Administration Of Capecitabine Research Articles

Effect of electroacupuncture of "Zusanli" (ST36) combined with capeOX on apoptosis and ferroptosis in nude mice with colorectal cancer.

To investigate the impact of combined treatment of colorectal cancer (CRC) with electroacupuncture (EA) and capeOX (combined administration of fluorouracil, oxaliplatin and capecitabine) on the tumor volume, weight, spleen coefficient, apoptosis and ferroptosis of tumor tissue, and liver and kidney functions in nude mice with CRC, so as to explore its mechanisms underlying inhibiting CRC and alleviating toxic reactions of capeOX. Female Balb/c nude mice were randomly assigned to 3 groups：model, capeOX, and EA+capeOX, with 8 nude mice in each group. The CRC model was established by subcutaneous injection of colon cancer cells at the right inguinal region. Nude mice of the capeOX group received intraperitoneal injection of oxaliplatin for 1 day and gavage of capecitabine from day 2 to day 7. EA (1 mA, 2 Hz/100 Hz) was applied to bilateral "Zusanli" (ST36) for 20 min, once daily for 7 days. During the interven-tion, the tumor volume and weight were measured every day, and at the end of intervention, the weight of the tumor tissue and spleen were measured, with tumor volume difference and spleen coefficient calculated. The proportion of apoptotic cells was measured by flow cytometry, and the contents of serum malondialdehyde (MDA), alanine aninotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were detected using ELISA. The expression level of glutathione peroxidase 4 (GPX4, a key regulator for ferroptosis) protein of the tumor tissue was determined using Western blot. Compared to the model group, both the capeOX group and EA+capeOX group showed a decrease in the tumor volume (on day 3 and 4 in the capeOX group, and from day 2 to 7 in the EA+capeOX group) and body weight (P<0.05, on day 3 to 7 in the EA+capeOX group and on day 2 to 7 in the capeOX group), being evidently lower in the tumor volume on day 7 in the EA+capeOX than in the capeOX group (P<0.05), and evidently higher in the body weight on day 6 and 7 in the EA+capeOX group than in the capeOX group (P<0.05). In comparison with the model group, the tumor volume difference, tumor weight and spleen coefficient in both capeOX and EA+capeOX groups were significantly decreased (P<0.05), and MDA content in EA+capeOX group was significantly decreased (P<0.05), while the contents of ALT, BUN and Cr in the capeOX group, the proportion of apoptotic cells in both capeOX and EA+capeOX groups, and the GPX4 expression level in the EA+capeOX group were all significantly increased (P<0.05). The tumor volume difference, tumor weight, and contents of MDA, ALT, AST, BUN and Cr in the EA+capeOX group were markedly lower than in the capeOX group (P<0.05), while the spleen coefficient, proportion of apoptotic cells and GPX4 expression level in the EA+capeOX group were markedly higher than those in the capeOX group (P<0.05). EA of ST36 can enhance the effect of capeOX in inhibiting colorectal cancer growth in nude mice with CRC, which may be related with its functions in promoting tumor cell apoptosis, inhibiting ferroptosis, and modulating immune tolerance. In addition, EA can lower the side effects of capeOX in hematopoietic and immune, liver, and kidney functions.

Dihydromyricetin reverses capecitabine-induced peripheral myelin dysfunction through modulation of oxidative stress.

Previous clinical reports have shown that capecitabine, an oral prodrug of 5-fluorouracil (5-Fu), can induce peripheral neuropathy, resulting in numbness, paresthesia and hypoesthesia. However, the mechanism through which capecitabine causes peripheral nerve injury remains unclear. Here, we demonstrate that systemic administration of capecitabine leads to myelin abnormalities in the peripheral nerves of mice, which are possibly attributed to the death of Schwann cells, the myelinating cells in the peripheral nervous system. Furthermore, our results show that 5-Fu induces significant oxidative stress in Schwann cells by inhibiting the expression of the anti-oxidative protein DJ-1, leading to a decrease in Schwann cell markers. We found that the anti-oxidant dihydromyricetin (DMY) reverses 5-Fu-induced Schwann cell death and oxidative stress and alleviates capecitabine-induced myelin abnormalities. Taken together, our data indicate that capecitabine induces peripheral myelin dysfunction by regulating DJ-1-mediated oxidative stress in Schwann cells and reveal DMY as a potential therapeutic strategy for capecitabine-induced peripheral neuropathy.

The effect of melatonin on capecitabine-induced hepatic and renal toxicity in rats.

