Combination Of 5-fluorouracil Research Articles

5-Fluorouracil and Curcumin Combination Coated with Pectin and Its Strategy towards Titanium Dioxide, Dimethylhydrazine Colorectal Cancer Model with the Evaluation of the Blood Parameters.

Colorectal cancer is considered the third most common cancer and the second leading cause of death globally. It has been proven that titanium dioxide nanoparticles produce oxidative stress and can lead to chronic inflammation, which could turn into diseases like cancer, cardiovascular disorders, diabetes, and so on. To evaluate the effect of 5-fluorouracil (5-FU) curcumin (CUR) conjugate coated with pectin on colorectal cancer induced by titanium dioxide nanoparticles (TiO2-NPs) and dimethylhydrazine (DMH), male rats were administered TiO2-NPs (5 mg/kg) orally and DMH (1 mg/kg) peritoneally for 70 days and treated with 5-FU (60 mg/kg) and CUR (240 mg/kg) conjugate (1:4 ratio) coated with pectin. The bodyweight of the animals was evaluated, and the blood sugar level was calculated. Further blood and plasma analyses were conducted. Hematological parameters, antioxidant parameters, and biochemical estimation were taken into consideration. The TiO2-NPs level in the blood and colorectal region was also calculated. With the induction of colon cancer using TiO2-NPs and DMH, a significant increase in the body weight of the animals was seen; eventually, with treatment, it was reduced. The bodyweight increase was due to an increase in the blood sugar level. There were also significant changes in the hematological parameters and biochemical estimation reports when comparing those of the positive control, negative control, and treated groups. No significant effect on biochemical estimation reports was seen. Conclusions: These reports suggest that 5-FU CUR conjugate coated with pectin helps in the management of colorectal cancer induced by TiO2-NPs and DMH.

Efficacy and Safety of Concurrent Chemoradiotherapy with Docetaxel for Locally Advanced Breast Carcinoma after Modified Radical Mastectomy

Background: Breast cancer is a common term for a malignant tumor that arises from the epithelial component of the breast. Concurrent chemoradiotherapy’s efficacy and safety are controversial, considering the impact on patients' quality of life. Objectives: The aim of this study was investigating the efficacy and safety of concurrent chemoradiotherapy with docetaxel in locally advanced breast cancer who have received a modified radical mastectomy. Methods: A cohort of 110 female patients with locally advanced breast cancer were included in the present study and divided by chemoradiotherapy mode into a concurrent chemoradiotherapy group (n=58) and a sequential chemoradiotherapy group (n=52). Docetaxel was administered concurrently during radiotherapy in the concurrent group, whereas the sequential group underwent adjuvant radiotherapy 1-3 weeks after chemotherapy. Then, the two groups were compared with respect to clinical efficacy, levels of tumor markers across vascular endothelial growth factor (VEGF) and Carcinoembryonic antigen (CEA), adverse reactions, and the 3-year overall survival (OS) rate. Results: The results showed that the mean age, operation, evaluation of Post treatment VEGF (pg / mg) and Post treatment CEA (/g / L), effectiveness of treatment in two sequential and concurrent treatment groups was not significant The results showed that the amount of Prior treatment VGEF (pg / mg) and Post treatment VGEF (pg / mg) in the two groups were statistically significant difference. Which shows the positive effect of this treatment before and after the intervention. Comparison of survival time in the two groups did not show a significant difference. Conclusion: The chemotherapy protocol with a combination of cyclophosphamide, fluorouracil and epirubicin with concurrent docetaxel presented higher efficacy and prolonged the overall survival in locally advanced breast cancer patients who had undergone a radical mastectomy, while it did not significantly increase the toxicity.

Is topical 5-fluorouracil or combination 5-fluorouracil and cryotherapy more effective than cryotherapy alone for the treatment of actinic keratosis?

Is topical 5-fluorouracil or combination 5-fluorouracil and cryotherapy more effective than cryotherapy alone for the treatment of actinic keratosis?

