Interaction Of 5-fluorouracil Research Articles

Interaction of 5-Fluorouracil on the Surfaces of Pristine and Functionalized Ca12O12 Nanocages: An Intuition from DFT.

The utilization of nanostructured materials for several biomedical applications has tremendously increased over the last few decades owing to their nanosizes, porosity, large surface area, sensitivity, and efficiency as drug delivery systems. Thus, the incorporation of functionalized and pristine nanostructures for cancer therapy offers substantial prospects to curb the persistent problems of ineffective drug administration and delivery to target sites. The potential of pristine (Ca12O12) and formyl (-CHO)- and amino (-NH2)-functionalized (Ca12O12-CHO and Ca12O12-NH2) derivatives as efficient nanocarriers for 5-fluorouracil (5FU) was studied at the B3LYP-GD3(BJ)/6-311++G(d,p) theoretical level in two electronic media (gas and solvent). To effectively account for all adsorption interactions of the drug on the investigated surfaces, electronic studies as well as topological analysis based on the quantum theory of atoms in molecules (QTAIM) and noncovalent interactions were exhaustively utilized. Interestingly, the obtained results divulged that the 5FU drug interacted favorably with both Ca12O12 and its functionalized derivatives. The adsorption energies of pristine and functionalized nanostructures were calculated to be -133.4, -96.9, and -175.6 kcal/mol, respectively, for Ca12O12, Ca12O12-CHO, and Ca12O12-NH2. Also, both topological analysis and NBO stabilization analysis revealed the presence of interactions among O3-H32, O27-C24, O10-C27, and N24-H32 atoms of the drug and the surface. However, 5FU@Ca12O12-CHO molecules portrayed the least adsorption energy due to considerable destabilization of the molecular complex as revealed by the computed deformation energy. Therefore, 5FU@Ca12O12 and 5FU@Ca12O12-NH2 acted as better nanovehicles for 5FU.

Molecular insights into the interaction of 5-fluorouracil and Fe3O4 nanoparticles with beta-casein: An experimental and theoretical study

We investigated the potential carrier of milk beta-casein (β-CN) and its interactions with 5-fluorouracil (5-FU) and iron oxide nanoparticles (Fe3O4 NPs). We used different spectroscopic methods of fluorescence, UV–Visble, circular dichroism (CD), synchronous fluorescence, zeta potential assay, and computational studies to clarify the protein interaction with 5-FU and Fe3O4 NPs. The fluorescence data indicated both Fe3O4 NPs and 5-FU could quench the intrinsic fluorescence of β-CN. Fluorescence measurements showed that the single interaction of β-CN with 5-FU or Fe3O4 NPs was static, while reacted β-CN with both 5-FU and Fe3O4 NPs simultaneously showed a dynamic quenching. Synchronous fluorescence data in both tests revealed that the tryptophan (Trp) residue of β-CN had a dominant role in quenching and the polarity of its microenvironment more than tyrosine (Tyr) increased in interaction with 5-FU. All the binding sites and thermodynamic parameters were obtained at 25, 37, and 42 °C. The analysis of thermodynamic parameters and Job’s plot techniques pointed to that both of these complexes with the 1:1 M ratio were exothermic (ΔH°<0) driven with the van der Waals and H-bonding interactions (in agreement with the docking results). The CD spectra in the region of far-UV and thermal denaturation study indicated minor changes in the secondary structure of β-CN in the presence of various concentrations of Fe3O4 NPs and 5-FU. Also, from the molecular dynamics (MD) analysis, as a result, the protein structure was stable during 100 ns. The outcomes highlighted that β-CN protein could form a great bind with 5-FU and Fe3O4 NPs ligands (supporting the zeta potential assay results) by independent binding sites. These results would be helpful insight to construct a potential magnetic nanocarrier β-CN base for 5-FU drug delivery.

