Oxaliplatin(OXA)can be used as a palliative treatment for advanced hepatocellular carcinoma(HCC).While most patients still have rapid disease progression after OXA due to the drug resistance.The lactate dehydrogenase ...Oxaliplatin(OXA)can be used as a palliative treatment for advanced hepatocellular carcinoma(HCC).While most patients still have rapid disease progression after OXA due to the drug resistance.The lactate dehydrogenase A(LDHA)inhibitors can reduce the inflammation-induced effects,metastasis,and proliferation potential of cancer cells.Here,we adopt the water-in-oil attractive Pickering emulsion gel(APEG)to deliver OXA and LDHA inhibitor,GSK2837808A(GSK).OXA is dissolved in water and GSK is dissolved in iodized oil.This drugs-loaded APEG has good biocompatibility and can release OXA and GSK slowly.OXA+GSK@gel has significant anti-tumor effect on HCC model,which can effectively inhibit tumor cell proliferation and promote tumor cell apoptosis.Meanwhile,flow analysis confirm that it could activate the tumor immune microenvironment in HCC.The infiltration of CD8^(+)T cells is increased,thereby providing better anti-tumor effect.The results suggest that the APEGs loaded with OXA and GSK can effectively improve the delivery efficiency and enhance the anti-tumor therapy.展开更多
BACKGROUND Drug-induced lung injury is a common adverse effect of chemotherapeutic agents.Diffuse alveolar hemorrhage(DAH)is a fatal complication associated with druginduced lung injury.Early diagnosis and treatment o...BACKGROUND Drug-induced lung injury is a common adverse effect of chemotherapeutic agents.Diffuse alveolar hemorrhage(DAH)is a fatal complication associated with druginduced lung injury.Early diagnosis and treatment of DAH is critical,as delayed management can lead to respiratory failure and poor outcomes.However,the diagnosis of DAH is difficult because of the nonspecific clinical manifestations;as such,bronchoscopy is necessary to establish a diagnosis.CASE SUMMARY The patient presented with fever and dry cough.He had been receiving fluoropyrimidine and oxaliplatin therapy for esophageal squamous cell carcinoma.Chest imaging revealed diffuse ground-glass opacities.Bronchoscopy with bronchoalveolar lavage was performed,which confirmed the diagnosis of DAH.Although the patient’s respiratory status rapidly worsened,high-dose corticosteroid therapy with respiratory support gradually improved the patient’s condition and he was successfully extubated.CONCLUSION Prompt DAH diagnosis and bronchoscopy in patients receiving oxaliplatincontaining chemotherapy presenting with acute respiratory failure are critical for improving outcomes.展开更多
BACKGROUND Keratin 80(KRT80),a type I intermediate filament protein,is a member of the keratin family with specialized functions in epithelial tissues.While KRT80 has been implicated in both normal physiological proce...BACKGROUND Keratin 80(KRT80),a type I intermediate filament protein,is a member of the keratin family with specialized functions in epithelial tissues.While KRT80 has been implicated in both normal physiological processes and various diseases,its role in gastric cancer(GC),particularly its expression and prognostic significance,remains poorly understood.In this study,we investigated the role and underlying molecular mechanisms of KRT80 in oxaliplatin resistance in GC.Our analysis revealed that KRT80 is significantly upregulated in GC tissues and is associated with poor clinical prognosis.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.AIM To explore the expression of KRT80 in GC and its impact on the prognosis of patients.METHODS KRT80 expression in GC tissues was analyzed using Western blotting,quantitative reverse transcription PCR,multiple immunofluorescence staining,and immunohistochemistry.Survival analysis was conducted using the Kaplan-Meier method with the log-rank test.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.Immunoprecipitation and mass spectrometry analyses identified elongation factor 1-alpha 1(EEF1A1)as a binding protein of KRT80.RESULTS Integrating our experimental findings with multiple published studies,we found that increased KRT80 expression is associated with poor prognosis in GC and promotes resistance to oxaliplatin.Moreover,we have preliminarily verified the interaction between KRT80 and EEF1A1.Therefore,this study provides a novel perspective on overcoming oxaliplatin resistance in GC.CONCLUSION Increased KRT80 expression predicts poor prognosis and promotes oxaliplatin resistance in GC,suggesting its potential as a novel prognostic biomarker.展开更多
Chiral anticancer drugs are the subject of ongoing research due to their optical characterization and pharmacological effects.Achieving a single enantiomer of a chiral anticancer drug is arduous,but it can significant...Chiral anticancer drugs are the subject of ongoing research due to their optical characterization and pharmacological effects.Achieving a single enantiomer of a chiral anticancer drug is arduous,but it can significantly improve its pharmacokinetics for tumor therapy.Here,the chiral nanocatchers,known as Dbiotin-P5■MCC NCs,were designed and prepared based on host-vip self-assembly between D-biotin anchored pillar[5]arene(D-biotin-P5)and myristoyl chloride choline(MCC).D-Biotin-P5■MCC NCs featuring the chiral separation and enzyme-induced disassemble were evaluated for their ability to selectively capture and subsequently target the release of(R,R)-OXA enantiomers into tumor cells.Furthermore,the use of D-biotin-P5■MCC NCs has demonstrated a significant enhancement in the intracellular uptake of OXA,with the drug being efficiently released to MCF-7 breast cancer cells.This has led to a superior inhibitory effect on MCF-7 cells when compared to free OXA,while also reducing the cytotoxicity of the drug in HEK 293 human embryonic kidney cells.This research not only paves a promising way for the fabrication of chiral supramolecular nanocarriers but also holds the potential to improve the processes of chiral drug separation and targeted therapy.展开更多
BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To stu...BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.展开更多