The Brown University Oncology Group Experience With FOLFOX + Nab-paclitaxel [FOLFOX-A] for Metastatic and Locally Advanced Pancreatic, BrUOG-292 and BrUOG-318.

Objectives:To evaluate response rate, toxicity, and efficacy of the novel combination of nab-paclitaxel, oxaliplatin, 5-fluorouracil, and leucovorin [FOLFOX-A] in patients with advanced pancreatic ductal adenocarcinoma [PDAC].Methods:BrUOG-292 and BrUOG-318 were two concurrently run, prospective, single-arm phase II studies evaluating FOLFOX-A as first-line therapy in patients with metastatic and locally advanced/borderline resectable PDAC respectively. The FOLFOX-A regimen consisted of 5-fluorouracil, 1200 mg/m2/d as a continuous intravenous (IV) infusion over 46 hours, leucovorin 400 mg/m2 IV, oxaliplatin 85 mg/m2 IV, and nab-paclitaxel 150 mg/m2 IV on day 1 every 14 days up to a maximum of 12 cycles. Patients with locally advanced or borderline resectable disease were permitted to stop treatment after 6 cycles and receive radiation therapy and/or surgical exploration if feasible. The primary end point was overall response rate [ORR]. Secondary end points were median progression-free survival [PFS], median overall survival [OS], and safety.Results:Seventy-eight patients with previously untreated PDAC were enrolled between June 2014 and November 2019; 76 patients were evaluable. The median follow-up was 40 months and 32 months, respectively. overall response rate was 34%. Among the patients enrolled on BrUOG-292 [48 patients], the PFS was 5 months and OS was 11 months, respectively. For those enrolled on BrUOG 318 [28 patients], the PFS was 11 months and OS was 22 months. Treatment-related toxicities included grade 3 fatigue [40%], diarrhea [14%], and neuropathy [2%].Conclusions:The combination of FOLFOX-A has promising activity in PDAC and may represent an alternative to FOLFIRINOX when reduction of gastrointestinal toxicity is required.

Formulation of two lipid-based membrane-core nanoparticles for FOLFOX combination therapy.

FOLFOX is a combination of folinic acid (FnA), 5-fluorouracil (5-Fu) and oxaliplatin (OxP). It has been used as the standard treatment for colorectal cancer (CRC) and hepatocellular carcinoma (HCC). This treatment is effective, but its high toxicity is dose limiting, and the drugs need to be taken for a long time. To lower the toxicity so that higher doses can be administered with minimal side effects, two lipid-based membrane-core (MC) nanoformulations, Nano-Folox and Nano-FdUMP, have recently been developed by using the nanoprecipitation technique. The combination of Nano-Folox (containing platinum drug and FnA) and Nano-FdUMP (containing fluorine drug) significantly improves the antitumor effect against CRC and HCC relative to FOLFOX (the combination of free drugs), resulting in long-term survival of animals without significant toxic signs. Here, we describe two formulation protocols. First, for Nano-Folox, a Pt(DACH)•FnA nanoprecipitate is formed by [Pt(DACH)(H2O)2]2+ (the active form of OxP) and FnA2-, and the resultant nanoprecipitate is encapsulated inside the lipid nanoparticles (NPs) modified with the PEGylated aminoethyl anisamide (AEAA, a targeting ligand for sigma-1 receptor overexpressing on CRC and HCC). Second, for Nano-FdUMP, FdUMP (the active metabolite of 5-Fu) is entrapped inside the amorphous Ca3(PO4)2 nanoprecipitate, and the resultant Ca3(PO4)2•FdUMP nanoprecipitate is encapsulated into the AEAA-targeted PEGylated lipid NPs. The procedures for Nano-Folox and Nano-FdUMP take ~17 h and ~4 h, respectively (~17 h if they are prepared simultaneously). Procedures for the physicochemical (~30 h) and cytotoxic (~54 h) characterization are also described.

Class III β-Tubulin Expression Is of Value in Selecting nab -Paclitaxel and Gemcitabine as First-Line Therapy in Unresectable Pancreatic Cancer.

Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III β-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response. We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration. High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS. Class III β-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.

