Prodrug Of 5-fluorouracil Research Articles

Capecitabine-Induced Hyperosmolar Hyperglycemic State

Abstract Capecitabine is an orally administered prodrug of 5-fluorouracil (5-FU) which is often used for treatment of solid tumour cancers such as breast cancer and gastrointestinal tumours. Common adverse effects include nausea, diarrhea, anorexia and erythrodysthesia (hand-foot syndrome). However, there have been case reports of metabolic disturbances linked to capecitabine including hyperlipidemia, and less commonly, hyperglycemia. We report a case of a new diagnosis of persistent diabetes mellitus following an acute presentation of hyperosmolar hyperglycemic syndrome (HHS) subsequent to treatment with the chemotherapy agent, capecitabine. A 72 year old female with a history of metastatic breast cancer was admitted to hospital for management of hyperglycemic hyperosmolar state (HHS) after bloodwork from her family doctor revealed an elevated random blood glucose (40.2 mmol/L). Leading up to her presentation, the patient had completed 7 cycles of capecitabine treatment for her breast cancer. Prior to her capecitabine treatment, the patient did not have a history of diabetes mellitus. However, on admission, her hemoglobin A1C (HbA1C) was found to elevated into the diabetic range. Offending medications were considered and given the temporal dysglycemia following the patient’s chemotherapy regimen, capecitabine was thought to be a probable offending agent. The patient was acutely treated for HHS, and eventually transitioned to a basal-bolus insulin regimen at discharge. Her capecitabine was held pending review with her oncology team and she was closely followed up by her family doctor. The patient’s insulin regimen was ultimately titrated down to basal insulin only. Given the increasing use of capecitabine therapy in breast cancer, it is important to recognize the risk of hyperglycemia and hyperglycemic emergencies as a potential adverse effect of this treatment. It highlights the need to ensure that blood glucose is monitored throughout treatment to prevent hyperglycemic emergencies.

A Physiologically Based Pharmacokinetic-Pharmacodynamic Model for Capecitabine in Colorectal Cancer Rats: Simulation of Antitumor Efficacy at Various Administration Schedules.

Capecitabine is an oral prodrug of 5-fluorouracil and is widely used for colorectal cancer (CRC) treatment. However, knowledge of its antitumor efficacy after modification of the dosing schedule is insufficient. The aim of this study was to predict the antitumor efficacy of capecitabine using a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model based on metabolic enzyme activities. CRC model rats were administrated 180mg/kg of capecitabine for 2weeks. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8h following capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured on days 1, 7, and 14. Metabolic enzyme activities were determined in vitro using the liver and small intestine of the CRC model rats. A PBPK-PD model was developed based on metabolic enzyme activities. The antitumor efficacy of capecitabine after regimen modification was simulated using the PBPK-PD model. Capecitabine antitumor efficacy was dose-dependent. A dose of >500μmol/kg was needed to inhibit tumor growth. After capecitabine regimen modification, a 1-week postponement of capecitabine administration was more efficacious than a reduction in the dosage to 80%. The PBPK-PD model could simulate the antitumor efficacy at various capecitabine administration schedules. PBPK-PD models can contribute to the development of an appropriate CRC chemotherapy regimen with capecitabine.

Smart pH-responsive Co-polymeric Hydrogels for Controlled Delivery of Capecitabine: Fabrication, Optimization and In Vivo Toxicology Screening.

