Pharmacokinetic evaluation of oxaliplatin combined with S-1 (SOX) chemotherapy in a rat model of colorectal cancer with acute kidney injury: predictive renal biomarkers for dose optimisation.

Dose adjustment based on renal function is essential in S-1, which contains the 5­fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats.AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (sCr) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours.No alterations in the area under the plasma concentration-time curve (AUC0-24h) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The AUC0-24h for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified sCr as a covariate in platinum distribution after SOX chemotherapy.To optimise dose adjustment of SOX chemotherapy in patients with AKI, sCr may be a key factor in determining the appropriate dose.

New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids.

5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development.

New In Vitro-In Silico Approach for the Prediction of In Vivo Performance of Drug Combinations.

Pharmacokinetic (PK) studies improve the design of dosing regimens in preclinical and clinical settings. In complex diseases like cancer, single-agent approaches are often insufficient for an effective treatment, and drug combination therapies can be implemented. In this work, in silico PK models were developed based on in vitro assays results, with the goal of predicting the in vivo performance of drug combinations in the context of cancer therapy. Combinations of reference drugs for cancer treatment, gemcitabine and 5-fluorouracil (5-FU), and repurposed drugs itraconazole, verapamil or tacrine, were evaluated in vitro. Then, two-compartment PK models were developed based on the previous in vitro studies and on the PK profile reported in the literature for human patients. Considering the quantification parameter area under the dose-response-time curve (AUCeffect) for the combinations effect, itraconazole was the most effective in combination with either reference anticancer drugs. In addition, cell growth inhibition was itraconazole-dose dependent and an increase in effect was predicted if itraconazole administration was continued (24-h dosing interval). This work demonstrates that in silico methods and AUCeffect are powerful tools to study relationships between tissue drug concentration and the percentage of cell growth inhibition over time.

Enzymes Photo-Cross-Linked to Live Cell Receptors Retain Activity and EGFR Inhibition after Both Internalization and Recycling.

In this work, we show that a prodrug enzyme covalently photoconjugated to live cell receptors survives endosomal proteolysis and retains its catalytic activity over multiple days. Here, a fusion protein was designed with both an antiepidermal growth factor receptor (EGFR) affibody and the prodrug enzyme cytosine deaminase, which can convert prodrug 5-fluorocytosine to the anticancer drug 5-fluorouracil. A benzophenone group was added at a site-specific mutation within the affibody, and the fusion protein was selectively photoconjugated to EGFR receptors expressed on membranes of MDA-MB-468 breast cancer cells. The fusion protein was next labeled with two dyes for tracking uptake: AlexaFluor 488 and pH-sensitive pHAb. Flow cytometry showed that fusion proteins photo-cross-linked to EGFR first underwent receptor-mediated endocytosis within 12 h, followed by recycling back to the cell membrane within 24 h. These findings were also confirmed by confocal microscopy. The unique cross-linking of the affibody-enzyme fusion proteins was utilized for two anticancer treatments. First, the covalent linking of the protein to the EGFR led to inhibition of ERK signaling over a two-day period, whereas conventional antibody therapy only led to 6 h of inhibition. Second, when the affibody-CodA fusion proteins were photo-cross-linked to EGFR overexpressed on MDA-MB-468 breast cancer cells, prodrug conversion was found even 48 h postincubation without any apparent decrease in cell killing, while without photo-cross-linking no cell killing was observed 8 h postincubation. These studies show that affinity-mediated covalent conjugation of the affibody-enzymes to cell receptors allows for prolonged expression on membranes and retained enzymatic activity without genetic engineering.

Pharmacokinetic and Pharmacodynamic Factors Contribute to Synergism between Let-7c-5p and 5-Fluorouracil in Inhibiting Hepatocellular Carcinoma Cell Viability.