BACKGROUND Gastric signet ring cell carcinoma(GSRC)is a distinctive type of gastric cancer.It is a mucus-secreting adenocarcinoma that may progress to distant metastasis at an early stage.Because of poor differentiati...BACKGROUND Gastric signet ring cell carcinoma(GSRC)is a distinctive type of gastric cancer.It is a mucus-secreting adenocarcinoma that may progress to distant metastasis at an early stage.Because of poor differentiation,aggressive invasion,rapid progre-ssion,and other high-risk characteristics,early surgical intervention should be prioritized.AIM To explore the clinical efficacy of fluorouracil(5-FU)combined with paclitaxel and oxaliplatin for the treatment of advanced GSRC.METHODS A total of 85 patients with advanced GSRC were selected between January 2020 and June 2021 and randomly divided into a control group(n=42,receiving standard chemotherapy)and a treatment group(n=43,receiving monotherapy with oxaliplatin,5-FU,and paclitaxel).Patients in the treatment group received a 135 mg/m2 infusion of paclitaxel for 3 hours,a 400 mg/m2 infusion of calcium folate(or 200 mg/m2 of levocalcium folate)for 2 hours,and an 85 mg/m2 infusion of oxaliplatin for 2 hours.This was followed by a continuous intravenous infusion of 2200-2400 mg/m25-FU for 46 hours using a portable pump.RESULTS The treatment group showed a median survival time of 11.7 months and an objective response rate(ORR)of 32.5%,significantly higher than the control group(P<0.05).Serum carcinoembryonic antigen(CEA),carbohydrate antigen 19-9(CA19-9),and albumin levels were correlated with treatment effectiveness in advanced GSRC(P<0.01),but total serum protein was not correlated(P>0.05).Safety and survival were assessed in all patients.Short-term efficacy was evaluated in 66 patients,with a disease control rate of 89.4%and an ORR of 48.5%.Median progression-free survival was 7.0 months(95%confidence interval[CI]:6.85-7.15),and median overall survival was 10.6 months(95%CI:9.86-11.3).Primary grade III/IV adverse events included neutropenia(22.1%)and peripheral neurotoxicity(10.3%).CONCLUSION This treatment regimen is more effective for patients with advanced GSRC.Serum levels of CEA,CA19-9,and albumin predicted chemotherapy efficacy,while total protein concentration correlated minimally and insigni-ficantly.展开更多
BACKGROUND Colorectal cancer(CRC)is the third most common cancer and a significant cause of cancer-related mortality globally.Resistance to chemotherapy,especially during CRC treatment,leads to reduced effectiveness o...BACKGROUND Colorectal cancer(CRC)is the third most common cancer and a significant cause of cancer-related mortality globally.Resistance to chemotherapy,especially during CRC treatment,leads to reduced effectiveness of drugs and poor patient outcomes.Long noncoding RNAs(lncRNAs)have been implicated in various pathophysiological processes of tumor cells,including chemotherapy resistance,yet the roles of many lncRNAs in CRC remain unclear.AIM To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance.METHODS Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance.Various bioinformatics tools were employed to elucidate molecular mechanisms.The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction.Functional assays,including MTT,wound healing,and Transwell,were conducted to investigate the functional implications of lncRNA alterations.Interactions between lncRNAs and trans-cription factors were examined using RIP and luciferase reporter assays,while Western blotting was used to confirm downstream pathways.Additionally,a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance.RESULTS LncRNA prion protein testis specific(PRNT)was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2(HIPK2)expression.PRNT was demonstrated to sponge transcription factor zinc finger protein 184(ZNF184),which in turn could regulate HIPK2 expression.Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin,with overexpression leading to decreased sensitivity and decreased expression reducing resistance.Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT.The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo.CONCLUSION The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184.This regulatory mechanism enhances CRC progression and resistance to oxaliplatin,positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.展开更多
BACKGROUND Advanced gastric cancer(AGC)remains a challenging malignancy with poor prognosis.The combination of oxaliplatin and trastuzumab has shown promising results in AGC treatment.This study aimed to investigate t...BACKGROUND Advanced gastric cancer(AGC)remains a challenging malignancy with poor prognosis.The combination of oxaliplatin and trastuzumab has shown promising results in AGC treatment.This study aimed to investigate the effects of oxaliplatin and trastuzumab combination therapy on serum tumor markers and T lymphocyte subsets in patients with AGC and to explore their potential as predictive biomarkers for treatment response.AIM To investigate the impact of oxaliplatin and trastuzumab combination therapy on serum markers and T cell subsets in patients with AGC.METHODS This prospective study enrolled 60 patients with AGC.All patients received oxaliplatin(130 mg/m^(2),every 3 weeks)and trastuzumab(8 mg/kg loading dose,followed by 6 mg/kg every 3 weeks)for six cycles.Serum carcinoembryonic antigen(CEA),cancer antigen 19-9(CA19-9),and cancer antigen 72-4(CA72-4)were measured before and after treatment.T-lymphocyte subsets,including CD3+,CD4+,CD8+,and CD4+/CD8+ratios,were also evaluated.The clinical response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.RESULTS After six cycles of treatment,the CEA,CA19-9,and CA72-4 serum levels significantly decreased compared to baseline levels(P<0.001).The percentages of CD3+and CD4+T lymphocytes increased significantly(P<0.05),whereas the percentage of CD8+T lymphocytes decreased(P<0.05).The CD4+/CD8+ratio also significantly increased after treatment(P<0.05).Patients with a higher decrease in serum tumor markers(≥50%reduction)and a higher increase in CD4+/CD8+ratio(≥1.5-fold)showed better clinical response rates(P<0.05).CONCLUSION Oxaliplatin and trastuzumab combination therapy effectively reduced serum tumor marker levels and modulated T lymphocyte subsets in patients with AGC.Combination therapy not only has a direct antitumor effect,but also enhances the immune response in patients with AGC.Serum tumor markers and T lymphocyte subsets may serve as potential predictive biomarkers for treatment response in patients with AGC receiving combination therapy.展开更多