Despite exhibiting promising anticancer potential, the clinical significance of capecitabine (a potent prodrug of 5-fluorouracil used for the treatment of colorectal cancer) is limited owing to its acidic and enzymatic hydrolysis, lower absorption following the oral administration, poor bioavailability, short plasma half-life, and poor patient compliance. The present study was aimed to fabricate the capecitabine as a smart pH-responsive hydrogel network to efficiently facilitate its oral delivery while shielding its stability in the gastric media. The smart pH-sensitive HP-β-CD/agarose-g-poly(MAA) hydrogel network was developed using an aqueous free radical polymerization technique. The developed hydrogels were characterized for drug-loading efficiency, structural and compositional features, thermal stability, swelling behaviour, morphology, physical form, and release kinetics. The pH-responsive behaviour of developed hydrogels was established by conducting the swelling and release behaviour at different pH values (1.2 and 7.4), demonstrating significantly higher swelling and release at pH 7.4 as compared with pH 1.2. The capecitabine-loaded hydrogels were also screened for acute oral toxicity in animals by analysing the body weight, water and food intake, dermal toxicity, ocular toxicity, biochemical analysis, and histological examination. The characteristic evaluations revealed that capecitabine (anticancer agent) was successfully loaded into the hydrogel network. The range of capecitabine loading was from 71.22% to 90.12%. An interesting feature of hydrogel was its pH-responsive behaviour which triggers release at basic pH (94.25%). Optimum swelling (95%)was seen at pH 7.4. Based upon regression coefficient R2(0.96 - 0.99) the best-fit model was zero-order. The extensive toxicity evaluations evidenced a good safety profile with no signs of oral, dermal, or ocular toxicities, as well as no variations in blood parameters and histology of vital organs. Our findings conclusively evinced that the developed hydrogel exhibited excellent pharmaceutical and therapeutic potential and thus can be employed as a pH-responsive system for the controlled delivery of anticancer agents.

Inclusion of capecitabine into cucurbiturils: DFT study for supramolecular encapsulation of anticancer drug

Electronic structure and stability of the encapsulated complexes of capecitabine (CAP, prodrug of 5-fluorouracil) with cucurbit [n = 5 ~ 8]urils (CB[n]) in water were studied by means of DFT computations with dispersion (D3) and geometrical counterpoise (gCP) corrections. Among CB [n = 5 ~ 8] with different inner sizes, CB [n = 6, 7] can form more stable inclusion complexes (CAP@CB[n]) with CAP than CB [n = 5, 8]. DFT computations showed that CAP@CB[7] with the normal CB[7] was the most stable in water, and some inverted CB[7] and CB[6] can also form relatively stable inclusion complexes. Dispersion correction played an important role in calculation of interaction energy between CAP and C [n]. Intermolecular non-covalent interaction and natural bond orbital analysis showed that electron transfer from CB[7] to CAP made CAP@CB[7] stable, when two hydrogen bonds (N–H…O and O–H…O) between CAP and CB[7] played positive role.

Synthesis and Kinetic Study of Novel Coumarin- Based Mutual Prodrug of 5-fluorouracil and 5-ethynyluracil

The oral use of 5-fluorouracil is being deserted in the last decades due to its atypical intestinal absorption, which is primarily attributed to the mutable activity of dihydropyrimidine dehydrogenase located in the gastrointestinal mucosa. In this work, a coumarin-based prodrug system was utilized to synthesize a novel mutual prodrug of 5-fluorouracil and 5-ethynyluracil. This prodrug was designed to afford a concurrent release of these two active drugs resulting in the improvement of the therapeutic efficacy of both. The synthetic pathway involved 7 linear steps starting from coumarin. The chemical structures of the intermediates and prodrug were established by analyzing their FTIR, 1H-NMR, and 13C-NMR spectra. The in vitro chemical stability of the synthesized prodrug was tested in the HCl buffer (pH 1.2) and phosphate-buffered saline (pH 6.8), while its ability to release the active moieties was studied in human serum. The outcomes of these in vitro studies revealed that the prodrug showed a significant stability in the HCl buffer and phosphate-buffered saline with half-lives of 33.19 h and 18.13 hr respectively, obeying pseudo-first-order kinetics. Also, the prodrug was able to release the two active components in human serum with a half-life of 4.62 h obeying zero-order kinetics. It is concluded that the synthesized prodrug represents a promising oral prodrug of 5-fluorouracil and 5-ethynyluracil to serve better in therapeutics.

Safety of alternate-day treatment with TS-1TM (tegafur/gimeracil/oteracil) in tumor-bearing dogs: a pilot study.

Tegafur is a prodrug of fluoropyrimidine 5-fluorouracil (5-FU), while TS-1TM is an oral fixed-dose combination of three active drugs, tegafur, gimeracil, and oteracil. This pilot study evaluated the safety of tegafur/gimeracil/oteracil in the treatment of cancers in dogs. Tegafur/gimeracil/oteracil was administered orally at a mean dose of 1.1 mg/kg twice daily on alternate days, Monday-Wednesday-Friday, every week to 11 dogs with tumors. Partial response and stable disease were observed in one dog each, whereas six exhibited progressive disease. Three dogs were not assessed. Adverse events, the most serious being grade 2, were noted in seven dogs. Adverse events were acceptable, and the drug was effective in some dogs. Therefore, tegafur/gimeracil/oteracil may be useful for treating malignant solid tumors in canines.

