O4 NPs stabilized with the extract. Adding the stabilizer concentration improved the particle zeta potential from −29.24 to −35.62 mV. Thermoresponsive performance of the Fe3O4 nanofluids with the green extract could render a remarkable heating capability under the hyperthermia condition. Magnetic resonance imaging (MRI) analysis presented that the samples possessed acceptable MRI signals. An anticancer drug 5-fluorouracil was successfully loaded onto the Fe3O4 NPs containing 2 weight percentage of the extract, which indicated a maximum release of 79% in a media with pH 7.4. In cytotoxicity assays, the drug-loaded Fe3O4 NPs at 15.62 and 31.25 µg.ml−1 concentration eliminated 29% and 35% of HCT116 colorectal cancer cells, respectively. This study, therefore, introduced that the green-synthesized Fe3O4 NPs can be a promising candidate for magnetic hyperthermia therapy, MRI nanoagents and drug delivery in colorectal cancer.

Thermally induced and physically cross-linked hydrogel doped with graphene oxide for controlled release.

Graphene oxide (GO) is an ideal hydrogel material because of its water solubility, non-toxicity, and excellent mechanical properties. Here, we added GO to oligo(lysine)-modified F127 to prepare a series of FLGO composite hydrogels. The FLGO hydrogel was thermally induced, stable and injectable. And the content of GO would affect the sol-gel transition, rheological properties and glass transition temperature of the FLGO hydrogel. GO was connected to the matrix through electrostatic interactions and hydrogen bonds. The cross-linking effect of GO enhanced the FLGO hydrogel. We also studied the release properties of the FLGO hydrogel loaded with anticancer drug 5-fluorouracil. Compared with F127 hydrogel, the FLGO hydrogel showed a linear, slower and stable release pattern within one week. The release rate of FLGO hydrogel could be adjusted by the pH and it was faster under acidic conditions. Therefore, the FLGO hydrogel is expected to be used as a drug release system in the field of biomedicine.

CS/Au/MWCNT nanohybrid as an efficient carrier for the sustained release of 5-FU and a study of its cytotoxicity on MCF-7.

The chemical reduction method has been used to adeptly synthesize a CS/Au/MWCNT nanocomposite, to be used as a carrier for the effectual delivery of the anticancer drug 5-Fluorouracil. The work aims at utilizing the less investigated ternary nanocomposite system containing chitosan (CS), gold (Au) and MWCNT's to attain higher encapsulation efficiency and to enable a more sustained and prolonged release of 5-FU. This system has improved cytotoxicity when compared to the CS/Au binary system. The prepared sample has been characterized using various techniques that confirm the formation of the nanocomposite, encapsulation of 5-FU into the nanocomposite, the structure of 5-FU and Au in the nanocomposite and the formation of the polymer matrix nanocomposite. An increase in the encapsulation efficiency to 98% and loading efficiency to 43% is observed when compared to the binary composite, elucidating the importance of incorporation of carbon nanotubes into the nanocomposite. A reduction in the release percentage of 5-FU by 40% indicates a more prolonged release, which will enable a reduction of the number of dosages that need to be administered. This in turn leads to a reduction in the side effects posed by the drug 5-FU. Moreover, the effectiveness of the drug loaded nanocomposite system towards the inhibition of breast cancer cells, apparent from the attainment of 50% cell viability while taking sample concentrations as low as 25 μg ml−1, makes this ternary nanocomposite superior and significant.

Selective Loading and Prolonged Release of 5-Fluorouracil in the Nanoconfined Interlayer Space of Montmorillonite.

Montmorillonite was used as a carrier for the anticancer drug 5-fluorouracil (5FU). The selective loading of 5FU into the nanoconfined interlayer space of montmorillonite was achieved by rinsing off the weakly bonded 5FU from the external surface. The 5FU loading content in montmorillonite was 3.2 mass%. The intercalated 5FU was in an amorphous state and might be arranged as a roughly vertical monolayer in the interlayer space of montmorillonite. The intercalated 5FU showed a high thermal stability due to the protection of the montmorillonite layers. The release profiles of the intercalated 5FU were well fitted with the modified Korsmeyer-Peppas model. The montmorillonite exhibited a prolonged release of 5FU due to the restriction of the outward diffusion of intercalated 5FU. The 5FU/montmorillonite system has promising potential for oral administration for colonspecific delivery.