Quantum chemical investigation on interaction of 5-fluorouracil with cucurbiturils

The electronic structure and stability of the encapsulated complexes of 5-fluorouracil (5FU) into cucurbit[n = 5–8]uril (CB[n]) in water were studied by means of PM6 and DFT computations. Among cucurbit[n]urils (n = 5–8) with different inner sizes, 5FU complexes with cucurbit[n = 6, 7]uril were more stable than those with cucurbit[n = 5, 8]uril. According to DFT computations, 5FU complex with the doubly inverted cucurbit[6]uril was the most stable and the mono- and doubly inverted isomers of CB[7] can also form relatively stable complexes.

Assessment of adsorption behavior of 5-fluorouracil and pyrazinamide on carbon nitride and folic acid-conjugated carbon nitride nanosheets for targeting drug delivery

In this study, in order to improve the therapeutic efficacy and enhancing targeted delivery of anticancer drugs, a kind of potential carrier based on conjugated with folic acid (FA) is designed. For this reason, the interactions of 5fluorouracil (5Fu) and pyrazinamide (PZA) anticancer drugs with pristine carbon nitride (CN) and its conjugated form with folic acid (FA-CN) using density functional theory (DFT) calculations and molecular dynamics (MD) simulation are investigated. The obtained results demonstrate that the functionalization of nanocarrier with FA not only improves the therapeutic efficacy but also causes the adsorption of the drugs to be stronger. Also, it found that the adsorption of 5Fu on the CN and FA-CN is stronger than PZA. The DFT-D performance in this work indicates that the dispersion correction has a strong effect on improving the obtained results. According to DFT-D calculations, the adsorption energy of 5Fu on the pristine nanocarrier is about −10 kJ/mol less than PZA. After the functionalization of nanocarrier, the adsorption energies about 20% become stronger. The closed-shell (non-covalent) interactions between the drugs and the nanosheets using the quantum theory of atoms in molecule (QTAIM) calculations are confirmed. Charge transfer calculation by employing the NBO method reveals that the nanosheets act as donors, and drugs act as acceptors. Furthermore, the obtained results from MD simulation have a good agreement with DFT results and showed similar trends. Generally, the results reveal that CN and FA-CN nanosheets can be used as suitable platforms for the delivery of anticancer drugs.

Partitioning of anticancer drug 5-fluorouracil in micellar media explored by physicochemical properties and energetics of interactions: Quantitative insights for implications in drug delivery

Drug delivery vehicles such as micelles, vesicles and other nanoemulsions are necessary for enhanced bioavailability of drugs in the body. We have measured and correlated physicochemical properties of an anticancer drug 5-fluorouracil in the micelles of anionic surfactant sodium dodecyl sulfate. cationic surfactant hexadecyltrimethylammonium bromide, and non-ionic surfactant triton X-100 with the energetics of interactions. Thermodynamic signatures accompanying the partitioning of drug into surfactant micelles along with standard partial molar volume and standard partial molar compressibilities of transfer from water to the micelles have been interpreted in terms of strength, nature and extent of partitioning. Functional groups on the drug responsible for interaction/partitioning in micelles have been identified. Interaction of 5-fluorouracil in two or three sequential partitioning behavior depending on the nature of the surfactant micelles has enabled detailed mechanistic analysis of the partitioning process. Structure-property-energetics relationship to obtain deeper insights into the nature of interaction between the drug and micelles has been addressed. Such studies provide information on the significance of functional groups on the drug molecule which can be modified for optimum partitioning in drug delivery vehicles to account for effective target oriented release.

The interaction of 5-fluorouracil with graphene in presence of external electric field: a theoretical investigation

In current research, the interaction between 5-fluorouracil (FU), as an anticancer drug, and graphene was studied in the M062X/6-311G(d,p) level of theory. The external electric field effects on the total energy, dipole moment, the energies corresponding to frontier orbitals and HOMO–LUMO gap of the fluorouracil···graphene molecule. Furthermore, the analysis of interaction of the 5-FU with graphene was carried out through the energy decomposition analysis (EDA). There were excellent linear relationships between electronic spatial extent (ESE), frontier orbital energies and energy of interaction with external electric field strength.