Efficacy and tolerability of preoperative chemoradiotherapy with S-1 alone for locally advanced rectal cancer.

Preoperative chemoradiotherapy with capecitabine or 5-fluorouracil is a standard treatment for locally advanced rectal cancer (LARC). S-1, a prodrug of 5-fluorouracil, is a candidate for this chemoradiotherapy regimen in Japan; however, treatment outcomes after S-1 treatment alone are not clear. This study aimed to assess the efficacy and tolerability of preoperative chemoradiotherapy with S-1 alone for LARC. We retrospectively evaluated 54 LARC patients who underwent preoperative chemoradiotherapy with S-1 alone in our institution between 2005 and 2017. The clinical tumor stage was cT2–3 in 31 patients and cT4 in 23 patients, and lymph node metastases were clinically evident in 31 patients. S-1, at a dose of 80 mg/m2/day, was orally administered during radiotherapy. A total dose of 45–50.4 Gy was delivered in 25–28 fractions (median: 50.4 Gy). Surgical resections were scheduled 6–10 weeks after chemoradiotherapy completion. The 3- and 5-year overall survival rates were 92.4 and 72.8%, respectively, with a median follow-up time of 51 months. The 3- and 5-year local control rates were 96.2 and 85.9%, respectively. A pathological complete response was observed in 7 patients (13.0%) at the time of surgery. Ten patients (18.5%) had grade 3 acute toxicities and 5 patients (9.3%) had grade 3 late toxicities. No grade 4 or 5 toxicities were observed. Preoperative chemoradiotherapy with S-1 alone followed by total mesorectal excision resulted in a low incidence of toxicities and comparable clinical results. Therefore, S-1 alone can be a treatment option for preoperative chemoradiotherapy in LARC patients.

Pumpless, unidirectional microphysiological system for testing metabolism-dependent chemotherapeutic toxicity.

Drug development is often hindered by the failure of preclinical models to accurately assess and predict the efficacy and safety of drug candidates. Body-on-a-chip (BOC) microfluidic devices, a subset of microphysiological systems (MPS), are being created to better predict human responses to drugs. Each BOC is designed with separate organ chambers interconnected with microfluidic channels mimicking blood recirculation. Here, we describe the design of the first pumpless, unidirectional, multiorgan system and apply this design concept for testing anticancer drug treatments. HCT-116 colon cancer spheroids, HepG2/C3A hepatocytes, and HL-60 promyeloblasts were embedded in collagen hydrogels and cultured within compartments representing "colon tumor", "liver," and "bone marrow" tissue, respectively. Operating on a pumpless platform, the microfluidic channel design provides unidirectional perfusion at physiologically realistic ratios to multiple channels simultaneously. The metabolism-dependent toxic effect of Tegafur, an oral prodrug of 5-fluorouracil, combined with uracil was examined in each cell type. Tegafur-uracil treatment induced substantial cell death in HCT-116 cells and this cytotoxic response was reduced for multicellular spheroids compared to single cells, likely due to diffusion-limited drug penetration. Additionally, off-target toxicity was detected by HL-60 cells, which demonstrate that such systems can provide useful information on dose-limiting side effects. Collectively, this microscale cell culture analog is a valuable physiologically-based pharmacokinetic drug screening platform that may be used to support cancer drug development.

Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer.

PurposeCapecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients.Materials and MethodsWhole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model.ResultsWe identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an extreme case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5’VNTR 2R/3R and 3′-untranslated region 6-bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression.ConclusionThis study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS.