A simple and efficient sequential electrokinetic and hydrodynamic injections in micellar electrokinetic chromatography method for quantification of anticancer drug 5-fluorouracil and its metabolite in human plasma.

A simple and sensitive preconcentration strategy using sequential electrokinetic and hydrodynamic injection modes in micellar electrokinetic chromatography with diode array detection was developed and applied for the separation and determination of anticancer agent, 5-fluorouracil and its metabolite, 5-fluoro-2'-deoxyuridine, in human plasma. Sequential injection modes with increased analyte loading capacity using the anionic pseudo-stationary phase facilitated collection of the dispersed neutral and charged analytes into narrow zones and improved sensitivity. Several important parameters affecting sample enrichment performance were evaluated and optimized in this study. Under the optimized experimental conditions, 614- and 643-fold and 782- and 803-fold sensitivity improvement were obtained for 5-fluorouracil and its metabolite when compared with normal hydrodynamic and electrokinetic injection, respectively. The method has good linearity (1-1,000 ng/ml) with acceptable coefficient of determination (r2 > 0.993), low limits of detection (0.11-0.14 ng/ml) and satisfactory analyte relative recovery (97.4-99.7%) with relative standard deviations of 4.6-9.3% (n = 6). Validation results as well as the application to analysis of human plasma samples from cancer patients demonstrate the applicability of the proposed method to clinical studies.

Crystal structure of the single-stranded DNA-binding protein SsbB in complex with the anticancer drug 5-fluorouracil: Extension of the 5-fluorouracil interactome to include the oligonucleotide/oligosaccharide-binding fold protein

Single-stranded DNA-binding proteins (SSBs) are essential to cells because they participate in DNA metabolic processes, such as DNA replication, repair, and recombination. Some bacteria possess more than one paralogous SSB. Three similar SSBs, namely, SsbA, SsbB, and SsbC, are found in Staphylococcus aureus. Whether the FDA-approved clinical drug 5-fluorouracil (5-FU) that is used to target the enzyme thymidylate synthase for anticancer therapy can also bind to SSBs remains unknown. In this study, we found that 5-FU could form a stable complex with S. aureus SsbB (SaSsbB). We cocrystallized 5-FU with SaSsbB and solved complex structures to assess binding modes. Two complex forms of the structures were determined, namely, the individual asymmetric unit (two SaSsbB monomers) containing one (PDB entry 7D8J) or two 5-FU molecules (PDB entry 7DEP). The locations of 5-FU in these two SaSsbB complexes were similar regardless of the binding ratio. The structures revealed that residues T12, K13, T30, F48, and N50 of SaSsbB were involved in 5-FU binding. The mutations of T12, K13, and F48 caused the low 5-FU binding activity of SaSsbB, a result consistent with the structural analysis results. Taken together, the complexed structure and the binding mode analysis of SaSsbB extended the anticancer drug 5-FU interactome to include the oligonucleotide/oligosaccharide-binding fold protein.

Surface functionalization of zeolite-based drug delivery systems enhances their antitumoral activity in vivo

Zeolites have attractive features making them suitable carriers for drug delivery systems (DDS). As such, we loaded the anticancer drug 5-fluorouracil (5-FU), into two different zeolite structures, faujasite (NaY) and Linde Type L (LTL), to obtain different DDS. The prepared DDS were tested in vitro using breast cancer, colorectal carcinoma, and melanoma cell lines and in vivo using the chick embryo chorioallantoic membrane model (CAM). Both assays showed the best results for the Hs578T breast cancer cells, with a higher potentiation for 5-FU encapsulated in the zeolite LTL. To unveil the endocytic mechanisms involved in the internalization of the zeolite nanoparticles, endocytosis was inhibited pharmacologically in breast cancer and epithelial mammary human cells. The results suggest that a caveolin-mediated process was responsible for the internalized zeolite nanoparticles. Aiming to boost the DDS efficacy, the disc-shaped zeolite LTL outer surface was functionalized using amino (NH2) or carboxylic acid (COOH) groups and coated with poly-l-lysine (PLL). Positively functionalized surface LTL nanoparticles revealed to be non-toxic to human cells and, importantly, their internalization was faster and led to a higher tumor reduction in vivo. Overall, our results provide further insights into the mechanisms of interaction between zeolite-based DDS and cancer cells, and pave the way for future studies aiming to improve DDS anticancer activity.

