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Viability of head and neck squamous cell carcinoma HTB-43 cells (closed symbols) and normal human lymphocytes (open symbols) exposed to CAP for 1 h at 37°C and measured by flow cytometry with thiazole orange and PI. Displayed is the mean of three experiments of 5 × 104 measurements each, error bars denote standard deviation, *P < 0.001. The contour diagrams above the plot show results for one representative experiment out of three for each CAP concentration
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The interaction between a chemical and a cell may strongly depend on whether this cell is normal or pathological. Side effects of anticancer drugs may sometimes overcome their benefit action, so it is important to investigate their effect in both the target and normal cells. Capecitabine (Xeloda, CAP), a prodrug of 5-fluorouracil, is mainly used in...
Citations
... The synergistic antiproliferative result of capecitabine and vorinostat justifies the proposal of Di Gennaro and collaborators to implement clinical trials to support this treatment, the hypothesis formulated more than 10 years ago. Wisniewska-Jarosinska et al. mentioned both an effect of free radicals and an increase in the G0/G1 cell population and reduction of the populations in the S phase as factors that support the cyto-and genotoxic effects in head and neck cancer cells and the protection of healthy cells associated with chemotherapy based on capecitabine [21,22]. ...
Capecitabine, an oral pro-drug that is metabolized to 5-FU, has been used in clinical
practice for more than 20 years, being part of the therapeutic standard for digestive and breast
cancers. The use of capecitabine has been evaluated in many trials including cases diagnosed in
recurrent or metastatic settings. Induction regimens or a combination with radiation therapy were
evaluated in head and neck cancers, but 5-FU still remained the fluoropyrimidine used as a part
of the current therapeutic standard. Quantifications of levels or ratios for enzymes are involved
in the capecitabine metabolism to 5-FU but are also involved in its conversion and elimination
that may lead to discontinuation, dose reduction or escalation of treatment in order to obtain the
best therapeutic ratio. These strategies based on biomarkers may be relevant in the context of the
implementation of precision oncology. In particular for head and neck cancers, the identification of
biomarkers to select possible cases of severe toxicity requiring discontinuation of treatment, including
“multi-omics” approaches, evaluate not only serological biomarkers, but also miRNAs, imaging and
radiomics which will ensure capecitabine a role in both induction and concomitant or even adjuvant
and palliative settings. An approach including routine testing of dihydropyrimidine dehydrogenase
(DPD) or even the thymidine phosphorylase (TP)/DPD ratio and the inclusion of miRNAs, imaging
and radiomics parameters in multi-omics models will help implement “precision chemotherapy” in
HNC, a concept supported by the importance of avoiding interruptions or treatment delays in this
type of cancer. The chemosensitivity and prognostic features of HPV-OPC cancers open new horizons
for the use of capecitabine in heavily pretreated metastatic cases. Vorinostat and lapatinib are agents
that can be associated with capecitabine in future clinical trials to increase the therapeutic ratio.
... The synergistic antiproliferative result of capecitabine and vorinostat justifies the proposal of Di Gennaro and collaborators to implement clinical trials to support this treatment, the hypothesis formulated more than 10 years ago. Wisniewska-Jarosinska et al. mentioned both an effect of free radicals and an increase in the G0/G1 cell population and reduction of the populations in the S phase as factors that support the cyto-and genotoxic effects in head and neck cancer cells and the protection of healthy cells associated with chemotherapy based on capecitabine [21,22]. ...