Hypertriglyceridemia induced by S-1: A novel case report and review of the literature

S-1, a compounding agent of tegafur, gimeracil, and oteracil potassium, is one of the most effective chemotherapeutic agents for colorectal cancer. In this case, following S-1 administration, we observed predominant elevation of serum triglyceride. A 49-year-old man with stage IV transverse colon adenocarcinoma received S-1 + irinotecan + bevacizumab. At the end of the S-1 administration period in every course, his serum triglyceride level was found to be elevated. Finally, it reached grade 4, without any symptoms of acute pancreatitis in the fifth course, and fenofibrate 80 mg once a day was administered.Management & outcome: Interestingly, the elevation spontaneously normalized without any pharmacotherapy 14 days after S-1 withdrawal, and this elevation did not occur when S-1 was not administered. Further, fenofibrate administration attenuated the hypertriglyceridemia to grades 1-3, with no complications. S-1 administration induced hypertriglyceridemia owing to the elevated serum triglyceride; however, a contrasting result was observed in the S-1 withdrawal period and during the S-1-cessation cycle. Since dietary intake was poorer during the S-1 administration period, it is considered that S-1 might have disturbed lipid metabolism. Further, we know that capecitabine, which is a prodrug of fluorouracil, also induces hypertriglyceridemia. As the end product of these medicines is fluorouracil, the presence of fluorouracil or its metabolizing enzymes, the genetic background of the patient might have affected the results. We have to be aware of the risk of asymptomatic and temporal occurrence of hypertriglyceridemia by S-1 administration for the early detection with appropriate pre-emptive treatment.

Assessment of pharmacokinetic variations of capecitabine after multiple administration in rats: a physiologically based pharmacokinetic model.

Capecitabine is a prodrug of 5-fluorouracil (5-FU) used for the treatment of colorectal cancer, with a two-week course of administration. However, the variance in plasma concentration and metabolic enzyme activities after multiple administration of capecitabine and its metabolites is unknown. The aim of this study was to identify the variance and predict the plasma concentration profile of capecitabine and its metabolites, using metabolic enzyme activities, to develop a more effective and safer medication. Rats orally received 180mg/kg of capecitabine once a day for two weeks. Blood samples were collected nine times, and plasma concentration was measured on day 1, 7, and 14. The liver and small intestine were removed after blood sampling and were used in vitro to evaluate metabolic enzyme activities of carboxylesterase, cytidine deaminase, and thymidine phosphorylase. A physiologically based pharmacokinetic (PBPK) model was developed using in vitro results. Area under the plasma concentration-time curve from 0h to infinity of 5-FU on day 7 and day 14 was significantly lower than that on day 1. Intrinsic clearance of thymidine phosphorylase in the liver on day 7 and day 14 was 1.4 and 1.3 times lower than that on day 1, respectively. The PBPK model described the observed plasma concentration of capecitabine and its metabolites. The decreased plasma concentration of capecitabine was caused by decreased metabolic enzyme activity. Efficacy can be improved by dose adjustment of capecitabine based on metabolic enzyme activities, using the PBPK model.

5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine

Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3-4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II-IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3-4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1-37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3-4 adverse events (OR = 10.40 [95% IC: 1.48-7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3-4 toxicity occurrence (OR = 10.9 [95% IC 1.2-96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity.

Development and Validation of HPLC and HPTLC Methods for Therapeutic Drug Monitoring of Capecitabine in Colorectal Cancer Patients.

Capecitabine is a prodrug of 5-fluorouracil, employed as a monotherapy or combination chemotherapy agent for treatment of colorectal cancer. Combination therapy of capecitabine consists of oxaliplatin, and hence, it becomes essential to determine that co-administration does not affect its metabolism. High-performance liquid chromatography and high-performance thin-layer chromatography methods were developed and validated to determine the plasma concentration of capecitabine. In this study, blood samples from 12 patients with colorectal cancer were collected and analyzed by both methods with a reference internal standard. Two groups consisting of six patients each were formed: the first group was treated with capecitabine monotherapy, the second group with capecitabine + oxaliplatin combination therapy. The results of analysis from both the methods indicated that there is no significant drug-drug interaction. The co-administration of oxaliplatin did not affect the metabolism of capecitabine. Both assay methods were compared for their sensitivity, robustness and specificity. It was found that both the assay methods were suitable for therapeutic drug monitoring of capecitabine.