Due to the limitations of conventional chemotherapy including side effects,poor prognosis,and drug resistance,there is an urgent need for the development of a novel multi-functional combined therapy strategy.Dopamine-...Due to the limitations of conventional chemotherapy including side effects,poor prognosis,and drug resistance,there is an urgent need for the development of a novel multi-functional combined therapy strategy.Dopamine-modified oxaliplatin prodrug(OXA-DA)was successfully synthesized in this study to ameliorate the organ distribution of oxaliplatin for improving the drug efficacy and reducing toxic side effects,and OXA-DA was applied to develop a porous oxaliplatin cross-linked polydopamine nanoparticle for loading siPD-L1 to construct multifunctional nanoplatform.The multifunctional nanoplatform was modified with poly(2-ethyl-2-oxazoline)(PEOz),which occurred charge reversal in the tumor microenvironment,and exerted the lysosomal escape effect in tumor cells to improve the bioavailability of small interfering RNA targeting programmed cell death-ligand 1(siPD-L1).The pH-responsive charge reversal,photothermal,biodegradation,lysosomal escape ability,PD-L1 protein degradation,toxicity properties and multiple antitumor effects were comprehensively evaluated in vitro and in vivo experiments.The findings indicated that OXA-DA-siPD-L1@PDA-PEOz excellently induced tumor cell necrosis and apoptosis as a result of the synergistic effect of chemo-photothermal therapy,and upregulated CD8+T cells produced interferon-γ(IFN-γ)to further attack the tumor cells.In conclusion,the novel nanoplatform-mediated chemo/photothermal/immunotherapy has promising clinical applications in the treatment of malignant tumors.展开更多
BACKGROUND Locally advanced gastric cancer(LAGC)is a common malignant tumor.In recent years,neoadjuvant chemotherapy has gradually become popular for the treatment of LAGC.AIM To investigate the efficacy of oxaliplati...BACKGROUND Locally advanced gastric cancer(LAGC)is a common malignant tumor.In recent years,neoadjuvant chemotherapy has gradually become popular for the treatment of LAGC.AIM To investigate the efficacy of oxaliplatin combined with a tigio neoadjuvant chemotherapy regimen vs a conventional chemotherapy regimen for LAGC.METHODS Ninety patients with LAGC were selected and randomly divided into control and study groups with 45 patients in each group,according to the numerical table method.The control group was treated with conventional chemotherapy,and the study group was treated with oxaliplatin combined with tigio-neoadjuvant che-motherapy.The primary outcome measures were the clinical objective response rate(ORR)and surgical resection rate(SRR),whereas the secondary outcome measures were safety and Karnofsky Performance Status score.RESULTS The ORR in the study group was 80.00%,which was significantly higher than that of the control group(57.78%).In the study group,SRR was 75.56%,which was significantly higher than that of the control group(57.78%).There were 15.56%adverse reactions in the study group and 35.56%in the control group.These differences were statistically significant between the two groups.CONCLUSION The combination of oxaliplatin and tigio before surgery as neoadjuvant chemotherapy for patients with LAGC can effectively improve the ORR and SRR and is safe.展开更多
Objectives:Colorectal cancer(CRC)is a serious threat to human health worldwide.Oxaliplatin is a platinum analog and is widely used to treat CRC.However,resistance to oxaliplatin restricts its effectiveness and applica...Objectives:Colorectal cancer(CRC)is a serious threat to human health worldwide.Oxaliplatin is a platinum analog and is widely used to treat CRC.However,resistance to oxaliplatin restricts its effectiveness and application while its target recognition and mechanism of action also remain unclear.Therefore,we aimed to develop an oxaliplatinresistant prognostic model to clarify these aspects.Methods:We first obtained oxaliplatin-resistant and parental cell lines,and identified oxaliplatin-resistant genes using RNA sequencing(RNA-seq)and differential gene analysis.We then acquired relevant data from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Cox regression and Least Absolute Shrinkage and Selection Operator(LASSO)regression were used to identify satisfactory resistance genes,and a prognostic model was established.Finally,small-molecule drugs targeting the high-risk(HR)and low-risk(LR)groups were predicted.Results:We identified 14 oxaliplatin-resistance genes in CRC.We built a model with these and used it to classify patients with CRC.Overall survival was better in the LR group than in the HR group(p<0.001).Multivariate and univariate prognostic analyses revealed that this newly developed model had an independent prognostic value(p<0.001).The risk score was found to be associated with the tumor microenvironment(TME)and 11 types of immune cells as per the CIBERSORT algorithm results.Finally,we screened 47 small-molecule drugs with half-maximal inhibitory concentration(IC50)values that were related to the risk scores.Conclusion:Our novel prognostic model for oxaliplatin resistance can be used to stratify the risk of CRC.展开更多
Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response ...Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response without benefit to survival.In this study,we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.Methods:This study was a subgroup analysis of a randomized clinical trial.A total of 180 patients with pathological stage N2 rectal cancer were eligible,85 received capecitabine with radiotherapy(RT),and 95 received capecitabine and oxaliplatin with RT.Patients in both groups received adjuvant chemotherapy[capecitabine and oxaliplatin(XELOX);or fluorouracil,leucovorin,and oxaliplatin(FOLFOX)]after CRT.Results:At a median follow-up of 59.2[interquartile range(IQR),34.0−96.8]months,the three-year diseasefree survival(DFS)was 53.3%and 64.9%in the control group and the experimental group,respectively[hazard ratio(HR),0.63;95%confidence interval(95%CI),0.41−0.98;P=0.04].There was no significant difference between the groups in overall survival(OS)(HR,0.62;95%CI,0.37−1.05;P=0.07),the incidence of locoregional recurrence(HR,0.62;95%CI,0.24−1.64;P=0.33),the incidence of distant metastasis(HR,0.67;95%CI,0.42−1.06;P=0.09)and grade 3−4 acute toxicities(P=0.78).For patients with survival longer than 3 years,the conditional overall survival(COS)was significantly better in the experimental group(HR,0.39;95%CI,0.16−0.96;P=0.03).Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.展开更多
Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and ...Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.展开更多
1文献类型治疗2证据水平1b3文献来源De Gramont A, Figer A, Seymour M, et al.Leucovorin and fluorouacil with or without oxaliplatin as first-line treatment in advanced colorectal cancer [J]. J Clin Oncol, 2000,18(16)
Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The r...Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.展开更多