Pharmacological interventions for hepatocellular carcinoma (HCC) are hindered by complex factors, and rational combination therapy may be developed to improve therapeutic outcomes. Very recently, we have identified a bioengineered microRNA let-7c-5p (or let-7c) agent as an effective inhibitor against HCC in vitro and in vivo. In this study, we sought to identify small-molecule drugs that may synergistically act with let-7c against HCC. Interestingly, we found that let-7c exhibited a strong synergism with 5-fluorouracil (5-FU) in the inhibition of HCC cell viability as manifested by average combination indices of 0.3 and 0.5 in Hep3B and Huh7 cells, respectively. By contrast, coadministration of let-7c with doxorubicin or sorafenib inhibited HCC cell viability with, rather surprisingly, no or minimal synergy. Further studies showed that protein levels of multidrug resistance-associated protein (MRP) ATP-binding cassette subfamily C member 5 (MRP5/ABCC5), a 5-FU efflux transporter, were reduced around 50% by let-7c in HCC cells. This led to a greater degree of intracellular accumulation of 5-FU in Huh7 cells as well as the second messenger cyclic adenosine monophosphate, an endogenous substrate of MRP5. Since 5-FU is an irreversible inhibitor of thymidylate synthetase (TS), we investigated the interactions of let-7c with 5-FU at pharmacodynamic level. Interestingly, our data revealed that let-7c significantly reduced TS protein levels in Huh7 cells, which was associated with the suppression of upstream transcriptional factors as well as other regulatory factors. Collectively, these results indicate that let-7c interacts with 5-FU at both pharmacokinetic and pharmacodynamic levels, and these findings shall offer insight into molecular mechanisms of synergistic drug combinations. SIGNIFICANCE STATEMENT: Combination therapy is a common strategy that generally involves pharmacodynamic interactions. After identifying a strong synergism between let-7c-5p and 5-fluorouracil (5-FU) against hepatocellular carcinoma cell viability, we reveal the involvement of both pharmacokinetic and pharmacodynamic mechanisms. In particular, let-7c enhances 5-FU exposure (via suppressing ABCC5/MRP5 expression) and cotargets thymidylate synthase with 5-FU (let-7c reduces protein expression, whereas 5-FU irreversibly inactivates enzyme). These findings provide insight into developing rational combination therapies based on pharmacological mechanisms.

Glycyrrhetinic acid modified MOFs for the treatment of liver cancer.

Liver cancer remains a major cause of cancer-related death across the globe. Nano medicines have emerged as promising candidates to improve liver cancer chemotherapy. In this study, a glycyrrhetinic acid (GA) modified metal-organic framework-based drug delivery system (GA-MOFs) was developed to enhance the liver targeting ability of 5-FU. The physicochemical properties of GA-MOFs regarding particle size, size distribution and morphology were evaluated. The results showed that the obtained 5-FU@GA-MOFs had an octahedral structure, a uniform particle size distribution, and a diameter of ∼200 nm. In vitro release experiments demonstrated that 5-FU@GA-MOFs exhibited a pH-dependent release pattern. MTT assays indicated that 5-FU-loaded GA-MOFs showed greater cytotoxicity towards HepG2 cells when compared to 5-FU alone at the same dose. In vivo tissue distribution demonstrated that the 5-FU@GA-MOFs significantly increased the accumulation of 5-FU in the liver. In vivo imaging analysis further manifested the liver targeting ability of GA-MOFs. Taken together, these results suggested that GA-modified MOFs showed promising potential as liver-targeting nanocarriers for the delivery of anti-tumor drugs.

Preparation and evaluation of phytantriol liquid crystal as a liquid embolic agent.

Transcatheter arterial chemoembolization (TACE) is the preferred treatment for patients with advanced hepatocellular carcinoma (HCC), but it lacks safe and effective embolic agents. 5-Fluorouracil (5-FU) is a broad-spectrum anticancer drug, but its clinical application is limited due to drug resistance and toxic side effects. Therefore, in this study, we developed a new liquid embolic agent with 5-FU as the model drug. We found that this liquid embolic agent possesses good gelling properties and embolic effects. An in vitro drug release model of the agent conformed to the Weibull model. Cumulative release of the drug over 7 d was ∼90%, consisting of an initial burst followed by sustained release. Cytotoxicity testing showed that each liquid embolic composition is cytocompatible and only mildly cytotoxic. Pharmacokinetic experiments showed that the formulation significantly prolongs the t1/2 of 5-FU (approximately five times that of 5-FU solution) and 5-FU residence time in the body (approximately three times that of 5-FU solution). These results indicate that the liquid embolic agent has embolic capacity and could be used as a potential therapeutic method for TACE.