Effects of CMF and MET on glutamate and dopamine levels in the brain, and their impact on cognitive function.

Chemotherapy can cause cognitive impairment in cancer survivors. CMF, the combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU), is employed for the treatment of several types of cancers, such as metastatic breast cancer. Metformin (MET) is an antidiabetic medication used to treat type 2 diabetes that can reportedly alleviate some toxic effects. In the current study, we investigated the ability of MET to alleviate the effects of CMF in neuronal toxicity. Rats were treated with two doses of CMF (intraperitoneal injection) and MET (in the daily drinking water). Rats were subjected to fear conditioning memory tests to evaluate memory function following treatment, and brain samples were collected and homogenized using neuronal lysis buffer for assessment of glutamate and dopamine levels by high-performance liquid chromatography (HPLC). Fear conditioning memory tests revealed a significant reduction in memory function in CMF and CMF+MET groups vs. controls, but no significant change in MET groups vs. controls was detected. Similarly, CMF and CMF+MET groups revealed a significant increase in glutamate and dopamine levels in the brain of MET, CMF, and MET+CMF groups vs. controls based on HPLC results. In addition, although glutamate and dopamine levels were increased, levels varied between groups, with highest levels in the CMF+MET group. Our results demonstrate that cognitive impairment in CMF and CMF+MET groups could result from increased glutamate and dopamine levels in the brain, leading to brain toxicity and failure of MET to alleviate the toxic effects of CMF.

Synergistic Role of Thymoquinone on Anticancer Activity of 5-Fluorouracil in Triple Negative Breast Cancer Cells.

Triple Negative Breast Cancer (TNBC) is considered as the most deadly subtype of breast cancer, because of heterogeneity, less treatment options and resistance to chemotherapy. To find out an efficient chemotherapeutic options, in this study we have investigated the combined therapy of 5-Fluorouracil (5-FU) and thymoquinone (TQ) against TNBC cell lines BT-549 and MDA-MB-231. We have tested 5-FU and TQ alone and in combination (5-FU + TQ) to observe the cellular growth, cell cycle and apoptosis status of BT-549 and MDA-MB-231 cells. Also we have measured the mRNA level expression of genes related to cell cycle and apoptosis. Experimental results suggest that both of 5-FU and TQ are effective in controlling cell growth, cell cycle and inducing apoptosis, but their combination is much more effective. 5-FU was found to be more effective in controlling cell growth, while TQ was found to be more effective in inducing apoptosis, but in both cases, their combination was most effective. TQ was found more effective in increasing and BAX/BCL-2 ratio, while 5-FU was more effective in inhibiting thymidylate synthase. They showed significant increasing effects on caspases and P53 and decreasing effect on CDK-2, where their combination was found most effective. Thus, TQ and 5-FU probably showed synergistic effect on both of cell cycle and apoptosis of tested TNBC cell lines. Our study reveals that TQ can synergise 5-FU action, and increase its anticancer efficiency against TNBC cells, which might be good choice in drug development for TNBC treatment.

Synergistic combination of PMBA and 5-fluorouracil (5-FU) in targeting mutant KRAS in 2D and 3D colorectal cancer cells

β-Boswellic acid (β-BA), a potent NF-kB signaling pathway inhibitor, has shown synergistic anti-cancerous activity (NCT03149081, NCT00243022 and NCT02977936) in various clinical trials as complementary therapies. The study has been conducted to investigate the effect and efficacy of 2-pyridin-4-yl methylene β-boswellic acid (PMBA) and 5-Flourouracil (5-FU) in combination therapy for the treatment of KRAS mutant colon cancer. Analysis of isobologram showed synergistic combination index (CI > 1) of PMBA and 5-FU against the HCT-116G13D and SW-620G12V cell lines. The growth-inhibiting PMBA also caused apoptosis mediating effects with dose-dependent increase in caspase-3 activity, while inhibiting the formation of colonies in combination with 5-FU. As evident, PMBA affected colorectal 3D CSC properties including the ability to self-renew along with the expression of multi-drug resistance genes, viz., ABCB1, ABCC1 and ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and CSC markers like CD44, CD166, EPCAM, OCT-4, SOX-2, and NANOG compared with those in 2D model explaining the expression pattern of oncogenic KRASG13D, G12V mutation. When examined for plasma level of PMBA (20 mg) and PMBA+5-FU (20 + 40 mg), a time-dependent increase in the level of the drug (5-FU) was detected, indicating its absorption and bioavailability with excellent half-life of the PMBA for both routes of administration (IV and Oral), thereby indicating a new adjuvant therapy for KRAS mutant colon cancer.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