To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway.METHODSmiR-34a ex...To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway.METHODSmiR-34a expression levels were detected in CRC tissues and CRC cell lines by quantitative real-time polymerase chain reaction. Computational search, functional luciferase assay and western blotting were used to demonstrate the downstream target of miR-34a in CRC cells. Cell viability was measured with Cell Counting Kit-8. Apoptosis and macroautophagy of CRC cells were analyzed by flow cytometry and transmission electron microscopy, and expression of beclin I and LC3-II was detected by western blotting.RESULTSExpression of miR-34a was significantly reduced while expression of TGF-β and Smad4 was increased in CRC patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased miR-34a levels and increased TGF-β and Smad4 levels in both parental cells and the OXA-resistant CRC cells. Activation of macroautophagy contributed to OXA resistance in CRC cells. Expression levels of Smad4 and miR-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells.CONCLUSIONmiR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.展开更多
AIM: To evaluate the efficacy and safety of gemcitabine-oxaliplatin (GEMOX) combined with huachansu (cinobufagin) injection treatment in patients with locally advanced or metastatic gallbladder carcinoma (GBC), and to...AIM: To evaluate the efficacy and safety of gemcitabine-oxaliplatin (GEMOX) combined with huachansu (cinobufagin) injection treatment in patients with locally advanced or metastatic gallbladder carcinoma (GBC), and to assess the quality of life (QOL) of such patients. METHODS: Twenty-fi ve patients with locally advanced or metastatic GBC were treated with intravenous gemcitabine (1000 mg/m2) over 30 min on days 1 and 8, 2 h infusion of oxaliplatin (120 mg/m2) on day 1, and 2-3 h infusion of huachansu (20 mL/m2) on days -3-11, every 3-4 wk. Treatment was continued until occurrence of unacceptable toxicity or disease progression. QOL of patients was assessed by the EORTC QLQ-C30 at baseline, at the end of the fi rst, third and sixth chemotherapy cycles, and 1 mo after the treatment. RESULTS: Among the 25 patients with a median age of 64 years (range 42-78 years), 23 were evaluable in the study. A total of 137 cycles of therapy were performed and the median cycle was 5 (range 1-8) per patient. Out of the 23 patients whose response couldbe evaluated, 8 partial responses (PR) were observed (34.8%), while 7 patients (30.4%) demonstrated a stable disease (SD). The disease control rate was 65.2%. Progression of cancer was observed in 8 (34.8%) patients. The median progression-free and overall survival time was 5.8 mo (95% CI: 4.5-7.1 mo) and 10.5 mo, respectively. The therapy was well tolerated, with moderate myelosuppression as the main toxicity. Anemia grade 2 was seen in 16.0%, neutropenia grade 3 in 8.0% and thrombocytopenia grade 3 in 24.0% of patients, respectively. Non-hematologic toxicity ranged from mild to moderate. No death occurred due to toxicity. The QOL of patients was improved after chemotherapy, and the scores of QOL were increased by 10 to 20 points. CONCLUSION: GEMOX combined with huachansu (cinobufagin) injection is well tolerated, effective, thus improving the QOL of patients with advanced GBC.展开更多
This paper reports the first case of a patient with hepatocellular carcinoma with lymph node metastasis treated by sorafenib combined with gemcitabine plus oxaliplatin,with a partial response and normalization of α f...This paper reports the first case of a patient with hepatocellular carcinoma with lymph node metastasis treated by sorafenib combined with gemcitabine plus oxaliplatin,with a partial response and normalization of α fetoprotein,which allowed curative surgery.The potential synergy between these three drugs needs to be confirmed,and is currently being investigated in a randomized phase Ⅱ trial.展开更多
AIM To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in hepatocellular carcinoma(HCC) with major portal...AIM To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in hepatocellular carcinoma(HCC) with major portal vein tumor thrombus(MPVTT).METHODS eighty-six patients with MPVTT accepted routine embolization. The catheter was kept in the hepatic artery and oxaliplatin(50 mg in 250 m L of glucose) was infused by pump for 4 h,followed by raltitrexed(2 mg in 100 m L of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated afterthe transarterial chemoembolization(TACe).RESULTS Full or partial embolization was achieved in 86 cases,where all the cases received low dose continuous hepatic arterial infusion chemotherapy. Complete responses(CRs),partial responses(PRs),stable disease(SD),and disease progression(PD) for intrahepatic disease were observed in 0,45,20,and 21 patients,respectively. The 1-,2-and 3-year overall survival rates of the 86 patients were 40.7%,22.1%,and 8.1% respectively,and the median survival time was 8.7 mo. Complication was limited. CONCLUSION TACE with low dose continuous hepatic arterial infusion of oxaliplatin and raltitrexed could be an option in MPVTT patient; it was shown to be effective in patients with advanced HCC with MPVTT with less toxicity.展开更多
Background:Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer.This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1,oxaliplatin,and leucovori...Background:Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer.This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1,oxaliplatin,and leucovorin(SOL) in the treatment of Chinese patients with metastatic colorectal cancer(mCRC).Methods:Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin(85 mg/m2) on day 1,oral S-1 twice daily(80-120 mg per day) on day 1-7,and leucovorin twice daily(50 mg per day)simultaneously with S-1,every 2 weeks.Results and discussion:Forty patients were enrolled in our study.In total,296 cycles of SOL were administered.The overall response rate was 50.0%.At a median follow-up of 27 months,progression-free survival and overall surviva were 7.0 months(95%confidence interval[CI]6.0-10.6 months) and 22.2 months(95%CI 15.1-29.3 months),respectively.The most common grade 3/4 non-hematological adverse events were diarrhea(n = 8,20.0%),nausea(n = 3,7.5%),and vomiting(n = 3,7.5%).The most common grade 3/4 hematological toxicities were thrombocytopenia(n = 3,7.5%),neutropenia(n = 1,2.5%),and abnormal alanine transaminase/aspartate transaminase levels(n = 1,2.5%).There was one treatment-related death.Conclusions:The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.Trial registration:Clinical trial展开更多
基金supported by Natural Science Foundation of Zhejiang Province(Nos.LY20H160033,LY22H160019)National Key Research and Development Program of China(No.YS2021YFC3000089)+1 种基金Zhejiang Province Science and Technology Plan Project(No.2024C03175)National Natural Science Foundation of China(Nos.82074208,22278352,82473004).