Capecitabine, an oral pro-drug that is metabolized to 5-FU, has been used in clinical
practice for more than 20 years, being part of the therapeutic standard for digestive and breast
cancers. The use of capecitabine has been evaluated in many trials including cases diagnosed in
recurrent or metastatic settings. Induction regimens or a combination with radiation therapy were
evaluated in head and neck cancers, but 5-FU still remained the fluoropyrimidine used as a part
of the current therapeutic standard. Quantifications of levels or ratios for enzymes are involved
in the capecitabine metabolism to 5-FU but are also involved in its conversion and elimination
that may lead to discontinuation, dose reduction or escalation of treatment in order to obtain the
best therapeutic ratio. These strategies based on biomarkers may be relevant in the context of the
implementation of precision oncology. In particular for head and neck cancers, the identification of
biomarkers to select possible cases of severe toxicity requiring discontinuation of treatment, including
“multi-omics” approaches, evaluate not only serological biomarkers, but also miRNAs, imaging and
radiomics which will ensure capecitabine a role in both induction and concomitant or even adjuvant
and palliative settings. An approach including routine testing of dihydropyrimidine dehydrogenase
(DPD) or even the thymidine phosphorylase (TP)/DPD ratio and the inclusion of miRNAs, imaging
and radiomics parameters in multi-omics models will help implement “precision chemotherapy” in
HNC, a concept supported by the importance of avoiding interruptions or treatment delays in this
type of cancer. The chemosensitivity and prognostic features of HPV-OPC cancers open new horizons
for the use of capecitabine in heavily pretreated metastatic cases. Vorinostat and lapatinib are agents
that can be associated with capecitabine in future clinical trials to increase the therapeutic ratio.
... It suffices to say that pyrimidines are structural motifs found in nucleic acids such as thymine, cytosine, and uracil. In addition, there are several established drugs which have a pyrimidine nucleus, including 5-fluoruracil-an anticancer drug ( Figure 23) [59,60]. Recently, an alternative approach was taken in which, instead of using benzaldehyde, benzyl alcohol was utilised. ...
... It suffices to say that pyrimidines are structural motifs found in nucleic acids such as thymine, cytosine, and uracil. In addition, there are several established drugs which have a pyrimidine nucleus, including 5-fluoruracil-an anticancer drug ( Figure 23) [59,60]. ...
... It suffices to say that pyrimidines are structural motifs found in nucleic acids such as thymine, cytosine, and uracil. In addition, there are several established drugs which have a pyrimidine nucleus, including 5-fluoruracil-an anticancer drug ( Figure 23) [59,60]. In a novel method by Nimkar et al., guanidine hydrochloride, aldehydes phenone ( Figure 24) were reacted in the presence of caesium hydroxide supp alumina after mixing for 1 h at room temperature and then refluxing for 4 h. ...
Multicomponent reactions (MCRs) have been gaining significance and attention over the past decade because of their ability to furnish complex products by using readily available and simple starting materials while simultaneously eliminating the need to separate and purify any intermediates. More so, most of these products have been found to exhibit diverse biological activities. Another paradigm shift which has occurred contemporarily is the switch to heterogeneous catalysis, which results in additional benefits such as the reduction of waste and an increase in the safety of the process. More importantly, it allows the user to recover and reuse the catalyst for multiple runs. In summary, both methodologies adhere to the principles of green chemistry, a philosophy which needs to become overarchingly enshrined. The plethora of reactions and catalysts which have been developed gives hope that chemists are slowly changing their ideology. As a result, this review attempts to discuss multicomponent reactions catalysed by operationally heterogeneous catalysts in the past 10 years. In this review, a further distinction is made between the MCRs which lead to the formation of heterocycles and those which do not.
... Apoptosis is a kind of programmed cell death, and its role in the antitumor effect of CAP has been confirmed [16,17]. Induction of T cell apoptosis is one of the classic antirejection mechanisms of immunosuppressants [18][19][20]. ...