Investigations on the Interactions of 5-Fluorouracil with Herring Sperm DNA: Steady State/Time Resolved and Molecular Modeling Studies

In the present study, the interaction of 5-Fluorouracil with herring sperm DNA is reported using spectroscopic and molecular modeling techniques. This binding study of 5-FU with hs-DNA is of paramount importance in understanding chemico–biological interactions for drug design, pharmacy and biochemistry without altering the original structure. The challenge of the study was to find the exact binding mode of the drug 5-Fluorouracil with hs-DNA. From the absorption studies, a hyperchromic effect was observed for the herring sperm DNA in the presence of 5-Fluorouracil and a binding constant of 6.153 × 103M-1for 5-Fluorouracil reveals the existence of weak interaction between the 5-Fluorouracil and herring sperm DNA. Ethidium bromide loaded herring sperm DNA showed a quenching in the fluorescence intensity after the addition of 5-Fluorouracil. The binding constants for 5-Fluorouracil stranded DNA and competitive bindings of 5-FU interacting with DNA–EB systems were examined by fluorescence spectra. The Stern–Volmer plots and fluorescence lifetime results confirm the static quenching nature of the drug-DNA complex. The binding constant Kbwas 2.5 × 104L mol-1and the number of binding sites are 1.17. The 5-FU on DNA system was calculated using double logarithmic plot. From the Forster nonradiative energy transfer study it has been found that the distance of 5-FU from DNA was 4.24 nm. In addition to the spectroscopic results, the molecular modeling studies also revealed the major groove binding as well as the partial intercalation mode of binding between the 5-Fluorouracil and herring sperm DNA. The binding energy and major groove binding as -6.04 kcal mol-1and -6.31 kcal mol-1were calculated from the modeling studies. All the testimonies manifested that binding modes between 5-Fluorouracil and DNA were evidenced to be groove binding and in partial intercalative mode.

Interaction of 5-Fluorouracil Loaded Nanoparticles with 1,2-Dimyristoyl-sn-glycero-3-phosphocholine Liposomes Used as a Cellular Membrane Model

Nuclear magnetic resonance (NMR) spectroscopy and steady-state fluorescence anisotropy were used to study the behavior and interaction of 5-fluorouracil, both in a free form (5FU) and included in the polymer matrix of poly(butylcyanoacrylate) nanoparticles (5FUPBCN) with a phospholipid bilayer of large unilammellar vesicles composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), as a model system of biomembranes. The results confirm an interaction and penetration of 5FU into the phospholipid bilayer of DMPC liposomes. Different mechanisms of drug transfer from the aqueous environment into the model membrane environment, for the free drug and that incorporated into polymer nanoparticles, are suggested: (i) concentration-dependent reversible diffusion of the free 5FU and (ii) sustained 5FU release from nanoparticles adsorbed on the liposome surface resulting in continuous delivery of the drug into the phospholipid bilayers of the DMPC liposomes.

Preparation and characterization of 5-fluorouracil pH-sensitive niosome and its tumor-targeted evaluation: in vitro and in vivo

The purpose of this study was to investigate preparation, characterization and tumor-targeted effect of pH-sensitive niosomes, composed of a nonionic surfactant mixed with cholesteryl hemisuccinate (CHEMS), a derivative of cholesterol (CHOL), as a pH-sensitive molecule.CHEMS was synthesized with CHOL and succinic acid, the structure of which was analyzed by Mass spectrometry (MS) and 1H Nuclear magnetic resonance (1H NMR) spectrum. Niosomes were prepared via film hydration-probe ultrasound method. Both normal niosomes and pH-sensitive niosomes showed spherical morphology under transmission electron microscope (TEM) with a average particle sizes of 172 ± 6.2 nm and 153 ± 4.7 nm, respectively. The thermotropic behavior, structure changes and interaction of 5-fluorouracil (5-Fu) with other materials were characterized by differential scanning calorimetry (DSC), and the disappearance of the melting peak of drug revealed the fact that drug was encapsulated in niosomes. Bulk-equilibrium reverse-dialysis method was chosen to investigate the behavior of drug release from normal niosomes and pH-sensitive niosomes in different pH medium, and the results showed that the noisome containing CHEMS had a pH-sensitive property. Tumor-targeted effect was proved by the fact that pH-sensitive niosomes showed a remarkable high concentration in tumor site of the mice transplanted with tumor cell.