Capecitabine (CAPE), an antimetabolite chemotherapy, can induce hepatic and renal toxicity. Melatonin (MEL), a neurohormone, possesses antioxidant, anti-apoptotic and anti-inflammatory effects. This study investigated the impact of MEL on capecitabine-induced hepatic and renal toxicity. Twenty-five male Wistar rats were categorized into five groups for the study. The groups included a control group, MEL10 group (rats receiving daily intraperitoneal injections of 5mg/kg MEL), CAPE 500 group (rats receiving weekly intraperitoneal injections of 500mg/kg CAPE), CAPE + MEL five group, and CAPE + MEL 10 group. All groups were treated for a duration of 6 weeks. Various hematological, serological, biochemical, and histopathological assessments were conducted to evaluate the objective of the study. The administration of CAPE led to significant liver and kidney toxicity, as evidenced by elevated levels of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), as well as serological markers including AST, ALT, ALP, BUN, and creatinine. CAPE exposure also resulted in a reduction in total antioxidant capacity (TAC) and glutathione peroxidase (GPx) levels. Histological examination revealed hyperemia in both liver and kidney tissues exposed to CAPE. However, treatment with MEL demonstrated positive effects. MEL administration alleviated oxidative stress, reduced levels of liver enzymes, BUN, and creatinine, and ameliorated histopathological degenerations. MEL also increased GPx and TAC levels. Moreover, MEL treatment aided in restoring the body weight that was lost due to CAPE exposure. Our findings indicated that the administration of MEL in rats significantly enhanced the hepatic and renal toxicity induced by CAPE.

Acupoint massage combined with Traditional Chinese Medicine soaking therapy and nursing of a patient with hand-foot syndrome caused by oral administration of capecitabine for colorectal cancer

Acupoint massage combined with Traditional Chinese Medicine soaking therapy and nursing of a patient with hand-foot syndrome caused by oral administration of capecitabine for colorectal cancer

Physiologically Based Pharmacokinetic Modeling for Prediction of 5-FU Pharmacokinetics in Cancer Patients with Hepatic Impairment After 5-FU and Capecitabine Administration.

5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment. Models including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment. The PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes' activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics. PBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios.

Baicalein prevents capecitabine-induced heart damage in female Wistar rats and enhances its anticancer potential in MCF-7 breast cancer cells

AimWe investigated the ability of baicalein (BAI) to enhance the anticancer potential of capecitabine (CAP) in the MCF-7 cell line and its protective effect on CAP-induced cardiotoxicity in female Wistar rats. Methods and key findingsIn vitro study involved evaluating the effect of BAI and/or CAP on cell viability, cell cycle progression, and BAX and Bcl2 gene expression in MCF-7 cells. Co-treatment of BAI with CAP significantly reduced the viability of MCF-7 cells, improved their cytotoxic effect, markedly elevated the percentage of the sub-G1 population, drastically reduced the G2/M population, and significantly altered the mRNA expression of BAX and Bcl2 genes compared with each treatment alone. In vivo study revealed that the oral administration of CAP (140 mg/kg BW) to adult female rats significantly elevated the levels of serum creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β and cardiac TNF-α, IL-1β malondialdehyde (MDA) concentration, whereas it reduced the serum and cardiac total antioxidant capacity (TAC), level of cardiac glutathione (GSH) and activity of glutathione peroxidase (GPx) with a vast array of circulatory, inflammatory, degenerative, and necrotic alterations in the cardiac tissue. Furthermore, CAP administration significantly upregulated the mRNA expression of NF-κB, TLR4, MyD88, ATF6, CHOP, and JNK genes. Concurrent administration of BAI (200 mg/kg BW) and CAP significantly improved the biochemical alterations and cardiac oxidant/antioxidant status and architecture. In addition, it modulated the TLR4/MyD88/NF-κB pathway and endoplasmic reticulum stress. SignificanceAltogether, BAI can augment the anticancer potential of CAP and alleviate its cardiotoxic effects during cancer treatment.

Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice.

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (5'DFCR), 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5'DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, Cmax and AUC0-6h values of 5'DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5'DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.

Breast Reconstruction Outcomes with Immediate Reconstruction Followed by Proton or Photon Postmastectomy Radiotherapy