文摘Oxaliplatin(OXA)can be used as a palliative treatment for advanced hepatocellular carcinoma(HCC).While most patients still have rapid disease progression after OXA due to the drug resistance.The lactate dehydrogenase A(LDHA)inhibitors can reduce the inflammation-induced effects,metastasis,and proliferation potential of cancer cells.Here,we adopt the water-in-oil attractive Pickering emulsion gel(APEG)to deliver OXA and LDHA inhibitor,GSK2837808A(GSK).OXA is dissolved in water and GSK is dissolved in iodized oil.This drugs-loaded APEG has good biocompatibility and can release OXA and GSK slowly.OXA+GSK@gel has significant anti-tumor effect on HCC model,which can effectively inhibit tumor cell proliferation and promote tumor cell apoptosis.Meanwhile,flow analysis confirm that it could activate the tumor immune microenvironment in HCC.The infiltration of CD8^(+)T cells is increased,thereby providing better anti-tumor effect.The results suggest that the APEGs loaded with OXA and GSK can effectively improve the delivery efficiency and enhance the anti-tumor therapy.
文摘BACKGROUND Drug-induced lung injury is a common adverse effect of chemotherapeutic agents.Diffuse alveolar hemorrhage(DAH)is a fatal complication associated with druginduced lung injury.Early diagnosis and treatment of DAH is critical,as delayed management can lead to respiratory failure and poor outcomes.However,the diagnosis of DAH is difficult because of the nonspecific clinical manifestations;as such,bronchoscopy is necessary to establish a diagnosis.CASE SUMMARY The patient presented with fever and dry cough.He had been receiving fluoropyrimidine and oxaliplatin therapy for esophageal squamous cell carcinoma.Chest imaging revealed diffuse ground-glass opacities.Bronchoscopy with bronchoalveolar lavage was performed,which confirmed the diagnosis of DAH.Although the patient’s respiratory status rapidly worsened,high-dose corticosteroid therapy with respiratory support gradually improved the patient’s condition and he was successfully extubated.CONCLUSION Prompt DAH diagnosis and bronchoscopy in patients receiving oxaliplatincontaining chemotherapy presenting with acute respiratory failure are critical for improving outcomes.
基金Supported by National Natural Science Foundation of China,No.874063.
文摘BACKGROUND Keratin 80(KRT80),a type I intermediate filament protein,is a member of the keratin family with specialized functions in epithelial tissues.While KRT80 has been implicated in both normal physiological processes and various diseases,its role in gastric cancer(GC),particularly its expression and prognostic significance,remains poorly understood.In this study,we investigated the role and underlying molecular mechanisms of KRT80 in oxaliplatin resistance in GC.Our analysis revealed that KRT80 is significantly upregulated in GC tissues and is associated with poor clinical prognosis.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.AIM To explore the expression of KRT80 in GC and its impact on the prognosis of patients.METHODS KRT80 expression in GC tissues was analyzed using Western blotting,quantitative reverse transcription PCR,multiple immunofluorescence staining,and immunohistochemistry.Survival analysis was conducted using the Kaplan-Meier method with the log-rank test.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.Immunoprecipitation and mass spectrometry analyses identified elongation factor 1-alpha 1(EEF1A1)as a binding protein of KRT80.RESULTS Integrating our experimental findings with multiple published studies,we found that increased KRT80 expression is associated with poor prognosis in GC and promotes resistance to oxaliplatin.Moreover,we have preliminarily verified the interaction between KRT80 and EEF1A1.Therefore,this study provides a novel perspective on overcoming oxaliplatin resistance in GC.CONCLUSION Increased KRT80 expression predicts poor prognosis and promotes oxaliplatin resistance in GC,suggesting its potential as a novel prognostic biomarker.
基金supported by the National Natural Science Foundations of China(Nos.22464022,22461048,and 22364023)Scientific Research Fund Project of Yunnan Education Department(No.2023j0204)+3 种基金Yunnan Normal University Doctoral Research Initiation Program(No.01100205020503180)Xing Dian Talent Support Program Foundations(No.01100208019916016)Yunnan Normal University Graduate Research Innovation Fund Project(No.YJSJJ23-B87)Yunnan Basic Research Funding Program(Nos.202401AT070128,202301AT070074,and 202201AU070056)。
文摘Chiral anticancer drugs are the subject of ongoing research due to their optical characterization and pharmacological effects.Achieving a single enantiomer of a chiral anticancer drug is arduous,but it can significantly improve its pharmacokinetics for tumor therapy.Here,the chiral nanocatchers,known as Dbiotin-P5■MCC NCs,were designed and prepared based on host-vip self-assembly between D-biotin anchored pillar[5]arene(D-biotin-P5)and myristoyl chloride choline(MCC).D-Biotin-P5■MCC NCs featuring the chiral separation and enzyme-induced disassemble were evaluated for their ability to selectively capture and subsequently target the release of(R,R)-OXA enantiomers into tumor cells.Furthermore,the use of D-biotin-P5■MCC NCs has demonstrated a significant enhancement in the intracellular uptake of OXA,with the drug being efficiently released to MCF-7 breast cancer cells.This has led to a superior inhibitory effect on MCF-7 cells when compared to free OXA,while also reducing the cytotoxicity of the drug in HEK 293 human embryonic kidney cells.This research not only paves a promising way for the fabrication of chiral supramolecular nanocarriers but also holds the potential to improve the processes of chiral drug separation and targeted therapy.
基金Supported by the National Natural Science Foundation of China,No.U24A20765 and No.T2321005Jiangsu Provincial Science and Technology Plan Special Fund,No.BM2023003+5 种基金Jiangsu Provincial Medical Key Discipline,No.ZDXK202247the Priority Academic Program Development of the Jiangsu Higher Education InstitutesJiangsu Engineering Research Center on Drug Evaluation and Translation of Organoids/Organ Chip(2024)the Science and Technology Plan of Suzhou,No.SKYD2023183the Research Project Established by Chinese Pharmaceutical Association Hospital Pharmacy Department,No.CPA-Z05-ZC-2023002Gusu Health Talent Research Project,No.GSWS2022015.