A Spectacular Response to the Docetaxel Cisplatin Fluorouracil (TPF) Protocol as Induction Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Lower Lip: A Case Report

Background: Oral-mucosal squamous cell carcinoma (omSCC) is a substantially more aggressive disease that affects the oral mucosa, tongue, floor of mouth, and oropharynx, where it is estimated that between 18.6% and 44% of patients present with nodal disease depending on the subsite. As the lip is a site of anatomical overlap, primary squamous cell carcinoma of the lip (lip SCC) exhibits higher rates of nodal spread, mortality, and poor clinical outcome compared with cutaneous SCC. For patients with locally advanced OSCC, rapid advancements regarding the choice of induction chemotherapy regimen have been made. There is substantial evidence related to the advantage and superiority of three-drug combination of Docetaxel, Cisplatin, and Fluorouracil (TPF) over the doublet regime of Cisplatin and Fluorouracil (PF) used previously as induction chemotherapy (ICT). Case presentation: A 54 years Moroccan women old, who has been accusing, for more than a year, of a neglected painful tumefaction of the lower lip. The clinical examination finds a budding and ulcerous tumefaction of the lower lip and a biopsy of his lip lesion was scheduled. Histopathology report poorly differentiated squamous cell carcinoma. Assessment of extension showed bilateral cervical lymphadenopathy and no distant locations. After a multidisciplinary discussion, the decision was to propose a conservative treatment, namely concurrent radio chemotherapy after induction chemotherapy made of the TPF protocol. The evaluation after 03 cycles of the protocol shows an almost complete disappearance of the apparent tumor with a good tolerance profile. Conclusion: Many analysis demonstrate a statistically significant reduction in locoregional recurrence amongst patients who received Induction chemotherpay despite that she has never provided an improvement to OS for OSCC patients. In the present case, chemotherapy with docetaxel, cisplatin and fluorouracil regimens is considered as an effective induction therapy ...

Modified docetaxel, cisplatin, and 5-fluorouracil combination regimen and capecitabine maintenance in metastatic gastric cancer: toxicity and efficacy results.

Little progress has been made, and there is an unmet medical need for treatment of metastatic gastric cancer (MGC). Docetaxel + cisplatin + 5-fluororacil (DCF) combination is an effective regimen with high rate of toxicity and is not well tolerated. We aimed to evaluate the efficacy and toxicity of a modified DCF (mDCF) combination regimen and capecitabine maintenance in MGC. Data of MGC patients were treated with first-line mDCF regimen (two weekly docetaxel 60mg/m2 day 1 iv, cisplatin 50mg/m2 day 1 iv, 5-fluouracil 400mg/m2 day 1 iv push, 2400mg/m2; day 1-day 2 iv infusion, leucovorin 400mg/m2 day 1 iv push) were recorded. Capecitabine maintenance was given as 2500mg/m2/ day 1-day 14 po, every 3weeks, to patients who do not have progressive disease and grade 3 treatment-related toxicity. A retrospective analysis was made. Forty patients were included. Mean age was 53 ± 11. Thirty-two patients had de novo metastasis. All patients' performance status was ECOG 1 or 2 (32/8). Median number of mDCF cycles given was 9 (min-max: 1-23). Overall response rate was 47.5%. Ten patients (25%) received capecitabine maintenance. Grade 3/4 toxicity was seen in 20 patients (50%). Hematologic grade 3/4 toxicity occurred in 13 patients (32.5%), and grade 3/4 neutropenia occurred in 11 patients (27.5%) and in 15 cycles. Nonhematologic grade 3/4 toxicity was seen in 7 patients (17.5%). Median follow-up time was 17.2months. Median time to progression (TTP) was 10.8 ± 1.9months (95% CI: 6.89-14.64). Median overall survival was 14.7 ± 1.73months (95% CI: 11.30-18.10). mDCF protocol was a tolerable chemotherapy regimen for the first-line treatment of MGC with higher ORR and longer TTP compared to standard DCF protocol. Capecitabine maintenance might increase TTP.