Pharmacokinetic study of the oral fluorouracil antitumor agent S-1 in patients with impaired renal function.

Although dose reduction of S-1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5-fluorouracil, 5-chloro-2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S-1 in patients with renal impairment. We classified patients receiving S-1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S-1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m2 ), 10 patients in cohort 2 (eGFR = 50-79 mL/min/1.73 m2 ), 10 patients in cohort 3 (eGFR = 30-49 mL/min/1.73 m2 ), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m2 ). Those in cohorts 3 and 4 treated with an adjusted dose of S-1 showed a similar area under the curve for 5-fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S-1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S-1 in patients with impaired renal function using eGFR is appropriate and safe.

Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients.

AIMS: Cetuximab associated with cisplatin and 5-fluorouracil is used to treat patients with inoperable or metastatic head and neck squamous cell carcinomas (HNSCC) up until disease progression or unacceptable toxicities. To date, no biomarkers of efficacy are available to select patients who will benefit from treatment. METHODS: An ancillary pharmacokinetics (PK) exploration was performed in the context of a prospective study investigating circulating-tumour cells vs progression-free survival (PFS). Cetuximab plasma concentrations were analysed according to a population PK model. Individual exposure parameters were confronted with soluble epidermal growth factor receptor (sEGFR) concentrations, tumour response and PFS. RESULTS: PK data (28 patients, 203 observations) were best described by a two-compartment model with linear elimination. Performance status (PS) significantly correlated to both cetuximab clearance and central volume of distribution with both parameters increasing by 33.3% (95% CI 1-65.6) for each 1-point increase of PS compared to PS = 0. Univariate analysis showed that patients with higher trough cetuximab concentrations at Day 7 (Cmin,D7 ) had better tumour response (P = 0.03) and longer PFS (P = 0.035). However, multivariate analysis revealed that only PS and tumour size at baseline remained significantly associated with PFS. Levels of sEGFR increased during cetuximab treatment but were not associated with PFS in the multivariate analysis. CONCLUSIONS: Our study prospectively indicates that PS is likely a confounding factor in the relationship between cetuximab PK and PFS, patients with a poor PS having lower cetuximab plasma exposure and lower PFS.

Population pharmacokinetic model of irinotecan and its metabolites in patients with metastatic colorectal cancer.

PURPOSE: Irinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment. METHODS: We used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates. RESULTS: The final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499. CONCLUSION: CPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.

Conflicting alterations in hepatic expression of CYP3A and enzyme kinetics in rats exposed to 5-fluorouracil: relevance to pharmacokinetics of midazolam.

1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120 mg/kg, ip). 2. 5-FU was shown to induce hepatic CYP3A2 protein 2 days after administration without changing the expression of CYP3A1/3A23. However, affinity of 5-FU-inducible CYP3A protein to MDZ for its 4- and 1'-hydroxylation was decreased. Furthermore, the susceptibility of MDZ hydroxylation activity to a CYP3A inhibitor differed between the control and 5-FU groups. 3. Pharmacokinetic analysis of the MDZ disposition demonstrated no significant differences in the total clearance (CLtot) and elimination rate constant (ke) between the control and 5-FU-treated rats. Lack of alteration in the metabolic clearance of MDZ may be attributable to the induction of CYP3A protein with reduced affinity for the substrate of CYP3A enzymes. 4. Our findings provide novel information regarding the manifestation of inductive and interfering actions of 5-FU toward hepatic CYP3A to help in assessing the pharmacokinetics of CYP3A substrate drugs.

Enhanced anti-colon cancer efficacy of 5-fluorouracil by epigallocatechin-3- gallate co-loaded in wheat germ agglutinin-conjugated nanoparticles.