3D Printed Calcium Phosphate Cement (CPC) Scaffolds for Anti-Cancer Drug Delivery.

One of the main applications of bone graft materials is filling the gap after the surgical removal of bone cancer or tumors. Insufficient healing commonly leads to non-union fracture which could lead to cancer resurgence or infection. Emerging 3D printing of on-demand bone graft biomaterials can deliver personalized solutions with minimized risk of relapse and recurrence of cancer after bone removal surgery. This research aims to explore 3D printed calcium phosphate cement (CPC) based scaffolds as novel anti-cancer drug delivery systems to treat bone cancer. For the study, various 3D printed CPC based scaffolds (diameter 5 mm) with interconnected pores were utilized. Various optimized polymeric solutions containing a model anticancer drug 5-fluorouracil (5-FU) was used to homogenously coat the CPC scaffolds. Both hydrophilic Soluplus (SOL) and polyethylene glycol (PEG) and a combination of both were used to develop stable coating solutions. The surface morphology of the coated scaffolds, observed via SEM, revealed deposition of the polymeric solution represented by a semi-smooth surface as opposed to the blank scaffolds that showed a smoother surface. An advanced surface analysis conducted via confocal microscopy showed a homogenous distribution of the drug throughout the coated scaffolds. Solid-state analysis studied by applying differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed semi-crystalline nature of the drug whereas mechanical analysis conducted via texture analysis showed no evidence in the change of the mechanical properties of the scaffolds after polymeric solutions were applied. The FTIR analysis revealed no major intermolecular interactions between 5-FU and the polymers used for coatings except for F2 where a potential nominal interaction was evidenced corresponding to higher Soluplus content in the formulation. In vitro dissolution studies showed that almost 100% of the drug released within 2 h for all scaffolds. Moreover, in vitro cell culture using two different cell lines (Hek293T-human kidney immortalized cell line and HeLa-human bone osteosarcoma epithelial cell line) showed significant inhibition of cell growth as a function of decreased numbers of cells after 5 days. It can be claimed that the developed 5-FU coated 3D printed scaffolds can successfully be used as bone graft materials to potentially treat bone cancer or bone neoplasm and for personalized medical solutions in the form of scaffolds for regenerative medicine or tissue engineering applications.

Acoustically Mediated Controlled Drug Release and Targeted Therapy with Degradable 3D Porous Magnetic Microrobots.

Microrobots for targeted drug delivery are of great interest due to their minimal invasiveness and wireless controllability. Here, a magnetically driven porous degradable microrobot (PDM) is reported that consists of a 3D printed helical soft polymeric chassis made of a poly(ethylene glycol) diacrylate and pentaerythritol triacrylate matrix containing magnetite nanoparticles and the anticancer drug 5-fluorouracil (5-FU). The encapsulated Fe3 O4 nanoparticles render the PDM a precise wireless magnetic actuation by means of rotating magnetic fields (RMFs). The increased surface area of the porous PDM facilitates the acoustically induced drug release due to a higher response to the acoustic energy. The drug release profile from the PDM can be selected on command from three different modes, referred to herein as natural, burst, and constant, by differentiating the ultrasound exposure condition. Finally, in vitro test results reveal different therapeutic results for each release mode. The observed great reduction of cancer cell viability in the burst- and constant-release modes confirms that ultrasound with the proposed PDM can enhance the therapeutic effect by increasing drug concentration and sonoporation.