Elucidating the mechanism underlying cognitive dysfunction by investigating the effects of CMF and MET treatment on hippocampal neurons.

Chemotherapy causes long-term cognitive impairment in cancer survivors. A combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) (i.e., CMF) is widely used for cancer treatment. Metformin (MET), an oral antidiabetic drug, confers protection against the adverse effects of chemotherapeutic agents, such as CYP. To elucidate the potential mechanism underlying cognitive dysfunction, we investigated the impact of CMF and MET treatment on the activities of mitochondrial respiratory chain complexes I and IV, as well as lipid peroxidation, in hippocampal neurons. Hippocampal neurons (H19-7) cells were treated for 24 h with MET (0.5 mM) alone; CYP (1 µM), MTX (0.5 µM), and 5-FU (1 µM); and MET (0.5 mM) + CYP (1 µM), MTX (0.5 mM), and 5-FU (1 µM). A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay was performed to evaluate cell survival. Neurons were collected and homogenized in a neuronal lysis buffer to assess mitochondrial complexes (I and IV) activity and lipid peroxidation. Compared to the control, MET-treated cells showed no significant difference in survival rate; however, CMF- and CMF + MET-treated cells showed a significant reduction in survival rate. In addition, relative to the control, CMF- and CMF + MET-treated cells showed a reduction in mitochondrial complex I activity, whereas no significant changes were observed in mitochondrial complex IV activity. MET-treated cells showed no significant differences in lipid peroxidation, but CMF- and CMF + MET-treated cells showed a slight increase in lipid peroxidation. The reduction in the activity of mitochondrial complex I and a slight increase in lipid peroxidation levels may explain the cognitive impairment following CMF and MET treatments.

Transfersome Hydrogel Containing 5-Fluorouracil and Etodolac Combination for Synergistic Oral Cancer Treatment.

Oral cancer is one of the most common malignancies with an increased rate of incidence. 5-Fluorouracil (5FU) is an effective chemotherapeutic indicated for oral cancer treatment. Etodolac (Et), a cyclooxygenase-2 inhibitor, can be used as an adjuvant agent to sensitize cancer cells to chemotherapy. The aim of this work was to prepare and characterize 5FU and Et dual drug-loaded transfersomes to treat oral cancer. Transfersomes were prepared by thin-film hydration method and characterized for the average particle size and zeta-potential using dynamic light scattering and scanning electron microscopy techniques. The prepared transfersomes were further characterized for their drug loading, entrapment efficiencies using amicon centrifuge tubes and drug release behavior using cellulose membrane. The synergistic activity of dual drug-loaded transfersomes was studied in FaDu oral cancer cells. Results showed that the average particle size, polydispersity index, and zeta potential were 91±6.4 nm, 0.28±0.03, and (-)46.9±9.5 mV, respectively, for 5FU- and Et (1:1)-loaded transfersomes. The highest encapsulation efficiency achieved was 36.9±3.8% and 79.8±6.4% for 5FU and Et (1:1), respectively. Growth inhibition studies in FaDu cells using different concentrations of 5FU and Et showed a combination index of 0.36, indicating a synergistic effect. The FaDu cell uptake of drug-loaded transfersomes was significantly (p<0.05) greater than that of free drugs. The transfersome hydrogel made of HPMC (2% w/w) showed similar flux, lag time, and permeation coefficient as that of drug-loaded transfersomes across excised porcine buccal tissue. In conclusion, 5FU and Et transfersome hydrogel can be developed for localized delivery to treat oral cancer.