3118 Case of Capecitabine-Induced Diarrhea Leading to Renal Failure Requiring Hemodialysis

INTRODUCTION: Capecitabine is a cytotoxic oral prodrug of 5-fluorouracil used as a chemotherapeutic adjuvant in the treatment of colorectal cancer. The most common adverse effects reported are hand-foot-syndrome and diarrhea. Incidence of diarrhea has been reported in up to 67% of patients. The pathophysiology of capecitabine induced diarrhea is not well understood with most cases being attributed to drug toxicity and overexpression of inflammatory cytokines. Chemotherapy induced diarrhea (CID) can be deleterious and, in some cases, life threatening. The subsequent case presents the development of acute renal failure requiring hemodialysis after treatment with capecitabine. CASE DESCRIPTION/METHODS: Case of a 50-year-old man with stage 3B T2N2M0 moderately differentiated adenocarcinoma of the rectum who presented with non-bloody diarrhea after recently starting his first chemotherapy treatment with CAPOX-Oxaliplatin and Capecitabine. Laboratory studies were significant for acute kidney failure with creatinine of 2.9 mg/dL and non-anion gap metabolic acidosis with bicarbonate of 18 mmol/L. Physical examination was unremarkable. Infectious workup for diarrhea was negative. Patient's renal function progressively worsened and ultimately required hemodialysis. After a negative colonoscopy and multiple bowel regimens, including lomotil, questran, octreotide and budesonide, his diarrhea was deemed to be secondary to Capecitabine therapy and only started to resolve after initiation of budesonide. Upon interval follow up with gastroenterology his diarrhea had completely resolved, and creatinine was at baseline. DISCUSSION: Grade 3–4 diarrhea occurs in 11.4% of patients treated with capecitabine monotherapy. However, when used in combination with other chemotherapeutic drugs also known to cause diarrhea such as oxaliplatin, the incidence increases to 18.2%. In general, treatment is conservative and limited to IV hydration, electrolyte replacement, and medications such as, loperamide and octreotide. However, in cases with standard treatment failure, it has been proven that budesonide effectively reduces the effects of 5-FU on the intestinal mucosa. In the literature, no other cases have been reported of acute renal failure requiring hemodialysis after treatment with capecitabine. Given the unpredictability of the effects of chemotherapy induced diarrhea and its potential to increase morbidity and mortality, it is essential to maintain close monitoring of such patients and provide adequate supportive treatment.

Histopathological changes in tumor budding between biopsy and resected specimens from patients treated with preoperative S-1 chemotherapy for oral cancer.

S-1 is an oral anticancer agent containing tegafur, a prodrug of 5-fluorouracil (5-FU). Preoperative S-1 chemotherapy is performed to prevent tumor proliferation before surgery in oral squamous cell carcinoma (OSCC). The aim of this study was to evaluate the effects of preoperative S-1 chemotherapy on tumor budding. We examined 248 cases of OSCC and evaluated the budding scores in biopsy and resected specimens by keratin immunohistochemistry. In S-1-untreated patients, the budding scores in resected specimens tended to show a mild increase. S-1 treatment had the effect of lowering the budding score, although some cases with dramatically increased budding scores in resected specimens were found in the early phase of administration. Relapse-free survival showed a significant difference (P<.01) according to the presence or absence of S-1 treatment among patients with high budding scores. The present findings indicate that S-1 administration may be more effective in patients with high budding scores than in those with lower budding scores.

Capecitabine Induced Hand-Foot Syndrome: A Systematic Review of Case Reports

Objective: Capecitabine, a prodrug of 5-fluorouracil, is currently used in the treatment of metastatic colorectal and breast cancers. The aim of this study was to review the pharmacological mechanisms, treatment strategies, and documented case reports of capecitabine-induced hand–foot syndrome (HFS).Methods: All case reports documented in the PubMed, Web of Science, and Scopus databases up to February 2018 were searched and reviewed using the keywords capecitabine, hand-foot syndrome, and case report.Results: The database search identified 373 articles in the literature; of these, 88 articles (having 111 case reports) in the English or Turkish language having a full-text access were included in the study. The median duration of capecitabine-induced HFS was 28 (range, 7–140) days, and the daily dose of capecitabine ranged between 850 and 5000 mg/m2 in cases wherein capecitabine was applied as monotherapy(n=19). A dose reduction or treatment discontinuation, systemic or topical treatment alone or in combination, and the use of henna, vitamin E, or pyridoxine were preferred options in the treatment of HFS.Conclusion: Health care providers and patients should be aware of developing capecitabine-induced HFS and its risk factors. Early recognition and treatment initiation for HFS are important to maintain effective chemotherapy in patients with cancer.