<h3>Purpose/Objective(s)</h3> To evaluate breast reconstruction outcomes among women undergoing immediate breast reconstruction (IBR) followed by postmastectomy radiotherapy (PMRT) with photon or proton radiotherapy. <h3>Materials/Methods</h3> We identified consecutive women with breast cancer who underwent IBR followed by unilateral PMRT at our institution from 2015 to 2021 and retrospectively reviewed reconstruction complications. IBR failure was defined as tissue expander or implant removal with loss of reconstruction or conversion to autologous reconstruction. Patient, disease, and treatment characteristics were assessed for association with complications using univariate Cox models. When analyzing the impact of RT-related variables, only complications occurring after the start of RT were included. <h3>Results</h3> Following IRB approval, 225 women were identified as eligible. One-hundred seventy-five (77.8%) elected to undergo prophylactic mastectomy and IBR for symmetry. Two-hundred eighteen patients (96.9%) had two-stage tissue expander-based IBR, and seven (3.1%) had direct-to-implant IBR. One-hundred sixty women (71.1%) were treated with proton therapy. Most (198, 88%) received 50 Gy in 25 fractions, with the remainder receiving 40.05 Gy in 15 fractions (25, 11.1%) or 42.56 Gy in 16 fractions (2, 0.9%). Seven (3.1%) and 28 patients (12.4%) received a boost to the chest wall and lymph node(s), respectively. At a median follow-up of 1.8 years, the 2-year risk of any complication on the irradiated side was 31.4% (24.4-38.3). This is compared to a contralateral risk of 15.0% (9.4-21.7) among the 175 bilateral mastectomy patients. Seventeen patients (7.6%) experienced an ipsilateral IBR failure, six of whom had no final reconstruction. The remaining 11 patients had an autologous reconstruction, two of whom initially planned for autologous reconstruction. There were no contralateral IBR failures. On univariate analysis, increasing age [HR per year: 1.10 (1.05-1.15), <i>p</i><.001], chest wall boost [HR: 4.81 (1.08-21.35), <i>p</i>=.039], and lymph node boost [HR: 3.97 (1.35-11.63), <i>p</i>=.012] were associated with IBR failure. There was no significant difference in IBR failure with protons compared to photons. Administration of capecitabine concurrently with RT predisposed to any complication [HR: 7.97 (1.91-33.33), <i>p</i>=.040], while use of Mepitel film during PMRT was protective [HR for no Mepitel: 1.85 (1.12-3.06), <i>p</i>=.017]. Receipt of neoadjuvant or adjuvant systemic therapy and concurrent T-DM1 were not associated with complications or IBR failure. <h3>Conclusion</h3> Among women who undergo IBR, receipt of PMRT increases the risk of complications by approximately twofold. To our knowledge, this is the largest report on women receiving IBR and proton-based PMRT. There was no difference in IBR failure with protons compared to photons. Despite nearly one-third experiencing complications with IBR and PMRT, most women (92.4%) achieved a successful reconstruction outcome.

Tumor Volume Regression of Rectal Cancer in Daily MRI during Preoperative Chemoradiotherapy with Capecitabine

<h3>Purpose/Objective(s)</h3> Although cone beam computed tomography (CBCT) has been available for over a decade, the pattern of tumor volume change in rectal cancer during preoperative concurrent chemoradiotherapy (CCRT) has been under the veil due to poor soft tissue contrast of registration CBCT. This study was conducted to investigate daily rectal tumor volume change using registration magnetic resonance imaging (MRI). <h3>Materials/Methods</h3> Patients diagnosed with cT3-4 and/or cN+ rectal adenocarcinoma undergoing preoperative CCRT with capecitabine on the pelvis up to 50 Gy in 25 daily fractions from November 2018 to June 2019 were consecutively included. Rectal tumor volume was uniformly measured by single physician (YKK) in daily 0.35T MRI obtained with MR-guided linear accelerator. The mean +/- standard deviation (SD) of daily tumor volume (cc), difference of tumor volume between first fraction and daily fraction (baseline tumor volume at first fraction – daily tumor volume), and tumor volume reduction rate (%, [baseline tumor volume at first fraction – daily tumor volume]/baseline tumor volume at first fraction x 100) were calculated. Statistical significance of differences were tested using the Wilcoxon's signed rank test and paired t-test. <h3>Results</h3> Twenty patients were included. Median age was 64 and majority of the patients were male (90%). Most tumors were T3 (70%) and N1-2 (95%). Tumors were located median 6.9 cm (range: 1 – 12) above anal verge. Median follow-up was 32 months (range: 2.5 – 36.8) and 4 patients had recurred at the time of analysis (2 local and 2 distant). Tumor volume steadily regressed with daily administration of CCRT (mean 2.47 +/- 4.46 cc; Figure 1). Significant tumor volume reduction compared to baseline was observed from 4^th fraction (mean 13.95 +/- 17.78 cc; <i>P</i> < 0.0001). The difference of tumor volume between baseline and the last fraction was mean 46.62 +/- 56.01 cc (<i>P</i> < 0.0001). The tumor volume reduction rate was significantly increased since 4^th fraction (mean 16.64 +/- 10.9 %; <i>P</i> < 0.0001). The tumor volume reduction rate at the last fraction was – 68.18 +/- 15.68 % (<i>P</i> < 0.0001). <h3>Conclusion</h3> For the first time, this study demonstrated daily tumor volume regression in preoperative rectal CCRT with capecitabine using daily MRI. Steady pattern of tumor regression may be explained in part by daily administration of capecitabine. Based on the hypothesis-generating observation, this study may warrant initiation of further investigations on rectal tumor volume change with CCRT using daily MRI.