FOLFIRINOX as First-line Chemotherapy in Japanese Patients Suffering from Metastatic Pancreatic Cancer (KOBE FOLFIRINOX Study)

Background/Aim: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) combination chemotherapy is the gold-standard therapy for advanced pancreatic cancer. In this study, FOLFIRINOX dosages for Japanese patients were established enabling FOLFIRINOX therapy optimization for efficient use. Patients and Methods: Patients with advanced pancreatic cancer were treated with varying doses of FOLFIRINOX to determine the optimum dosage for highest remission outcomes with the least post-chemotherapy toxicities. Results: Patients given 180 mg of irinotecan and a 400 mg bolus of 5-fluorouracil (5-FU) showed a marked difference in outcome when compared to irinotecan 180 mg given without the 5-FU bolus, with the overall response rate being 28%, a survival time of 6.4 months and progression-free survival time of 4.5 months. Conclusion: The optimum dose of FOLFIRINOX was a dosage combination of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, l-leucovorin 400 mg/m2 and 5-FU 2,400 mg/m2, administered as a continuous 46-h infusion.

Drug treatment for chemotherapy-induced peripheral neuropathy in patients with pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease where most tumors are too advanced at diagnosis for resection, leaving chemotherapy as the mainstay of treatment. Although the prognosis of unresectable PC is poor, it has been dramatically improved by new chemotherapy treatments, such as the combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel. However, as oxaliplatin and paclitaxel are common neurotoxic drugs, chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse effect of both treatments. As there are no agents recommended in the ASCO guidelines, we review the methods used to treat CIPN caused by PC treatment. The efficacy of duloxetine was observed in a large randomized controlled trial (RCT). In addition, pregabalin was more effective than duloxetine for CIPN in two RCTs. Although duloxetine and pregabalin can be effective for CIPN, they have several side effects. Therefore, the choice between the two drugs should be determined according to effect and tolerability. Mirogabalin is also used in patients with PC and there is hope it will yield positive outcomes when treating CIPN in the future.

Efficacy Analysis of Trastuzumab Combined With FLOT as Neoadjuvant Treatment of Human Epidermal Growth Factor Receptor 2 Positive Advanced Gastric Cancer

This research aims to assess the efficacy of neoadjuvant trastuzumab with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel for the treatment of human epidermal growth factor receptor 2 positive metastatic gastric cancer. To conduct the research, we recruited 80 patients having human epidermal growth factor receptor 2 positive advanced gastric cancers between January 2020 and December 2021 admitted to our institution and randomly allocated them to the control and observation groups, each with 40 cases. Patients in the 5-fluorouracil, leucovorin, oxaliplatin and docetaxel group served as controls, while those in the observation group underwent a combination of trastuzumab and 5-fluorouracil, leucovorin, oxaliplatin and docetaxel. The short-term curative outcome of patients after neoadjuvant therapy was evaluated; the levels of carcinoembryonic antigen, serum glycoprotein 19-9 and glycoprotein (carcinoembryonic antigen 72-4) were measured by chemiluminescence immunoassay. Side effects experienced by patients in both groups were recorded when they occurred during therapy. The disease control rate and objective response rate of the observation group were found to be statistically and clinically higher than those of the control group (p<0.05), per the findings of the short-term effectiveness assessment. After treatment, there was a notable reduction in serum carcinoembryonic antigen, carcinoembryonic antigen 19-9 and carcinoembryonic antigen 72-4 in both groups (both p<0.05) and the levels of carcinoembryonic antigen 72-4, carcinoembryonic antigen 19-9 and carcinoembryonic antigen in the observation group were considerably lower than the control group (p<0.05). There was no evident difference between the two patient groups in adverse reactions. Trastuzumab combined with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel has high efficacy and safety in neoadjuvant therapy for human epidermal growth factor receptor 2-positive advanced gastric cancer patients and it can be popularized and applied as a new model of clinical treatment.