文摘BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.
文摘BACKGROUND Gastric signet ring cell carcinoma(GSRC)is a distinctive type of gastric cancer.It is a mucus-secreting adenocarcinoma that may progress to distant metastasis at an early stage.Because of poor differentiation,aggressive invasion,rapid progre-ssion,and other high-risk characteristics,early surgical intervention should be prioritized.AIM To explore the clinical efficacy of fluorouracil(5-FU)combined with paclitaxel and oxaliplatin for the treatment of advanced GSRC.METHODS A total of 85 patients with advanced GSRC were selected between January 2020 and June 2021 and randomly divided into a control group(n=42,receiving standard chemotherapy)and a treatment group(n=43,receiving monotherapy with oxaliplatin,5-FU,and paclitaxel).Patients in the treatment group received a 135 mg/m2 infusion of paclitaxel for 3 hours,a 400 mg/m2 infusion of calcium folate(or 200 mg/m2 of levocalcium folate)for 2 hours,and an 85 mg/m2 infusion of oxaliplatin for 2 hours.This was followed by a continuous intravenous infusion of 2200-2400 mg/m25-FU for 46 hours using a portable pump.RESULTS The treatment group showed a median survival time of 11.7 months and an objective response rate(ORR)of 32.5%,significantly higher than the control group(P<0.05).Serum carcinoembryonic antigen(CEA),carbohydrate antigen 19-9(CA19-9),and albumin levels were correlated with treatment effectiveness in advanced GSRC(P<0.01),but total serum protein was not correlated(P>0.05).Safety and survival were assessed in all patients.Short-term efficacy was evaluated in 66 patients,with a disease control rate of 89.4%and an ORR of 48.5%.Median progression-free survival was 7.0 months(95%confidence interval[CI]:6.85-7.15),and median overall survival was 10.6 months(95%CI:9.86-11.3).Primary grade III/IV adverse events included neutropenia(22.1%)and peripheral neurotoxicity(10.3%).CONCLUSION This treatment regimen is more effective for patients with advanced GSRC.Serum levels of CEA,CA19-9,and albumin predicted chemotherapy efficacy,while total protein concentration correlated minimally and insigni-ficantly.
基金Supported by Hebei Provincial Health Commission Youth Science and Technology Project,No.20210027.
文摘BACKGROUND Colorectal cancer(CRC)is the third most common cancer and a significant cause of cancer-related mortality globally.Resistance to chemotherapy,especially during CRC treatment,leads to reduced effectiveness of drugs and poor patient outcomes.Long noncoding RNAs(lncRNAs)have been implicated in various pathophysiological processes of tumor cells,including chemotherapy resistance,yet the roles of many lncRNAs in CRC remain unclear.AIM To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance.METHODS Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance.Various bioinformatics tools were employed to elucidate molecular mechanisms.The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction.Functional assays,including MTT,wound healing,and Transwell,were conducted to investigate the functional implications of lncRNA alterations.Interactions between lncRNAs and trans-cription factors were examined using RIP and luciferase reporter assays,while Western blotting was used to confirm downstream pathways.Additionally,a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance.RESULTS LncRNA prion protein testis specific(PRNT)was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2(HIPK2)expression.PRNT was demonstrated to sponge transcription factor zinc finger protein 184(ZNF184),which in turn could regulate HIPK2 expression.Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin,with overexpression leading to decreased sensitivity and decreased expression reducing resistance.Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT.The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo.CONCLUSION The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184.This regulatory mechanism enhances CRC progression and resistance to oxaliplatin,positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.
文摘BACKGROUND Advanced gastric cancer(AGC)remains a challenging malignancy with poor prognosis.The combination of oxaliplatin and trastuzumab has shown promising results in AGC treatment.This study aimed to investigate the effects of oxaliplatin and trastuzumab combination therapy on serum tumor markers and T lymphocyte subsets in patients with AGC and to explore their potential as predictive biomarkers for treatment response.AIM To investigate the impact of oxaliplatin and trastuzumab combination therapy on serum markers and T cell subsets in patients with AGC.METHODS This prospective study enrolled 60 patients with AGC.All patients received oxaliplatin(130 mg/m^(2),every 3 weeks)and trastuzumab(8 mg/kg loading dose,followed by 6 mg/kg every 3 weeks)for six cycles.Serum carcinoembryonic antigen(CEA),cancer antigen 19-9(CA19-9),and cancer antigen 72-4(CA72-4)were measured before and after treatment.T-lymphocyte subsets,including CD3+,CD4+,CD8+,and CD4+/CD8+ratios,were also evaluated.The clinical response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.RESULTS After six cycles of treatment,the CEA,CA19-9,and CA72-4 serum levels significantly decreased compared to baseline levels(P<0.001).The percentages of CD3+and CD4+T lymphocytes increased significantly(P<0.05),whereas the percentage of CD8+T lymphocytes decreased(P<0.05).The CD4+/CD8+ratio also significantly increased after treatment(P<0.05).Patients with a higher decrease in serum tumor markers(≥50%reduction)and a higher increase in CD4+/CD8+ratio(≥1.5-fold)showed better clinical response rates(P<0.05).CONCLUSION Oxaliplatin and trastuzumab combination therapy effectively reduced serum tumor marker levels and modulated T lymphocyte subsets in patients with AGC.Combination therapy not only has a direct antitumor effect,but also enhances the immune response in patients with AGC.Serum tumor markers and T lymphocyte subsets may serve as potential predictive biomarkers for treatment response in patients with AGC receiving combination therapy.
基金the National Natural Science Foundation of China(Nos.32071342 and 32101065)the Natural Science Foundation of Guangdong Province(Nos.2023A1515012015,2022A1515110271 and 2020A1515011353).