Colon adenocarcinoma is the third most common cause of cancer-related deaths worldwide owing to its aggressive nature. Here, we developed a novel oral drug delivery system (DDS) that comprised active targeted nanoparticles made from gelatin and chitosan (non-toxic polymers). The nanoparticles were fabricated using a complex coacervation method, which was accompanied by conjugation of wheat germ agglutinin (WGA) onto their surface by glutaraldehyde cross-linking. Specifically, we integrated 5-fluorouracil (5-FU), the first-line treatment agent against colon cancer, and (-)-epigallocatechin-3-gallate (EGCG), which inhibits tumor growth via anti-angiogenesis and apoptosis-inducing effects, into the nanoparticles, named WGA-EF-NP. The 5-FU and EGCG co-loaded nanoparticles showed sustained drug release, enhanced cellular uptake, and longer circulation time. WGA-EF-NP exhibited superior anti-tumor activity and pro-apoptotic efficacy compared to the drugs and nanoparticles without WGA decoration owing to better bioavailability and longer circulation time in vivo. Thus, WGA-EF-NP shows promise as a DDS for enhanced efficacy against colon cancer.

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma.

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.

Microsponges enriched gel for enhanced topical delivery of 5-fluorouracil.

This study aimed to develop microsponges based topical gel formulation of 5-Fluorouracil (5-FU) for the treatment of skin cancer with enhanced skin deposition and reduced skin irritation potential. Microsponges were prepared by Quasi-emulsion solvent diffusion method using ethyl cellulose and Eudragit RL 30 D; and was optimised through detailed in vitro characterisation. Brunauer-Emmett-Teller (BET) analysis demonstrated higher surface area (2.4393 m2/g) and pore volume of developed microsponges formulation. Optimised formulation showed better thixotropic and texture properties compared to commercial cream formulation, used as control for comparison purpose. Further, the optimised formulation demonstrated 5.5-fold increase in skin deposition documented via in-vivo local bioavailability study, with significant reduction in skin irritation compared to the commercial formulation. Hence, the developed microsponges based formulation seems to be a viable alternative with enhanced topical delivery of 5-FU as compared to the commercial formulation.

A Study of 5-Fluorouracil Desorption from Mesoporous Silica by RP-UHPLC.

In cancer treatment, the safe delivery of the drug to the target tissue is an important task. 5-fluorouracil (5-FU), the well-known anticancer drug, was encapsulated into the pores of unmodified mesoporous silica SBA-15, as well as silica modified with 3-aminopropyl and cyclohexyl groups. The drug release studies were performed in two different media, in a simulated gastric fluid (pH = 2) and in a simulated body fluid (pH = 7) by RP-UHPLC. The simple and rapid RP-UHPLC method for quantitative determination of 5-fluorouracil released from unmodified and modified mesoporous silica SBA-15 was established on ODS Hypersil C18 column (150 × 4.6 mm, 5 µm) eluted with mobile phase consisted of methanol: phosphate buffer in volume ratio of 3:97 (v/v). Separation was achieved by isocratic elution. The flow rate was kept at 1 mL/min, the injection volume was set at 20 µL and the column oven temperature was maintained at 25 °C. The effluent was monitored at 268 nm. This paper provides information about the quantitative determination of the released 5-FU from silica. It was found out that larger amount of the drug was released in neutral pH in comparison with the acidic medium. In addition, surface functionalisation of silica SBA-15 influences the release properties of the drug.

Cocrystal of 5-Fluorouracil: Characterization and Evaluation of Biopharmaceutical Parameters.

To prepare the cocrystals of 5-fluorouracil (5-FU) with GRAS status coformers via a cocrystallization technique with an aim to improve physicochemical properties as well as bioavailability for colon cancer, breast cancer, and prostate cancer. The mechanochemical method was used in the preparations of three crystals of 5-FU with gentisic acid (5-FUGA), 3,4-dihydroxybenzoic acid (5-FUBA), and 4-aminopyridine (5-FUPN). A thermoanalytical and spectroscopic technique was used for their characterization. Their biological evaluation was done in different cancer cell lines. The new solid pure crystal forms were characterized by DSC, FTIR, and PXRD. The crystal structure was determined from single crystal and PXRD that exposed the existence of the monoclinic and triclinic crystal system with P21/n and P-1 space groups. The dermatokinetic studies on the rat skin revealed two- to threefold improvement in relative bioavailability as compared to pure 5-FU. "MTT assay was performed by varying the concentrations of the drug from 1 to 50 µg mL-1. After 24 h, the cell viability dropped to 70.67%, 74.05%, and 76.37% in MCF-7, Hela, and Caco-2 cell lines when the concentration of 5-FU was 50 µg mL-1", while it dropped dramatically in cocrystals 5-FUGA (22.06%, 24.63%, and 25.61%), 5-FUBA (31.22%, 29.46%, and 32.81%), and 5-FUPN (21.65%, 32.64%, and 21.46%). All the results indicated that 5-FU cocrystals possess better antitumor efficacy than free drug. Thus, cocrystallization expands the extent of the existing pre-formulation options ahead of pure API form to ameliorate the bioavailability and permeability.