Interaction of 5-Fluorouracil and its derivatives with bovine serum albumin

Fluorouracil (5-FU) and its derivatives are the most commonly used drugs to treat many types of cancer. Two dual functional agents, FUPAE and FUPAP, derived from 5-Fluorouracil (5-FU) have shown radiosensitizing activity but unlike their components were not cytotoxic. This study was designed to examine the interaction of BSA with 5-Fluorouracil (5-FU) and two of its derivatives; FUPAE and FUPAP at physiological conditions, using a constant protein concentration and various drug contents. FTIR, UV–Vis spectroscopic methods as well as molecular modelling were used to determine the drugs binding mode, the binding constants and the effects of drug complexation on BSA stability and conformation. Structural analysis showed that 5-Fluorouracil, FUPAE and FUPAP bind BSA via polypeptide polar groups with overall binding constants of K 5-FU–BSA = 3.02(±0.09) × 10 3, K FUPAE–BSA = 1.08(±0.04) × 10 4, K FUPAP–BSA = 1.21(±0.06) × 10 4 M −1. BSA conformation was altered by a major reduction of α-helix from 69% (free BSA) to 34% with 5-FU, 40% with FUPAE, 38% with FUPAP. These results suggest that serum albumins might act as carrier proteins for FUPAE and FUPAP in delivering them to target tissues.

Adsorption and interaction of 5-fluorouracil with montmorillonite and saponite by FT-IR spectroscopy

Adsorption of 5-fluorouracil (5-FU) on montmorillonite and saponite has been investigated using FT-IR spectrometry. The intercalation of 5-FU within montmorillonite or saponite has been shown by X-ray diffraction to increase the interlayer spacing. In order to investigate interaction of 5-FU with clays, the harmonic and anharmonic vibrational wavenumbers of free 5-FU and 5-FU interacting with Al(OH) 3 have been calculated at the DFT/B3LYP level with 6-31++G(d,p) basis set by using Gaussian 03 program set. The solution effect on 5-FU was also calculated by using polarizable continuum model (PCM). Experimental and calculated results indicated that 5-FU interacted with clays by direct or indirect coordination (through water molecules) to the Lewis acidic centers.

Combination of 5-fluorouracil and irinotecan on modulation of thymidylate synthase and topoisomerase I expression and cell cycle regulation in human colon cancer LoVo cells: clinical relevance.

This study was designed to explore the possible interaction of 5-fluorouracil (5-FU) and 7-ethyl-10-hydroxycamptothecin (SN-38) in vitro. Human colon cancer LoVo cells were treated in both a dose- and time-dependent manner using clinically relevant concentrations of and exposure to 5-FU and/or SN-38. The expression of thymidylate synthase (TS), topoisomerase I, and cell cycle kinetics were evaluated by Western blot analysis and flow cytometry, respectively. Cytotoxicity was evaluated by MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide) assay. The cytotoxic effects of combination treatment were determined by median effect analysis. Topoisomerase I expression was downregulated following 12 hours of exposure to treatment, and topoisomerase I expression recovered 8 hours after SN-38 was removed. The TS expression was decreased following 24 hours of 5-FU and it remained at reduced levels for > 24 hours after removal of 5-FU. SN-38 induced an arrest at S/G2/M phase, reaching its maximum effect at 12 hours. This cell cycle arrest was reversed 24 hours after SN-38 was removed. 5-FU induced an arrest at the S phase, and maximum arrest occurred at 12 hours and lasted for > 48 hours. After 12 hours of sequential SN-38, LoVo cells were arrested in S phase, thereby potentiating the effect of 5-FU. Cytotoxicity studies confirmed the synergistic interaction between 5-FU and irinotecan. These findings suggest that the proper sequencing of 5-FU/irinotecan depends on regulation of topoisomerase I, and cell cycle kinetics

Interaction of 5‐Fluorouracil with folates

Interaction of 5‐Fluorouracil with folates

The interaction of 5-fluorouracil, hydroxyurea, and radiation in two human head and neck cancer cell lines.