Electrically controlled release of anticancer drug 5-fluorouracil from carboxymethyl cellulose hydrogels

Transdermal drug delivery is a technique used to introduce a drug through the skin and into the blood system. The drug-matrix hydrogels based on carboxymethyl cellulose (CMC) were prepared by solution casting method using citric acid as the crosslinking agent at various amounts. The 5-fluorouracil, an anticancer non-ionic drug, was released from the CMC hydrogels under applied electrical field. The diffusion coefficient and the release mechanism of the drug of the CMC hydrogels were investigated by the modified Franz-diffusion cell with the PBS buffer solution at the pH value of 7.4 and at 37 °C for the duration of 24 h. The effects of mesh size, electric potential, and electrode polarity were systematically investigated. The swelling test illustrated an increase in the mesh size with decreasing crosslinking agent. In addition, the drug diffusion coefficient increased with decreasing crosslinker: repeated group mole ratio. The diffusion coefficient depended critically on the applied electric potential and the electrode polarity. The non-ionic drug release mechanisms were identified as the matrix deswelling and electroosmosis, in addition to the pure diffusion without electric field. Thus, CMC has been shown a potential bio-based matrix for electrically controlled non-ionic drug delivery.

Whole-exome sequencing of 79 xenografts as a potential approach for the identification of genetic variants associated with sensitivity to cytotoxic anticancer drugs.

Chemotherapy response remains unpredictable in most patients with cancer. In this study, we performed whole-exome sequencing of 79 cancer xenografts derived from human cancer tissues to identify genetic predictors of chemosensitivity to nine cytotoxic anticancer drugs. Xenografts were harvested from 12 organs with cancer and implanted into nude mice. The mice were exposed to one of nine cytotoxic anticancer drugs (5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C, methotrexate, vincristine, and vinblastine) to assess the correlation between chemosensitivity response and variant allele frequency. We found 162 candidate variants that were possibly associated with chemosensitivity to one or more of the nine anticancer drugs (P < 0.01). In a subgroup analysis of breast and gastric cancer xenografts, 78 and 67 variants, respectively, were possibly associated with chemosensitivity. This approach may help to contribute to the development of personalized treatments that may allow for the prescription of optimal chemotherapy regimens among patients with cancer.

RETRACTED ARTICLE: 5-Fluorouracil Trapping in a Porous Ba(II)-organic Framework: Drug Delivery and Anti-thyroid Cancer Activity Evaluation

Solvothermal treatment of Ba(NO3)2 with the rigid tricarboxylic acid linker 4,4′,4″-s-triazine-2,4,6-triyltribenzoic acid (H3TATB) in a mixture of H2O and N,N-dimethylformamide (DMF) produces a new three-dimensional porous metal-organic framework having the chemical formula of [Ba(HTATB)-(H2O)2](DMF)4 (I). The complex I has been characterized by powder X-ray diffraction, elemental analysis and single crystal X-ray diffraction (CIF file CCDC no. 1898532). In light of its large inner spaces as well as widely distributed open metal sites, the guest-free I (Ia) has been used as a crystalline vessel for trapping the anticancer drug 5-fluorouracil (5-FU), which has been investigated both experimentally and computationally. Furthermore, MTT assay was employed to evaluate the in vitro cytotoxicity of the carrier 5-FU loaded Ia against the human thyroid cancer cell lines.

HPLC determination of massoia lactone in fermented Cordyceps sinensis mycelium Cs-4 and its anticancer activity in vitro.

The fermentation product of Cordyceps sinensis mycelium Cs-4 was commonly used as alternative substitutes of natural C. sinensis. Massoia lactone is the dominant component in the volatile oil of Cs-4 mycelium. In this research, we present a high performance liquid chromatography (HPLC) method for the quantitation of massoia lactone in Cs-4 mycelium. The high and stable contents of massoia lactone with values of 2.98-3.77mg/g, indicated that massoia lactone could be considered as a marker for the quality assessment of this product. The results of MTT and CCK-8 assay showed that Cs-4 mycelium volatiles exhibited cytotoxicity against eight malignant tumor cells (IC50 =6.0-49.8μg/ml) in comparison to the anticancer drug 5-fluorouracil (IC50 =17.0-425.3μg/ml), and massoia lactone might be the chemical basis for the anticancer effects of Cs-4 mycelium. Compared to the commercial drugs paclitaxel and docetaxel (IC50 =253-1973μg/ml), the Cs-4 mycelium volatiles and massoia lactone were discovered to possess inhibitory to taxol-resistant cell lines (IC50 =1.5-8.6μg/ml). PRACTICAL APPLICATIONS: Considering that there is still a lack of marker components distinctive to Cs-4 mycelium, the HPLC method represents a useful tool for the quality evaluation of Cs-4 mycelium. Moreover, the volatile oil of Cs-4 mycelium and massoia lactone have prominent anticancer property in vitro. It gives a clue that Cs-4 mycelium, the volatile oil and massoia lactone could be potentially employed in the food and medical industries for its anticancer applications.