КОМБИНИРОВАННОЕ ЛЕЧЕНИЕ РАКА ПРЯМОЙ КИШКИ С ИСПОЛЬЗОВАНИЕМ ДВУХКОМПОНЕНТНОЙ РАДИОМОДИФИКАЦИИ В СХЕМАХ НЕОАДЪЮВАНТНОЙ ЛУЧЕВОЙ ТЕРАПИИ НА ФОНЕ ЛЕКАРСТВЕННОЙ ТЕРАПИИ

Purpose: to evaluate the effectiveness of a “short” course of neoadjuvant radiation therapy using two radio modifiers with different mechanisms of radio-modulating action together with a drug therapy. Material and methods: To increase the effectiveness of radiation therapy there was created a variant of combined treatment of patients with rectal cancer, using the concept of polyradiomodification. Two radio modifiers have been applied (local microwave hyperthermia and intrarectal Metronidazole administration as part of a polymer composition) together with neoadjuvant radiation therapy and oral administration of Capecitabine, followed by surgical intervention 4–6 weeks after the end of radiation therapy. For intrarectal delivery of Metronidazole to the tumor, a new medical device was created, which is a biopolymer composition in the form of a hydrogel with a Metronidazole substance physically immobilized in it (RF Patent No. 2007139304, 2007). Results: The study included 520 patients, of whom 114 underwent a new variant of combined treatment with modulation of the effect of irradiation with two different radiomodifiers together with a drug therapy (group-1), 193 patients underwent only single-mode radiation therapy (group-2), and 213 patients underwent a combination of radiation therapy with local microwave hyperthermia (group-3). Toxic manifestations in group-1 was diagnosed in 38 (33,3 %) of 114 patients, general toxic manifestations of the III degree – in 13 (11,4 %) of 114. Postoperative complications in the group-1 was observed in 21 (18,4 %) of 114 patients, which was significantly less than in the group-2 and group-3, where they occurred in 78 (40,4 %) of 193 (p=0,0001) and in 78 (36,6 %) of 213 (p=0,0006). With a median follow-up of 54,6 months. relapses of cancer in the group-1 was not detected in any of 114 patients, which is significantly less than in the group-2, in which cancer relapses were diagnosed in 17 (8,8 %) of 193 patients (p=0,0011), and in the group-3, where they were detected in 10 (4,7 %) of 213 patients (p=0,0188). This made it possible to increase the number of sphincter-preserving operations performed in the group-1 to 84,2 %, which is significantly more compared to 53,4 % in the group-2 (p=0,00001) and 56,8 % in the group-3 (p=0,00001). It was also possible to significantly increase the rate of five-year relapse-free survival in the group-1 up to 82,9 % compared to 65,3 % at group-2 (p=0,01106) and 61,1 % at group-3 (p=0,00276). Conclusion: The treatment option using polyradiomodification is effective in improving local antitumor control of the disease and increasing relapse-free survival rates compared to other combined treatment options.

A dynamic multiple reaction monitoring strategy to develop and optimize targeted metabolomics methods: Analyzing bile acids in capecitabine-induced diarrhea

ObjectiveWe sought to develop and optimize a targeted bile acids (BAs) metabolomics method based on a dynamic multiple reaction monitoring (dMRM) strategy and explored the dynamic alterations of BAs in diarrhea induced by capecitabine in a mouse model. MethodThe targeted metabolomics method was developed using an Agilent 6460A triple quadrupole mass spectrometer, and 41 types of BAs were monitored in negative ionization mode. The mass spectrometer detection was optimized using dMRM to enhance the responses, separation, and peak shape and to shorten the analysis time. A mouse model of diarrhea was established by multiple administration of capecitabine, and plasma samples were collected at baseline and the end of drug administration for subsequent BAs analysis. ResultsThe targeted BA metabolomics method achieved shorter chromatographic separation time (10 min) for 41 BAs, with good peak shapes and response increases of 3- to 10-fold after application of dMRM. The mouse model of capecitabine-induced diarrhea was established, and the three BAs 23-norcholic acid, isolithocholic acid, and isodeoxycholic acid in the baseline samples contributed the most to differentiating mice with diarrhea from those without diarrhea. For mice that ultimately developed diarrhea, apocholic acid, isodeoxycholic acid, and 7-ketodeoxycholic acid exhibited the largest change in concentrations compared with their baseline concentrations. ConclusionThe dMRM strategy has obvious advantages compared with common MRM. The results in model mice showed that a differentiated profile of BAs in the baseline may indicate biomarkers of diarrhea induced by capecitabine, and disturbed homeostasis may explain the metabolomic mechanism of diarrhea occurrence.