Probing the binding mechanism of capecitabine to human serum albumin using spectrometric methods, molecular modeling, and chemometrics approach

Capecitabine as a prodrug of 5-Fluorouracil plays an important role in the treatment of breast and gastrointestinal cancers. Herein, in view of the importance of this drug in chemotherapy, interaction mechanism between Capecitabine (CAP) and human serum albumin (HSA) as a major transport protein in the blood circulatory system has been investigated by using a combination of spectroscopic and molecular modeling methods. The fluorescence spectroscopic results revealed that capecitabine could effectively quench the intrinsic fluorescence of HSA through a static quenching mechanism. Evaluation of the thermodynamic parameters suggested that the binding process was spontaneous while hydrogen bonds and van der Waals forces played a major role in this interaction. The value of the binding constant (Kb = 1.820 × 104) suggested a moderate binding affinity between CAP and HSA which implies its easy diffusion from the circulatory system to the target tissue. The efficiency of energy transfer and the binding distance between the donor (HSA) and acceptor (CAP) were determined according to forster theory of nonradiation energy transfer as 0.410 and 4.135 nm, respectively. Furthermore, UV–Vis spectroscopic results confirmed that the interaction was occurred between HSA and CAP and caused conformational and micro-environmental changes of HSA during the interaction. Multivariate curve resolution-alternating least square (MCR-ALS) methodology as an efficient chemometric tool was used to separate the overlapped spectra of the species. The MCR-ALS result was exploited to estimate the stoichiometry of interaction and to provide concentration and structural information about HSA-CAP interactions. Molecular docking studies suggested that CAP binds mainly to the subdomain IIA of HSA, which were compatible with those obtained by experimental data. Finally, molecular dynamics simulation (MD) was performed on the best docked complex by considering the permanence and flexibility of HSA-CAP complex in the binding site. MD result showed that CAP could steadily bind to HSA in the site I based on the formation of hydrogen bond and π-π stacking interaction in addition to hydrophobic force.

Abstract P1-13-09: Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer

Abstract Background: Two randomized controlled trials comparing the efficacy of oral tegafur-uracil (UFT) (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (6 courses) were conducted in patients with resected early breast cancer. UFT is an oral fluoropyrimidine that combines tegafur, a prodrug of 5-fluorouracil, with uracil in a 1:4 molar ratio. One study was the N-SAS-BC01 trial (Watanabe et al, J Clin Oncol 2009), which was conducted in patients with high-risk node-negative breast cancer (n=733). The other was the CUBC trial (Park et al, Br J Cancer 2009), which was performed in patients with node-positive breast cancer (n=377). We reported the pooled analysis of these two randomized control trials using individual patient data (Ohashi et al, Breast Cancer Res Treat 2010). This pooled analysis showed that UFT was non-inferior to CMF in terms of inhibiting recurrence of estrogen receptor (ER)-positive early breast cancer. In addition, an exploratory subgroup analysis showed that UFT may be more effective in ER-positive patients who were 50 years or older. The present study was conducted to investigate the long-term efficacy of UFT or CMF in patients with early breast cancer. Methods: Long-term follow-up data for disease recurrence and survival were collected. Hazard ratios (HR) were determined using the Cox model stratified by study and adjusted for clinical characteristics, namely age, tumor size, nodal status, histological type, ER, and progesterone receptor (PgR). Survival curves were estimated by the Kaplan-Meier method. Hochberg multiplicity adjustment was applied in the previous pooled analysis, and non-inferiority of UFT versus CMF was shown in terms of relapse-free survival (RFS) in the ER-positive patient group. We investigated the non-inferiority of UFT in the same patient group with updated data. Restricted mean survival time (RMST) was calculated to consider the relative efficacy of UFT. This study is registered with JapicCTI-163321. Results: In total, 1,057 patients were analyzed (CMF, n=528; UFT n=529). The median follow-up time was 11.1 years (12.1 years in the N-SAS-BC 01 trial and 8.3 years in the CUBC trial). Table 1 shows the 10-year RFS and overall survival (OS) in all patients and ER-positive patients. The difference in RMST between arms at 20 years in terms of RFS was -2.7 months in all patients and 3.4 months in ER-positive patients. Table 2 shows the HR for RFS according to ER status and age. UFT (%)CMF (%)UFT to CMF; HR (95% CI)10-year RFSall patients74.477.11.02 (0.81–1.30)ER-positive patients75.075.10.91 (0.66–1.27)10-year OSall patients86.886.90.98 (0.72–1.34)ER-positive patients89.987.90.86 (0.54–1.37) Age &amp;lt;50 yearsAge ≥50 yearsER negative1.76 (0.95–3.26)0.93 (0.58–1.51)ER positive1.29 (0.74–2.23)0.76 (0.50–1.16) Conclusion: This study shows that UFT was shown to be non-inferior to CMF in terms of RFS in ER-positive early breast cancer. This result is similar to that of the previous pooled analysis. Sponsor: Taiho Pharmaceutical Co., LTD Citation Format: Yonemori K, Ohsumi S, Takao S, Tokuda Y, Ito Y, Nakagami K, Takahashi M, Yoshidome K, Nakayama T, Yamaguchi Y, Ohashi Y, Inaji H, Watanabe T. Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-09.