Increase of MAL-II Binding Alpha2,3-Sialylated Glycan Is Associated with 5-FU Resistance and Short Survival of Cholangiocarcinoma Patients.

BACKGROUND AND OBJECTIVES: Sialylation plays important roles in tumor progression. Our present study aimed to demonstrate the alteration of sialylation and its role in cholangiocarcinoma (CCA). MATERIALS AND METHODS: The α2,3- and α2,6-sialylation in CCA tissue was analyzed by lectin-histochemistry using Maackia amurensis lectin-II (MAL-II) and Sambucus nigra agglutinin (SNA). CCA cell lines were treated with the pan-sialylation inhibitor 3Fax-peracetyl-Neu5Ac (3F-Sia) followed by proliferation and chemosensitivity assays. RESULTS: MAL-II binding α2,3-Sialylated Glycan (MAL-SG) and SNA binding α2,6-Sialylated Glycan (SNA-SG) were both elevated in CCA compared with hyperplastic/dysplastic (HP/DP) and normal bile ducts (NBD). The positive staining for MAL-SG or SNA-SG were found in 82% (61/74) of the CCA cases. Higher expression of MAL-SG in CCA was associated with shorter survival of the patients. The median survival of patients with high and low MAL-SG were 167 and 308 days, respectively, with overall survival of 233 days, suggesting the involvement of MAL-SG in CCA progression. MAL-SG expression of CCA cell lines was markedly decreased after treatment with 3F-Sia for 48 to 72 h. While proliferation of CCA cells were not affected by 3F-Sia treatment, their susceptibility to 5-fluorouracil (5-FU) was significantly enhanced. These results suggest that sialylation is involved in the development of 5-FU resistance and the sialylation inhibitor 3F-Sia can be used as a chemosensitizer for CCA. CONCLUSIONS: Sialylation is critically involved in the development of chemoresistance of CCA, and sialylation inhibitors may be used as a chemosensitizer in CCA treatment.

High molecular weight cross linked chitosan nanoparticles for controlled release of 5-Fluorouracil; Enhances its bioavailability.

The aim of study was cross linking of high molecular weight chitosan nanoparticles containing 5-fluorouracil to improve dissolution rate and ultimately enhance its bioavailability by reverse emulsion/micelles method and cross-linking agent i.e. glutaraldehyde (GA 25% aqueous solution in water). The nature and outer morphologies were evaluated by scanning electron microscopy (SEM). Drug release models were functional to support way from cross linked NPs. Cross linking of 5-fluorouracil with glutaraldehyde improved dissolution rate. Mean dissolution time of 5-fluorouracil decreased significantly upon reverse emulsion/cross linking as encapsulated drug is protective and thermally stable within cross linked chitosan NPs. FTIR studies showed formation of intermolecular hydrogen bonding between 5-fluorouracil and GA-co-CHNPs. DSC studies indicated a less crystalline state of 5-fluorouracil in cross linking. SEM showed spherical nanoparticles with somewhat rough surface. 5-FU release followed Korsmeyer-Peppas model which indicate diffusion and dissociation control drug release from GA-co-CH-NPs. 5-FU cross linked chitosan nanoparticles can be safe and useful tool for other chemotherapeutic agents.

Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: A phase I study.

Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m2 on day 1) and fluorouracil (1000 mg/m2 on days 1-4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum-tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.

A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours.

BACKGROUND: Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS: Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5-fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. RESULTS: Ninety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). CONCLUSIONS: The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.