A phase Ib, open-label, multi-cohort study of metronomic capecitabine plus camrelizumab for treatment of refractory solid tumor: McCrest trial.

e16079 Background: The efficacy of immune checkpoint inhibitors (ICIs) monotherapy for refractory solid tumor is relatively poor. Combination therapy is an effective strategy to improve its efficacy. Metronomic chemotherapy that can modulate tumor immunomicroenvironment is a potential partner for ICIs, which is also well-tolerated and low-cost. Methods: This was a phase Ib, open-label, single-center, multi-cohort study designed to evaluate the safety and efficacy of camrelizumab combined with metronomic capecitabine for refractory solid tumors. Patients who were disease progression after standard treatment could be enrolled. PD-L1 status was not compulsory. Capecitabine was administrated orally at 500mg bid every day, with camrelizumab at 200mg IV on Day 1 of a 14-day cycle. Primary endpoint was adverse events (AEs). Secondary endpoints including progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR). The exploratory endpoint was also set to identify the potential molecular alterations during treatment by liquid biopsy analysis. Results: As of December 12, 2021, 19 patients were enrolled including gastric cancer (8), esophageal cancer (6), pancreatic cancer (2), cholangiocarcinoma (2) and duodenal cancer (1). Ten patients had 2 or more prior lines of therapy. The common treatment-related AEs including reactive cutaneous capillary endothelial proliferation (10/19), fatigue (9/19), leukemia (5/19), anemia (5/19), hyponatremia (4/10) and blood bilirubin increased (4/19). Grade 3 AEs including fatigue (2/19) and bronchitis (1/19), and no grade 4 AEs was observed. Three patients suffered severe AEs, including bowel perforation (1), bowel obstruction (1) and bleeding (1), which were all treatment unrelated. There were 4 patients still under treatment, and median number of treatment cycle was 4 (1-16 cycles). The median PFS and OS was 2.1 months (95%CI 1.9-2.3 months) and 5.1 months (95%CI 1.6-8.5 months) respectively. Partial response was observed in 1 esophageal cancer patient with PD-L1 TPS &lt; 1. For 12 patients with assessable lesions, the DCR was 41.6% (5/12). Peripheral blood samples were collected during treatment, and molecular alterations after administration of metronomic capecitabine and camrelizumab were under analysis. Conclusions: The combination of metronomic capecitabine plus camrelizumab was well tolerated in patients with refractory solid tumors. Its efficacy should be assessed in further study. Clinical trial information: NCT04508686, NCT04510818, NCT04932187.

Facile construction of dual-drug loaded nanoparticles for improvement synergistic chemotherapy in prostate cancer

Recently, functionalized materials have been extensively investigated and reported as drug delivery carriers. Furthermore, many groups have concentrated their efforts on establishing unique and effective therapeutic modalities, such as photothermal and photodynamic therapy, which have displayed promising anticancer ability. In the suggested techniques, the described treatments demonstrated better cooperative behavior and the capacity to substitute for the negative effects of traditional monotherapy. Herein, we developed a thermosensitive dual-targeting drug delivery system traction to improve the administration of capecitabine and two photosensitizers (indocyanine green (ICG) and methylene blue (MB). Capecitabine and photosensitizers were incorporated into nanoparticles using the thin film hydration process. Meanwhile, the dynamic identification of tumor cells may be achieved by modifying the targeted peptide cRGD and the folate targeting molecule coated on the surface of the nanoparticles. According to DLS experiments, the fabricated nanoparticles possessed an excellent dispersive index and a homogeneous size of ∼103.12 nm. Compared to free nanoparticles, the nanoparticles demonstrated dose-dependent in vitro cytotoxic properties in DU145 and PC3 cells. Based on the results examined from a confocal laser scanning microscope, the modified nanoparticles were more efficiently endocytosed by DU145 cancer cells compared to PC3 cells. On DU145 cells, the photothermal conversion-triggered release of drug and phototherapies resulted in an apoptotic rate of ∼80%. Additionally, the apoptosis cell death mechanism was displayed that the nanoparticles significantly induce apoptosis in the DU145 and PC3 cancer cells. The impressive findings concluded that the developed delivery system had put in a lot of work and established many changes to achieve precise interaction and provide a potential prostate cancer treatment strategy.

Repurposing the PDMA-approved drugs in Japan using an insect model of staphylococcal infection.