文摘Due to the limitations of conventional chemotherapy including side effects,poor prognosis,and drug resistance,there is an urgent need for the development of a novel multi-functional combined therapy strategy.Dopamine-modified oxaliplatin prodrug(OXA-DA)was successfully synthesized in this study to ameliorate the organ distribution of oxaliplatin for improving the drug efficacy and reducing toxic side effects,and OXA-DA was applied to develop a porous oxaliplatin cross-linked polydopamine nanoparticle for loading siPD-L1 to construct multifunctional nanoplatform.The multifunctional nanoplatform was modified with poly(2-ethyl-2-oxazoline)(PEOz),which occurred charge reversal in the tumor microenvironment,and exerted the lysosomal escape effect in tumor cells to improve the bioavailability of small interfering RNA targeting programmed cell death-ligand 1(siPD-L1).The pH-responsive charge reversal,photothermal,biodegradation,lysosomal escape ability,PD-L1 protein degradation,toxicity properties and multiple antitumor effects were comprehensively evaluated in vitro and in vivo experiments.The findings indicated that OXA-DA-siPD-L1@PDA-PEOz excellently induced tumor cell necrosis and apoptosis as a result of the synergistic effect of chemo-photothermal therapy,and upregulated CD8+T cells produced interferon-γ(IFN-γ)to further attack the tumor cells.In conclusion,the novel nanoplatform-mediated chemo/photothermal/immunotherapy has promising clinical applications in the treatment of malignant tumors.
文摘BACKGROUND Locally advanced gastric cancer(LAGC)is a common malignant tumor.In recent years,neoadjuvant chemotherapy has gradually become popular for the treatment of LAGC.AIM To investigate the efficacy of oxaliplatin combined with a tigio neoadjuvant chemotherapy regimen vs a conventional chemotherapy regimen for LAGC.METHODS Ninety patients with LAGC were selected and randomly divided into control and study groups with 45 patients in each group,according to the numerical table method.The control group was treated with conventional chemotherapy,and the study group was treated with oxaliplatin combined with tigio-neoadjuvant che-motherapy.The primary outcome measures were the clinical objective response rate(ORR)and surgical resection rate(SRR),whereas the secondary outcome measures were safety and Karnofsky Performance Status score.RESULTS The ORR in the study group was 80.00%,which was significantly higher than that of the control group(57.78%).In the study group,SRR was 75.56%,which was significantly higher than that of the control group(57.78%).There were 15.56%adverse reactions in the study group and 35.56%in the control group.These differences were statistically significant between the two groups.CONCLUSION The combination of oxaliplatin and tigio before surgery as neoadjuvant chemotherapy for patients with LAGC can effectively improve the ORR and SRR and is safe.
基金financed by the National Natural Science Foundation(81874058 to Jianping Zhang).
文摘Objectives:Colorectal cancer(CRC)is a serious threat to human health worldwide.Oxaliplatin is a platinum analog and is widely used to treat CRC.However,resistance to oxaliplatin restricts its effectiveness and application while its target recognition and mechanism of action also remain unclear.Therefore,we aimed to develop an oxaliplatinresistant prognostic model to clarify these aspects.Methods:We first obtained oxaliplatin-resistant and parental cell lines,and identified oxaliplatin-resistant genes using RNA sequencing(RNA-seq)and differential gene analysis.We then acquired relevant data from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Cox regression and Least Absolute Shrinkage and Selection Operator(LASSO)regression were used to identify satisfactory resistance genes,and a prognostic model was established.Finally,small-molecule drugs targeting the high-risk(HR)and low-risk(LR)groups were predicted.Results:We identified 14 oxaliplatin-resistance genes in CRC.We built a model with these and used it to classify patients with CRC.Overall survival was better in the LR group than in the HR group(p<0.001).Multivariate and univariate prognostic analyses revealed that this newly developed model had an independent prognostic value(p<0.001).The risk score was found to be associated with the tumor microenvironment(TME)and 11 types of immune cells as per the CIBERSORT algorithm results.Finally,we screened 47 small-molecule drugs with half-maximal inhibitory concentration(IC50)values that were related to the risk scores.Conclusion:Our novel prognostic model for oxaliplatin resistance can be used to stratify the risk of CRC.
基金supported by grants from Sanming Project of Medicine in Shenzhen(No.SZSM202211030)the Science and Technology Department Basic Research Project of Shanxi(No.202203021221284)。
文摘Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response without benefit to survival.In this study,we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.Methods:This study was a subgroup analysis of a randomized clinical trial.A total of 180 patients with pathological stage N2 rectal cancer were eligible,85 received capecitabine with radiotherapy(RT),and 95 received capecitabine and oxaliplatin with RT.Patients in both groups received adjuvant chemotherapy[capecitabine and oxaliplatin(XELOX);or fluorouracil,leucovorin,and oxaliplatin(FOLFOX)]after CRT.Results:At a median follow-up of 59.2[interquartile range(IQR),34.0−96.8]months,the three-year diseasefree survival(DFS)was 53.3%and 64.9%in the control group and the experimental group,respectively[hazard ratio(HR),0.63;95%confidence interval(95%CI),0.41−0.98;P=0.04].There was no significant difference between the groups in overall survival(OS)(HR,0.62;95%CI,0.37−1.05;P=0.07),the incidence of locoregional recurrence(HR,0.62;95%CI,0.24−1.64;P=0.33),the incidence of distant metastasis(HR,0.67;95%CI,0.42−1.06;P=0.09)and grade 3−4 acute toxicities(P=0.78).For patients with survival longer than 3 years,the conditional overall survival(COS)was significantly better in the experimental group(HR,0.39;95%CI,0.16−0.96;P=0.03).Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.
基金financially supported by the National Natural Science Foundation of China (Nos.82020108029, 82073398)supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University (No.SKLNMZZ202021)+4 种基金the"111"Project from the Ministry of Education of Chinathe State Administration of Foreign Experts Affairs of China (No.B16046)Double First-Rate construction plan of China Pharmaceutical University (Nos.CPU2018GY06,CPU2022QZ18)China Postdoctoral Science Foundation (Nos.2021M703598, 2022M720173)Jiangsu Funding Program for Excellent Postdoctoral Talent and International Postdoctoral Exchange Fellowship Program 2022。
文摘Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.