Transplant oncology is a newly emerging discipline integrating oncology, transplant medicine, and surgery and has brought malignancy treatment into a new era via transplantation. In this context, obtaining a drug with both immunosuppressive and antitumor effects can take into account the dual needs of preventing both transplant rejection and tumor recurrence in liver transplantation patients with malignancies. Capecitabine (CAP), a classic antitumor drug, has been shown to induce reactive oxygen species (ROS) production and apoptosis in tumor cells. Meanwhile, we have demonstrated that CAP can induce ROS production and apoptosis in T cells to exert immunosuppressive effects, but its underlying molecular mechanism is still unclear. In this study, metronomic doses of CAP were administered to normal mice by gavage, and the spleen was selected for quantitative proteomic and phosphoproteomic analysis. The results showed that CAP significantly reduced the expression of HSP90AB1 and SMARCC1 in the spleen. It was subsequently confirmed that CAP also significantly reduced the expression of HSP90AB1 and SMARCC1 and increased ROS and apoptosis levels in T cells. The results of in vitro experiments showed that HSP90AB1 knockdown resulted in a significant decrease in p-Akt, SMARCC1, p-c-Fos, and p-c-Jun expression levels and a significant increase in ROS and apoptosis levels. HSP90AB1 overexpression significantly inhibited CAP-induced T cell apoptosis by increasing the p-Akt, SMARCC1, p-c-Fos, and p-c-Jun expression levels and reducing the ROS level. In conclusion, HSP90AB1 is a key target of CAP-induced T cell apoptosis via Akt/SMARCC1/AP-1/ROS axis, which provides a novel understanding of CAP-induced T cell apoptosis and lays the experimental foundation for further exploring CAP as an immunosuppressant with antitumor effects to optimize the medication regimen for transplantation patients.
... Both 5-FU and CIS have anti-proliferative and apoptotic properties [6,35,36]. PCNA is a DNA replicationlinked nuclear protein found during cellular division process. This protein plays a role in the initial stages of cellular proliferation by increasing the expression of DNA polymerase [37]. ...
Purpose
The determination on how antineoplastic agents interfere on the progression of periodontitis is critical for improvement and even development of novel therapeutic approaches for periodontal management. This study evaluated the influence of chemotherapy with 5-fluorouracil (5-FU) or cisplatin (CIS) on healthy periodontal tissues and on the progression of experimental periodontitis (EP).
Methods
One hundred forty-four male rats were divided into six groups (n = 24). Each group was treated with physiological saline solution (PSS) 0.9%, 5-FU, or CIS. Experimental periodontitis (EP) was induced by ligature placement. Animals were euthanized at 7, 15, and 30 days after treatment. Data were statistically analyzed (p ≤ 0.05).
Results
The groups with EP and treated with 5-FU or CIS showed lower percentage of bone volume in the furcation region and higher percentage of alveolar bone loss, higher number of TRAP-positive cells, and lower number of PCNA-positive cells when compared group with EP and treated with PSS (p ≤ 0.05). Groups with EP and treated with 5-FU or CIS showed high immunolabelling pattern of RANKL, TNF-α, and IL-1β, moderate of BAX, and low of HIF-1α. Histological analysis showed severe tissue breakdown in the groups with EP and treated with 5-FU or CIS.
Conclusions
Chemotherapy with antineoplastic agents 5-FU and CIS increased the intensity and duration of the inflammation and compromised tissue repair by reduction in cellular and vascular turnover. The more severe periodontal breakdown was caused by 5-FU.
... Exposing the cells to the combination of capecitabine+mocetinostat, on the other hand, led to a substantial increase in wound area ( Figure 5). Capecitabine inhibits DNA synthesis in rapidly proliferating cancer cells and mocetinostat affects apoptosis, but the exact mechanism is unknown (37,38). One of the methods to determine apoptosis is genomic DNA fragmentation. ...
Objectives:
Mouse breast cancer cell line 4T1 can accurately mimic the response to immune receptors and targeting therapeutic agents. Combined therapy has emerged as an important strategy with reduced side effects and maximum therapeutic effect. Mocetinostat (MGCD0103) is one of the members of Class I Histone Deacetylase Inhibitors (HDACi) and its mechanism of action has not been defined, yet. Capecitabine (Xeloda) is an antimetabolite and currently is widely utilized to treat a wide range of solid tumors. The aim of this study was to investigate the effects of the capecitabine, mocetinostat and their combined application on the 4T1 cell line.