We have investigated the effects of 5-fluorouracil (5-FU) and hydroxyurea (HU) with radiation on two human head and neck squamous carcinoma cell lines. SQ-20B has a D0 of 239 cGy and an S phase fraction of 37%, while SQ-38 has a D0 of 146 cGy and an S phase fraction of 31%. For SQ-20B the surviving fraction at 100 cGy was significantly reduced (p < 0.05) when cells were exposed to HU or to 5-FU or both chemotherapy agents together with radiation. No significant effect was seen for SQ-38 with either chemotherapy agent alone or in combination with radiation as compared with radiation alone. Therefore, additive cytotoxicity between 5-FU and HU and radiotherapy was observed only in a head and neck cancer cell line with a higher D0 and a higher S phase fraction.

Cell death in relation to cell cycle in a mouse ascites tumor growing in vivo after combined treatment with cisplatin and 5-fluorouracil

The interaction of 5-fluorouracil (5-FU) and cisplatin (CDDP) was studied in Bp8 ascites sarcoma cells growing in mice. By density gradient centrifugation in Percoll solution, non-viable cells were separated from viable cells. Single drug treatment with doses of 12 and 36 mg/kg body weight of 5-FU and 0.4 and 0.8 mg/kg body weight of CDDP did not yield non-viable cells during the time period studied (96 h). Combination of the drugs increased the non-viable cells to about 10-25% depending on the doses given. This indicates a supra-additive cytotoxic effect. Analysis of the distribution of viable cells in the different cell cycle phases by flow cytometry showed an accumulation of cells in the S-phase after 5-FU and in the S- and G2-phases of the CDDP or combined 5-FU-CDDP treatment. Similar analysis of non-viable cells showed a similar cell cycle distribution, which suggests that supra-additive cytotoxicity is not cell cycle specific. By labeling the DNA of the tumor cells with [125T]-deoxyuridine and using whole body measurement, the cell loss was studied. No changes in cells loss after single drug and combined treatment were found during the observation time. The molecular basis for the interaction between 5-FU and CDDP should be elucidated.

Effect of combined 5-fluorouracil and radiation on murine hematopoietic tissue

The interaction of 5-fluorouracil (5-FU) and radiation in hematopoietic tissue was assessed as the survival of hematopoietic stem cells (CFUs) by means of the spleen colony assay. 5-FU was given intraperitoneally in the dose range 50–500 mg/kg body weight. In this dose range, stem cell survival decreased exponentially as a function of 5-FU dose. After 150 mg/kg of 5-FU alone (i.e. the maximum tolerated dose, MTD), the stem cell survival rapidly decreased, reaching a minimum after 1–2 days. The decrease was followed by a regeneration phase with a doubling time of about 28 h, with return to pretreatment values on day 7, and with an overshoot of survival on day 10–28. A similar regeneration was observed after 0.75 Gy radiation alone, but there was no evidence of an overshoot of stem cell number. 5-FU given 15 min before whole-body irradiation resulted in a pronounced reduction in stem cell survival due to an increase in the slope of the radiation survival curve by a factor of 2.1. After combined 5-FU and radiation, the survival rapidly decreased to a minimum at day 1, and it showed only a slight increase within the next 7 days. After this delay, the stem cells regenerated with a doubling time of about 30 h, reaching pretreatment values on day 15. The delayed stem cell regeneration was not seen following 3.5 Gy radiation alone or 225 mg/kg 5-FU alone, which resulted in the same nadir of CFUs survival as found after the combined treatment. Thus, 5-FU greatly enhances the hematopoietic damage after radiation by reducing the number of surviving stem cells and delaying the stem cell regeneration.