A total of 1253 compounds approved as therapeutic drugs in Japan (Pharmaceuticals and Medical Devices Agency (PMDA)-approved compounds) were screened for their therapeutic effects against Staphylococcus aureus infection using the silkworm infection model. In the first stage of screening with an index of prolonged survival, 80 compounds were identified as hits. Of these, 64 compounds were clinically used as antimicrobial agents, and the remaining 16 compounds were not. The 16 compounds were examined for their dose-dependent therapeutic effects on the silkworm model as a second screening step, and we obtained five compounds as a result. One of the compounds (capecitabine) had no documented in vitro minimum inhibitory concentration (MIC) value against S. aureus. The MIC value of capecitabine against S. aureus strains ranged from 125 to 250µg/ml, and capecitabine was therapeutically effective at a dose of 200mg/kg in a murine model of S. aureus infection. These results suggest that silkworm-based drug repositioning studies are of potential value. Furthermore, the therapeutic effects of capecitabine demonstrated in this study provide an important scientific rationale for clinical observational studies examining the association between staphylococcal infection events and capecitabine administration in cancer chemotherapy patients.

Clinical pharmacokinetics of capecitabine and its metabolites in colorectal cancer patients

BackgroundCapecitabine is one of the fluoropyrimidine anticancer agents which is extensively used in the management of colorectal cancer. We have noticed a discrepancy between the doses we are using in our patients and the recommended dosing regimen. Thus, this study aims to assess the pharmacokinetic parameters of capecitabine and its metabolites in colorectal cancer patients and report some clinical outcomes. MethodsThis study is a prospective observational pharmacokinetic study. It was conducted at the Oncology Center at King Saud University Medical City. The study included adult patients who received capecitabine for any stage of colorectal cancer. Blood samples were collected following the oral administration of capecitabine. Capecitabine and its metabolites concentration in plasma were determined using HPLC and pharmacokinetic parameters were estimated using PKanalix software. ResultsThe study included 30 colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1. 60 % of the patients were in stage IV. The average total daily dose was 1265 ± 350 mg/m2/day. Cmax for capecitabine was 5.2 ± 1.3 μg/ mL and Tmax was 1 ± 0.25 h. AUClast for capecitabine was 28 ± 10 μg.h/ mL. Vdobs and Clobs for capecitabine were 186 ± 28 L and 775 ± 213 mL/min, respectively. Calculated half-life (t1/2) was 2.7 h. Half of our patients showed partial tumor response and 20% showed stable disease. Only two patients had to discontinue the treatment because of the toxicity. ConclusionDespite using lower doses, capecitabine and its metabolites parameters were found to be similar to previous studies except for the longer half-life found in our patients. In addition, lower doses of capecitabine showed acceptable response rate which might indicate that higher doses are not always necessary to achieve desired therapeutic effect.

Abstract P3-10-02: Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic breast cancer

Abstract Purpose Capecitabine is one of a treatment option in anthracycline and taxane pre-treated metastatic breast cancer (MBC) patients. We have performed miRNA microarray of durable and poor responders to capcitabine, and compared with cell line miRNA expression profile (MCF-7, tamoxifen-resistant MCF-7 [MCF-TAM] cell line treated with 5-FU. Methods Between Jan 2006 to Jan 2021, 66 patients treated with capecitabine after anthracycline and taxane failure were enrolled. Twenty-three archival tumor tissues (11 durables and 12 poor responders, each) were collected and went through nCounter miRNA expression assay. MCF-7, tamoxifen resistant MCF-7 (MCF-TAM) cell line was treated with tamoxifen or 5-FU for proliferation assay and also went through nCounter miRNA expression assay. Results HR positive patients who received anti-estrogen treatment before capecitabine showed longer PFS (median 7.7 vs. 4.03 months, P=0.006). MCF-7 treated with tamoxifen and 5-FU showed decreased proliferation compared to 5-FU treated MCF-7. There was significant difference of miR-579-3p expression between durable and poor responders (log2FC -3.02, P=0.004). Tamoxifen-treated MCF-7 cell line showed upregulation of miR-579-3p compared to MCF-7. Tamoxifen + 5-FU treated MCF-7 cell line showed decreased expression of miR-579-3p compared to 5-FU treated MCF-7 cell line. MCF-7 cell line was treated with 5-FU and miR-579-3p. Compared to 5-FU only treated cell line, 5-FU + miR-579-3p treated cell line showed trends for decreased cell proliferation, suggesting that miR-579-3p may have chemo-sensitizing role during systemic chemotherapy. Based on miRNA database, authors hypothesized that MDM2 may be target protein of miR-579-3p and planning to perform further analysis. Conclusions Anti-estrogen treatment before capecitabine administration was associated to better survival in HR positive MBC. Anti-estrogen potentiated the effect of 5-FU in MCF-7. MiR-579-3p was upregulated in durable responders and tamoxifen treated MCF-7 cell line. Further study is planned to analyze the role of miR-579-3p and its potential target, MDM2 in breast cancer. Citation Format: Jieun Lee, Seung Yeon Joe, Ji-Sun Lee, Dong-Min Kim, Ahwon Lee. Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-10-02.

P38 MAPK, NF-κB, and JAK-STAT3 Signaling Pathways Involved in Capecitabine-Induced Hand-Foot Syndrome via Interleukin 6 or Interleukin 8 Abnormal Expression.