Synthesis and Anticancer Activity of New 2-Aryl-4-(4-Methoxybenzylidene)-5-Oxazolone Scaffolds

A new series of 4-(4-methoxybenzylidene)-2-substitutedphenyl-5(4H)-oxazolone derivatives has been synthesized through the application of Erlenmeyer condition (Ac2O, AcONa, and 4-anisaldehyde) to the reaction products of the highly versatile p-aminohippuric acid with various electrophilic reagents such as aromatic aldehydes, phenyl isothiocyanate, diazotization-coupling reaction (malononitrile and 2-amino-4-phenylthiazole) and cyanoacetyl-pyrazole. IR, 1H NMR, and mass spectroscopic techniques were utilized to confirm the structures of these oxazolone scaffolds. The synthesized oxazolone derivatives were evaluated against four human cancer cell lines (HepG2, HTC-116, PC-3, and MCF-7). Compound 3e showed the best activity against hepatocellular carcinoma (IC50 8.9±0.30 μg/mL) and colorectal carcinoma (IC50 9.2±0.63 μg/mL) cell lines compared with the standard anticancer drug 5-fluorouracil.

Antitumor efficacy of cytosine deaminase-armed vaccinia virus plus 5-fluorocytosine in colorectal cancers

BackgroundVaccinia viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Cytosine deaminase (CD), which is derived from bacteria or yeast, can convert a relatively nontoxic prodrug 5-fluorocytosine (5-FC) into the active anticancer drug 5-Fluorouracil (5-FU). Vaccinia virus armed with the prodrug-activator CD gene would result in augmented antitumor effects that combined the effect of vaccinia virus and 5-FU together, and particularly limited the anticancer drug to tumor regions.MethodsThe attenuated vaccinia Tian Tan strain Guang 9 (VG9), with active yeast CD expression and thymidine kinase (TK) deficiency, was successfully constructed. Then, in vitro and in vivo antitumor efficacy of vaccinia VG9-CD plus 5-FC administration was evaluated in colorectal cancer cells.ResultsVaccinia viruses displayed different oncolytic potency in vitro cells, no relationship with whether they were cancer cells or normal cells. In colorectal tumor models, mice treated with vaccinia VG9-TK− showed better tumor remission ability and prolonged survival. Moreover, vaccinia VG9-CD in combination with gavage administration of 5-FC displayed the best antitumor efficacy, especially for the prolongation of survival.ConclusionsVaccinia VG9-CD in combination with 5-FC plays combined effect of vaccinia virus and chemotherapy, and becomes a promising virotherapy for cancer.

The Lactobacillus brevis 47 f Strain Protects the Murine Intestine from Enteropathy Induced by 5-Fluorouracil.

We report that the results of our study indicate that Lactobacillus brevis 47 f strain isolated from the faeces of a healthy individual prevents the manifestations of experimental mucositis induced by treatment of Balb/c mice with the anticancer drug 5-fluorouracil (5 FU; 100 mg/kg i.p. × 3 days). The presence of damage to the intestine and the colon was determined by a morphometric analysis of specimens including the height of villi, the amount of goblet cells and infiltrating mononuclear cells, and the expression of the proliferative Ki-67 antigen. Changes in the lipid peroxidation in the blood and the intestine were determined by severalfold increase of the concentration of malonic dialdehyde. Oral administration of L. brevis 47 f strain prior to 5 FU decreased the drug-induced morphological and biochemical changes to their respective physiological levels; the ability of intestinal epitheliocytes to express Ki-67 was partially restored. These effects of L. brevis 47 f strain were more pronounced or similar to those of the reference compound Rebamipid, a quinoline derivative known to protect the gut from drug-induced toxicity. Thus, the new lactobacilli strain attenuates the severity of 5 FU-induced enteropathy.

Phase I pharmacological study of continuous chronomodulated capecitabine treatment

PurposeCapecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy).MethodsPatients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8.ResultsA total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment.ConclusionThe MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1–14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.