Materials and methods:
The effects of combined administration of mocetinostat and capecitabine on 4T1 cells were investigated by cell viability and migration assays, apoptosis analysis, and Western blotting technique.
Results:
The concentrations of drugs that give a half-maximal response (IC50) were detected for capecitabine (1700 µM), mocetinostat (3,125 µM), and 50 µM Capecitabine+1,5 µM Mocetinostat for 48 hr. In capecitabine+mocetinostat combine group, we observed that cell migration decreased, DNA fragmentation increased compared to the control group. capecitabine + mocetinostat group induced apoptosis by decreasing Bcl-2, PI3K, Akt, c-myc protein levels, while increasing Bax, Caspase-3, PTEN, cleaved-PARP, Caspase-7, Caspase-9, p53, cleaved-Cas-9 protein levels in 4T1 cells.
Conclusion:
Capecitabine and mocetinostat played a toxic role through inducing apoptosis on 4T1 cancer cells in a time- and concentration-dependent manner. These results showed that combined therapy with low concentrations were detected to be more effective than that with high-concentration alone drug treatment.
... Both 5-FU and CIS have anti-proliferative and apoptotic properties [6, 35,36]. PCNA is a DNA replication-linked nuclear protein found during cellular division process. ...
Purpose
The determination on how antineoplastic agents interfere on the progression of periodontitis is critical for improvement and even development of novel therapeutic approaches for periodontal management. This study evaluated the influence of chemotherapy with 5-fluorouracil (5-FU) or cisplatin (CIS) on healthy periodontal tissues and on the progression of experimental periodontitis (EP).
Methods
One-hundred-forty-four male rats were divided into six groups (n = 24). Each group was treated with physiological saline solution (PSS) 0.9%, 5-FU or CIS. Experimental periodontitis (EP) was induced by ligature placement. Animals were euthanized at 7, 15 and 30 days after treatment. Data were statistically analyzed (p ≤ 0.05).
Results
The groups with EP and treated with 5-FU or CIS showed lower percentage of bone volume in the furcation region and higher percentage of alveolar bone loss, higher number of TRAP-positive cells and lower number of PCNA-positive cells when compared group with EP and treated with PSS (p ≤ 0.05). Groups with EP and treated with 5-FU or CIS showed high immunolabelling pattern of RANKL, TNF-α, IL-1β, moderate of BAX and low of HIF-1α. Histological analysis showed severe tissue breakdown in the groups with EP and treated with 5-FU or CIS.
Conclusions
Chemotherapy with antineoplastic agents 5-FU and CIS increasing the intensity and duration of the inflammation; and compromising tissue repair by reduction in cellular and vascular turnover. The more severe periodontal breakdown was caused by 5-FU.
... To exemplify how we calculated the probability of drug sensitivity (PDS) (equation (A)), the following drug regimen was considered in the pancreatic adenocarcinoma cohort consisting of 129 patients: capecitabine (cytotoxic chemotherapy agent) + ruxolitinib (targeted agent). For this regimen the predictive biomarkers were MBD4, TYMP, TYMS -, DPYD -(for capecitabine) [36][37][38][39] and JAK1, JAK2, TYK2 (for ruxolitinib). 40 Entering this gene set (which includes all selected biomarkers for all drugs in the regimen) into cBioPortal, 41 we found that 20 patients (20/129 or 15.5% = overall probability of sensitivity) carried at least one marker of sensitivity to the regimen. ...