Hand-foot syndrome (HFS) is a major adverse reaction to capecitabine (CAP). The exact pathogenesis of this disease remains unclear. In this study, metabolomics combined with cell RNA sequencing was used to study the mechanisms of CAP-induced HFS. The murine model of HFS was constructed by intragastric administration of CAP or its metabolites. Quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays were used to verify the mechanisms. Metabolomics showed the phosphatidylinositol signaling pathway and amino acid and fatty acid metabolism to be the major metabolic alterations related to the occurrence of HFS. Transcriptomics profiles further revealed that the cytokine-cytokine receptor interaction, IL17 signaling pathway, Toll-like receptor signaling pathway, arachidonic acid metabolism, MAPK signaling pathway, and JAK-STAT3 signaling pathway were the vital steps in skin toxicity induced by CAP or its metabolites. We also verified that the inflammation mechanisms were primarily mediated by the abnormal expression of interleukin (IL) 6 or IL8 and not exclusively by COX-2 overexpression. Finally, the P38 MAPK, NF-κB, and JAK-STAT3 signaling pathways, which mediate high levels of expression of IL6 or IL8, were identified as potential pathways underlying CAP-induced HFS.

An open-label, multicenter, randomized controlled study of mXELIRI versus FOLFIRI in combination with bevacizumab as the first-line treatment in metastatic colorectal cancer: A single-center report.

52 Background: The first-line treatments in metastatic colorectal cancer were FOLFOX, CAPOX, FOLFIRI and even FOLFOXIRI as basic chemotherapy regimen combined with targeted therapy. XELIRI regimen was not recommended because of the concerns about the toxicity, efficacy and controversy in optimal dosage. An increasing number of studies indicated promising efficacy with manageable safety profile of dosage and administration-adjusted XELIRI regimen. Therefore, the present study investigated the efficacy, safety and appropriate dosage of mXELIRI regimen in the first-line treatment of advanced colorectal cancer. Methods: The EXIST study was a multicenter, randomized controlled, non-inferiority study and we performed stratification based on the tumor location (left or right side). In the mXELIRI+Bev group, patients received intravenous infusion of irinotecan (a reduced dosage,150mg/m2) with bevacizumab (5mg/kg) on day 1 and oral administration of capecitabine (2000mg/m2/day) tablet on day 1-10/Q14 days. Patients in FOLFIRI+Bev group received intravenous infusion of irinotecan (180mg/m2), calcium folinate (400mg/m2) and 5-Fu (400mg/m2) bolus with bevacizumab (5mg/kg) on day 1 followed by a 46-hour continuous infusion of 5-Fu (2400mg/m2)/Q14 days. The primary endpoint was progression-free survival rate at 12 month(PFSR12m) and the secondary endpoints included ORR,OS and safety. Results: 142 patients were enrolled and randomly assigned to receive mXELIRI+Bev (n=76) or FOLIRI+Bev (n=66) in our center between May 2018 and April 2021. Baseline characteristics were well balanced between two groups. In the mXELIRI+Bev group, 70 patients were evaluable with an ORR of 60.0% (1 complete response, CR; 41 partial response, PR; 24 stable disease, SD; 4 progression disease PD). While 57 patients were evaluable in the FOLFIRI+Bev group, with an ORR of 63.2% (36 PR; 15 SD; 6 PD). The PFSR12m for two groups were 32.3% and 21.3%, the median PFS were 9.72 months and 8.77 months, respectively. For safety profiles, no statistical differences were observed in adverse events, such as nausea, vomiting, diarrhea, bone marrow suppression and abnormal liver function. While 10 serious adverse events were recorded in the mXELIRI+Bev group, including intestinal obstruction occurred in 8 patients, intestinal perforation occurred in 1 patients and venous thrombosis occurred in 1 patient. In the FOLIRI+Bev group, intestinal obstruction, venous thrombosis and pulmonary thrombosis was reported in one patient respectively. Conclusions: The modified biweekly XELIRI plus bevacizumab regimen demonstrated promising effect and could be well tolerated based on the data from a single center. Clinical trial information: NCT04247984.

Randomized phase II study of nalicap (nal-IRI/capecitabine) compared to NAPOLI (nal-IRI/5-FU/LV) in gemcitabine-pretreated advanced pancreatic cancer: Trial-in-progress.