Interaction of 5-fluorouracil and total body irradiation in murine hematopoietic tissue : O.S. Nielsen, H. von der Maase, J. Overgaard Danish Cancer Society, Dept. Exp. Clin. Oncol., Aarhus, and Dept. of Oncology, Herlev, Denmark

Interaction of 5-fluorouracil and total body irradiation in murine hematopoietic tissue : O.S. Nielsen, H. von der Maase, J. Overgaard Danish Cancer Society, Dept. Exp. Clin. Oncol., Aarhus, and Dept. of Oncology, Herlev, Denmark

Basic investigations on interaction of 5-fluorouracil and tumor ischemia in the treatment of liver malignancies.

Pharmacokinetic considerations are the main rationale for locoregional treatment of hepatic malignancies with anticancer drugs [3, 6,10]. The advantage of regional exposure of arterially infused drugs increases when the blood flow rate into the target region is reduced [6,13]. Impairment of tumor blood flow and synchronous intra-arterial chemotherapy have been employed in various clinical studies using 5-fluorouracil (5-FU) [8, 9, 18]. The antimetabolite 5-FU is activated in the tumor cell, requiring several energy-dependent anabolic steps (Fig. 1). This applies to the drug’s action on RNA as well as DNA synthesis [14, 17]. Whether active carrier-mediated transport into the tumor cell of 5-FU is also involved is still a matter of discussion [17].KeywordsTime LapseBasic InvestigationTumor Blood FlowRegional ExposureStarch MicrosphereThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Irradiation of murine lip mucosa in combination with 5-fluorouracil, administered by single dose injection or continuous infusion

The possible interaction of 5-fluorouracil (5-FU) and irradiation on mouse lip mucosa was studied, with special interest for the influence of the route of administration of the drug, either by single intraperitoneal (i.p.) injection or by 7 days continuous subcutaneous infusion. Apart from the possible modification by the drug of radiation-induced damage to the lip mucosa assessment was made of the systemic toxicity. No modification of the radiosensitivity of mouse lip mucosa nor of its repair capacity was observed with the use of 5-FU given either by i.p. injection or by continuous infusion. However, the combination of 5-FU and irradiation resulted in an increased systemic toxicity which was only seen when 5-FU was administered by an i.p. injection in close timing with irradiation. It is suggested that this increased systemic toxicity is caused by the combined effects of irradiation and 5-FU on the alimentary tract, although we could not demonstrate the mechanism of it.

Combination of 5-fluorouracil and cyclophosphamide in L1210 and P388 leukemias with changes in optimum treatments as a function of the age of the L1210 tumor at first treatment.

The interaction of 5-fluorouracil and cyclophosphamide in the treatment of L1210 and P388 leukemias was studied using response surface methodology. Single dose treatment of each drug was administered simultaneously or with a 24-hr interval between 5-fluorouracil and cyclophosphamide to the advanced tumors or at various times after L1210 inoculation. While at low doses the action of the combination of the two drugs was greater than expected, there was no therapeutic synergism if the drugs were given together (optimum doses cyclophosphamide 366 mg/kg and 364 mg/kg, respectively, in advanced L1210 and P388 leukemias) or in the early tumor when cyclophosphamide was given 24 hours after 5-fluorouracil. In the advanced tumor, using the regimen employing a 24-hr interval between drugs, therapeutic synergism could be demonstrated (optimum doses 5-fluorouracil 130 mg/kg followed by cyclophosphamide 248 mg/kg in advanced L1210 leukemia and 5-fluorouracil 110 mg/kg followed by cyclophosphamide 263 mg/kg in advanced P388 leukemia). The evidence generated suggested that improved therapy could be found in two separate regions of the treatment space, raising the possibility of more than one mechanism of drug interaction. The location of the optimal treatment depended on the tumor burden at the time treatment was initiated. A shift from one region to the other occurred after 4-6 days of tumor growth when the original inoculum was 10(5) i.p. L1210 cells. Another more obvious conclusion that can be drawn is that treatment was less effective as the tumor became more advanced. The notion that different tumor stages may require different ratios of drugs in a clinically useful combination should receive attention.