Predicting oncologic outcome is challenging due to the diversity of cancer histologies and the complex network of underlying biological factors. In this study, we determine whether machine learning (ML) can extract meaningful associations between oncologic outcome and clinical trial, drug‐related biomarker and molecular profile information. We analyzed therapeutic clinical trials corresponding to 1102 oncologic outcomes from 104 758 cancer patients with advanced colorectal adenocarcinoma, pancreatic adenocarcinoma, melanoma and nonsmall‐cell lung cancer. For each intervention arm, a dataset with the following attributes was curated: line of treatment, the number of cytotoxic chemotherapies, small‐molecule inhibitors, or monoclonal antibody agents, drug class, molecular alteration status of the clinical arm's population, cancer type, probability of drug sensitivity (PDS) (integrating the status of genomic, transcriptomic and proteomic biomarkers in the population of interest) and outcome. A total of 467 progression‐free survival (PFS) and 369 overall survival (OS) data points were used as training sets to build our ML (random forest) model. Cross‐validation sets were used for PFS and OS, obtaining correlation coefficients (r) of 0.82 and 0.70, respectively (outcome vs model's parameters). A total of 156 PFS and 110 OS data points were used as test sets. The Spearman correlation (rs) between predicted and actual outcomes was statistically significant (PFS: rs = 0.879, OS: rs = 0.878, P < .0001). The better outcome arm was predicted in 81% (PFS: N = 59/73, z = 5.24, P < .0001) and 71% (OS: N = 37/52, z = 2.91, P = .004) of randomized trials. The success of our algorithm to predict clinical outcome may be exploitable as a model to optimize clinical trial design with pharmaceutical agents.
... Unexpectedly, although IM does not act directly on DNA, in the present study it was found genotoxic probably because, as reported by Fabarius et al. [25], it induces centrosome aberrations in vitro and then genetic instability. The slightly genotoxic potential of CAP could be due to single strand breaks caused by an incomplete synthesis of DNA [26]. Tables 1 and 2 show the results obtained from the evaluation of tail intensity in the Comet assay, expressed as NOAEC (no observable adverse effect concentration) and LOAEC (lowest observable adverse effect concentration) in comparison to the respective chronic toxicity data reported by Parrella et al. [6], expressed as NOEC and LOEC. ...
The eco-genotoxicity of six anti-neoplastic drugs, 5-fluorouracil, capecitabine, cisplatin, doxorubicin, etoposide, and imatinib, belonging to five classes of anatomical therapeutic classification (ATC), was studied applying the in vivo comet assay on cells from whole organisms of Daphnia magna and Ceriodaphnia dubia. For the first time, this test was performed in C. dubia. In addition, to have a wider genotoxic/mutagenic profile of the anticancer drugs selected, SOS chromotest and Salmonella mutagenicity assay were performed. The comet results showed that all drugs induced DNA damage, in both Cladocerans, with environmental concern; indeed Doxorubicin induced DNA damage in the order of tens of ngL(-1) in both crustaceans, as well as 5-flurouracil in C. dubia and cisplatin in D. magna. In the SOS Chromotest all drugs, except imatinib, were able to activate the repair system in Escherichia coli PQ37 while in the Salmonella mutagenicity assay, doxorubicin was the only drug able to cause direct and indirect frameshift and base-pair substitution mutations. Comet assay was the most sensitive tool of genotoxic exposure assessment, able to detect in vivo the adverse effects at concentration lower than those evaluated in vitro by bacterial assays.
Copyright © 2015. Published by Elsevier B.V.
... In a phase III study, combination of capecitabine plus gemcitabine improved objective response rate and progression free survival when compared with gemcitabine alone, associated with a trend toward to improve overall survival (p ¼ 0.08) [56]. Capecitabine induces apoptosis in HTB-43 cells (a human larynx cancer cell line) in a dose dependent manner, not affecting human lymphocyte control cells [57]. The combination of capecitabine with vorinostat (a histone deacetylase inhibitor) seems to synergistically increase the apoptotic rate in colorectal cancer cells, probably through up-regulation of thymidine phosphorilase [58]. ...
Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2-3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs.