TPS621 Background: Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and folinic acid (LV), called the NAPOLI regimen, improves survival in advanced pancreatic cancer patients who failed gemcitabine-based chemotherapy (Wang-Gillam A et al. 2016). Capecitabine is an oral anti-cancer agent as the prodrug of 5-FU. Capecitabine has proven its efficacy in gastrointestinal cancers like stomach cancer, colon cancer, or pancreatic cancer. Replacing continuous 5-FU infusions with oral capecitabine with equivalent efficacy has been tested and is now widely used. However, in pancreatic cancer, replacing continuous infusion of 5-FU with an oral drug has not yet been tested. Therefore, this trial is being conducted with the aim of improving patient convenience while maintaining efficacy, when the continuous infusion of 5-FU/LV in NAPOLI (nal-IRI/5-FU/LV) regimen are replaced with oral capecitabine. This study is a two-arm, open-label, multicenter, randomized phase 2 trial to assess whether capecitabine plus nal-IRI combination treatment (NaliCap) is non-inferior to NAPOLI regimen in gemcitabine-pretreated patients with advanced pancreatic cancer. Methods: Eligible patients have histologically confirmed pancreatic adenocarcinoma who have failed to gemcitabine-based chemotherapy. This trial is composed of two parts: safety lead-in-part and randomization part. NaliCap regimen consists of administration of capecitabine twice daily for day 1-14 and intravenous administration of nal-IRI for day 1 every 3weeks. To figure out recommended phase 2 dose of the NaliCap combination regimen, the safety lead-in-part is being conducted as a 3+3 design. In the randomization part, patients will be assigned to NAPOLI or NaliCap in a 1:1 ratio. The planned enrollment is 184 patients in the randomization part. Patients allocated to the NaliCap group will receive recommended phase 2 dose of NaliCap determined through the safety lead-in-part. Patients allocated with the NAPOLI group will receive nal-IRI 70mg/m2 intravenously day 1, LV 400mg/m2 IV day 1, and continuous 5-FU 2400mg/m2 infusion over 48hours every 2weeks. Response assessments are performed every 6 weeks using the RECIST criteria version 1.1 (every 2 cycles in the NaliCap group and every 3 cycles in the NAPOLI group). The primary endpoint is progression-free survival, with a non-inferior margin of the hazard ratio of 1.4. Key secondary endpoints are overall response rate, disease control rate, overall survival, safety, and quality of life. This study is prospectively registered at ClinicalTrials.gov, NCT04371224. Clinical trial information: NCT04371224.

Tumor volume regression of rectal cancer in daily MRI during preoperative chemoradiotherapy with capecitabine.

123 Background: Although cone beam computed tomography (CBCT) has been available for over a decade, the pattern of tumor volume change in rectal dancer during preoperative concurrent chemoradiotherapy (CCRT) has been under the veil due to poor soft tissue contrast of registration CBCT. This study was conducted to investigate daily rectal tumor volume change using registration magnetic resonance imaging (MRI). Methods: Patients diagnosed with cT3-4 and/or cN+ rectal adenocarcinoma undergoing preoperative CCRT with capecitabine on the pelvis up to 50 Gy in 25 daily fractions from November 2018 to June 2019 were consecutively included. Rectal tumor volume was uniformly measured by single physician (YKK) in daily 0.35T MRI obtained with ViewRay MRIdian Linac (ViewRay Inc., Oakwood, USA). The mean +/- standard deviation (SD) of daily tumor volume (cc), difference of tumor volume between first fraction and daily fraction (daily tumor volume – baseline tumor volume at first fraction), and tumor volume reduction rate (%, (daily tumor volume – baseline tumor volume at first fraction)/baseline tumor volume at first fraction x 100) were calculated. Statistical significance of differences were tested using the Wilcoxon’s signed rank test and paired t-test. Results: Thirteen patients were included. Median age was 65 and majority of the patients were male (92.3%). Most tumors were T3 (76.9%) and N1-2 (92.3%). Tumors were located median 6 cm (range: 2.4 – 9) above anal verge. Median follow-up was 27.3 months (range: 11.7 – 30.6) and 2 patients had recurred at the time of analysis (1 local and 1 distant). Tumor volume steadily regressed with daily administration of CCRT (mean 2.06 +/-1.73 cc; Figure 1). Significant tumor volume reduction compared to baseline was observed from fourth fraction (mean -12.37 +/- 16.72 cc; P &lt; 0.0005). The difference of tumor volume between baseline and the last fraction was mean -49.33 +/- 68.13 cc ( P &lt; 0.0002). The tumor volume reduction rate was significantly increased since fourth fraction (mean - 17.2 +/- 11.78 %; P &lt; 0.0002). The tumor volume reduction rate at the last fraction was - 70.62 +/- 14.01 % ( P &lt; 0.0001). Conclusions: For the first time, this study demonstrated daily tumor volume regression in preoperative rectal CCRT with capecitabine using daily MRI. Steady pattern of tumor regression may be explained in part by daily administration of capecitabine. Based on the hypothesis-generating observation, this study may warrant initiation of further investigations such as analysis and comparison with daily tumor volume regression with CCRT using leucovorin and 5-FU.