BIX-01294 enhances the effect of chemotherapy on colorectal cancer by inhibiting the expression of stemness genes

During the development of colorectal cancer, tumor cells will generate some cancer stem cells with self-renewal ability because they adapt to the environment. Therefore, in the treatment of colorectal cancer, it has certain potential clinical application value to effectively inhibit cancer stem cells. A small molecule EHMT-2 inhibitor, BIX-01294, was evaluated for its activity in inhibiting cancer stem cells in human colorectal cancer by in vitro and in vivo experiments. Transcriptome analysis was performed on BIX-01294 treated cells for holistic analysis to elucidate how BIX-01294 inhibits the expression of genes related to cancer stem cells. The results show that BIX-01294 significantly inhibited the proliferative phenotype of human colorectal cancer in vivo and in vitro, reduced the proportion of cancer stem cells, and inhibited some stemness-related gene. Morever, it is synergistic with 5-fluorouracil in inhibiting the proliferation of colorectal cancer. In summary, EHMT-2 is a novel target of anti-tumor drugs. The combination of BIX-01294 and 5-fluorouracil has a synergistic therapeutic effect on human colorectal cancer.

Mirogabalin vs pregabalin for chemotherapy-induced peripheral neuropathy in pancreatic cancer patients

BackgroundThe prognosis of pancreatic cancer (PC) has been improved by new chemotherapy regimens (combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP)). Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of these two regimens. The efficacy of pregabalin for CIPN has been reported in previous studies. However, the efficacy of mirogabalin for CIPN remains unknown. Thus, in this study, we aimed to clarify which drug (mirogabalin or pregabalin) was more valuable for improving CIPN.MethodsA total of 163 PC patients who underwent FOLFIRINOX or GnP between May 2014 and January 2021 were enrolled. Among them, 34 patients were diagnosed with CIPN. Thirteen patients were treated with mirogabalin (mirogabalin group), and twenty-one patients were treated with pregabalin (pregabalin group). Treatment efficacy was compared between the two groups.ResultsIn both the mirogabalin group and the pregabalin group, the grade of patients with CIPN at 2, 4, and 6 weeks after the initiation of treatment showed significant improvement compared to the pretreatment grade. Notably, the rate of CIPN improvement was higher in the mirogabalin group than in the pregabalin group (2 weeks: 84.6% (11/13) vs 33.3% (7/21), P value = 0.005; 4 weeks, 6 weeks: 92.3% (12/13) vs 33.3% (7/21), P value = 0.001).ConclusionsAlthough both mirogabalin and pregabalin were effective at improving CIPN, mirogabalin might be a suitable first choice for CIPN in PC patients.Trial registrationNot applicable

The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress.

Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC. Using an unbiased reverse-phase protein array, we detected phospho-activation of heat shock protein 27 (Hsp27) as the most up-regulated event after FIRINOX treatment in PDAC cells. Silencing HSP27 by RNA interference or by a small-molecule inhibitor enhanced apoptosis caused by FIRINOX in vitro. Mechanistically, FIRINOX up-regulated tumor necrosis factor–α (TNFα), causing autocrine phosphorylation and activation of transforming growth factor–β–activated kinase 1 (TAK1), MAPK activated protein kinase 2 (MAPKAPK2 or MK2), and, ultimately, Hsp27. Targeting MK2, the kinase that directly phosphorylates Hsp27, abrogated Hsp27 activation, sensitized PDAC cells to apoptosis, and suppressed SN-38–induced protective autophagy in vitro, in part by blocking phospho-activation of Beclin1. In an autochthonous PDAC mouse model, the MK2 inhibitor ATI-450 decreased PDAC development and progression. When combined with FIRINOX, ATI-450 eliminated most PDAC foci and marked prolonged mouse survival without causing additional toxicity. Last, we found that high phospho-MK2 expression in tumors was associated with poorer survival of patients with PDAC. Our study identified MK2 as a mediator of genotoxic stress–induced activation of prosurvival pathways and provides preclinical support for combining an MK2 inhibitor with FIRINOX-based chemotherapies to treat PDAC.