Impact of renal function on the efficacy and safety of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer.

301 Background: S-1 is an oral agent consisting of a mixture of tegafur which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyrimidine (DHP) and potassium oxonate. Serum concentration of 5-FU increases in case of renal dysfunction due to decrease of DHP excretion into urine. The aim of this study was to evaluate the influence of renal function to the efficacy and safety of S-1 with concurrent radiotherapy (RT) for locally advanced pancreatic cancer (LAPC). Methods: This study was an integrated exploratory analysis of JCOG1106 and LAPC- S1RT, in which pts with LAPC received RT (50.4Gy/28 fr over 5.5 weeks) and concurrent S-1 (40 mg/m2/dose, bid. on the day of irradiation). Eligibility criteria for this study were pts who received both irradiation and S-1 at least once without induction chemotherapy, and who had creatinine clearance (CCr) ≥ 50 ml/min at the time of registration. We assigned pts into high (≥ 80 ml/min) and low (&lt; 80 ml/min) CCr groups. The primary endpoint was the incidence of ≥ Grade 3 adverse reactions (ARs). Secondary endpoints were the incidence of ≥ Grade 2 gastrointestinal ARs (GI-ARs) defined as anorexia, nausea, vomiting, diarrhea and mucositis oral, relative dose intensity of S-1, CA19-9 response, progression-free survival, and overall survival. Results: Fifty and 59 pts were included in this study from JCOG1106 and LAPC-S1RT, respectively. Median age was 65 years old (range: 31–80), and 57 pts were male. Median CCr was 80.4 ml/min. High CCr group included 57 pts and the median was 97.5 ml/min (range 80.0–194.6), and low CCr group included 52 pts and the median was 64.4 ml/min (range 50.0–78.3). Low CCr group tended to have more ≥ Grade 3 ARs and ≥ Grade 2 GI-ARs compared to high CCr group (30.8% vs. 15.8% and 51.9% vs. 36.8%). However, no evident tendencies were observed in other secondary endpoints. Multivariable analysis showed risk ratio of low CCr group for ≥ G3 ARs was 1.493 [95% CI: 0.710–3.145], although risk ratio of females was 2.486 [95% CI: 1.043–5.924]. Conclusions: Our study indicated that renal dysfunction may increase adverse reactions in the treatment of S-1 with concurrent RT for LAPC, and we should pay attention to renal function and consider for dose reduction.

Capecitabine for the treatment of pancreatic cancer

ABSTRACTIntroduction: Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) which is converted to 5FU by a series of reactions catalyzed by different enzymes, the last of the enzymes being thymidine phosphorylase (TP). TP is found to be elevated in tumor cells in comparison to normal cells, which consequently tumor-localizes the production of 5-FU, thereby limiting its systemic toxicity. Today, capecitabine is extensively used for the treatment of many solid malignancies, with a particular focus in breast and gastrointestinal tumors, but also in pancreatic cancer.Areas covered: This review summarizes the pharmacology and the clinical evidence relevant to the use of capecitabine in the treatment of pancreas cancer. The authors provide, furthermore, provide their expert perspectives on its use.Expert opinion: Capecitabine has the advantage over other therapeutics in so much that it has both convenient oral administration and a favorable toxicity profile. Current data has promised the use of capecitabine in all stages of pancreatic cancer. However, predictive markers for outcome and toxicity remain to be validated.