文摘1文献类型治疗2证据水平1b3文献来源De Gramont A, Figer A, Seymour M, et al.Leucovorin and fluorouacil with or without oxaliplatin as first-line treatment in advanced colorectal cancer [J]. J Clin Oncol, 2000,18(16)
基金National Natural Science Foundation of China(Grant No.81272468,81372266,91429305 and 21001011)WU JIEPING Medical Foundation(Grant No.320.6750.12196)
文摘Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.
基金Supported by Science Foundation of Education Department of Heilongjiang Province,China,no.12541430
文摘To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway.METHODSmiR-34a expression levels were detected in CRC tissues and CRC cell lines by quantitative real-time polymerase chain reaction. Computational search, functional luciferase assay and western blotting were used to demonstrate the downstream target of miR-34a in CRC cells. Cell viability was measured with Cell Counting Kit-8. Apoptosis and macroautophagy of CRC cells were analyzed by flow cytometry and transmission electron microscopy, and expression of beclin I and LC3-II was detected by western blotting.RESULTSExpression of miR-34a was significantly reduced while expression of TGF-β and Smad4 was increased in CRC patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased miR-34a levels and increased TGF-β and Smad4 levels in both parental cells and the OXA-resistant CRC cells. Activation of macroautophagy contributed to OXA resistance in CRC cells. Expression levels of Smad4 and miR-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells.CONCLUSIONmiR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.
文摘AIM: To evaluate the efficacy and safety of gemcitabine-oxaliplatin (GEMOX) combined with huachansu (cinobufagin) injection treatment in patients with locally advanced or metastatic gallbladder carcinoma (GBC), and to assess the quality of life (QOL) of such patients. METHODS: Twenty-fi ve patients with locally advanced or metastatic GBC were treated with intravenous gemcitabine (1000 mg/m2) over 30 min on days 1 and 8, 2 h infusion of oxaliplatin (120 mg/m2) on day 1, and 2-3 h infusion of huachansu (20 mL/m2) on days -3-11, every 3-4 wk. Treatment was continued until occurrence of unacceptable toxicity or disease progression. QOL of patients was assessed by the EORTC QLQ-C30 at baseline, at the end of the fi rst, third and sixth chemotherapy cycles, and 1 mo after the treatment. RESULTS: Among the 25 patients with a median age of 64 years (range 42-78 years), 23 were evaluable in the study. A total of 137 cycles of therapy were performed and the median cycle was 5 (range 1-8) per patient. Out of the 23 patients whose response couldbe evaluated, 8 partial responses (PR) were observed (34.8%), while 7 patients (30.4%) demonstrated a stable disease (SD). The disease control rate was 65.2%. Progression of cancer was observed in 8 (34.8%) patients. The median progression-free and overall survival time was 5.8 mo (95% CI: 4.5-7.1 mo) and 10.5 mo, respectively. The therapy was well tolerated, with moderate myelosuppression as the main toxicity. Anemia grade 2 was seen in 16.0%, neutropenia grade 3 in 8.0% and thrombocytopenia grade 3 in 24.0% of patients, respectively. Non-hematologic toxicity ranged from mild to moderate. No death occurred due to toxicity. The QOL of patients was improved after chemotherapy, and the scores of QOL were increased by 10 to 20 points. CONCLUSION: GEMOX combined with huachansu (cinobufagin) injection is well tolerated, effective, thus improving the QOL of patients with advanced GBC.
文摘This paper reports the first case of a patient with hepatocellular carcinoma with lymph node metastasis treated by sorafenib combined with gemcitabine plus oxaliplatin,with a partial response and normalization of α fetoprotein,which allowed curative surgery.The potential synergy between these three drugs needs to be confirmed,and is currently being investigated in a randomized phase Ⅱ trial.
基金the National Key R and D Program of China,No.2016YFC0106604the National Natural Science Foundation of China,No.81502591
文摘AIM To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in hepatocellular carcinoma(HCC) with major portal vein tumor thrombus(MPVTT).METHODS eighty-six patients with MPVTT accepted routine embolization. The catheter was kept in the hepatic artery and oxaliplatin(50 mg in 250 m L of glucose) was infused by pump for 4 h,followed by raltitrexed(2 mg in 100 m L of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated afterthe transarterial chemoembolization(TACe).RESULTS Full or partial embolization was achieved in 86 cases,where all the cases received low dose continuous hepatic arterial infusion chemotherapy. Complete responses(CRs),partial responses(PRs),stable disease(SD),and disease progression(PD) for intrahepatic disease were observed in 0,45,20,and 21 patients,respectively. The 1-,2-and 3-year overall survival rates of the 86 patients were 40.7%,22.1%,and 8.1% respectively,and the median survival time was 8.7 mo. Complication was limited. CONCLUSION TACE with low dose continuous hepatic arterial infusion of oxaliplatin and raltitrexed could be an option in MPVTT patient; it was shown to be effective in patients with advanced HCC with MPVTT with less toxicity.
文摘Background:Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer.This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1,oxaliplatin,and leucovorin(SOL) in the treatment of Chinese patients with metastatic colorectal cancer(mCRC).Methods:Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin(85 mg/m2) on day 1,oral S-1 twice daily(80-120 mg per day) on day 1-7,and leucovorin twice daily(50 mg per day)simultaneously with S-1,every 2 weeks.Results and discussion:Forty patients were enrolled in our study.In total,296 cycles of SOL were administered.The overall response rate was 50.0%.At a median follow-up of 27 months,progression-free survival and overall surviva were 7.0 months(95%confidence interval[CI]6.0-10.6 months) and 22.2 months(95%CI 15.1-29.3 months),respectively.The most common grade 3/4 non-hematological adverse events were diarrhea(n = 8,20.0%),nausea(n = 3,7.5%),and vomiting(n = 3,7.5%).The most common grade 3/4 hematological toxicities were thrombocytopenia(n = 3,7.5%),neutropenia(n = 1,2.5%),and abnormal alanine transaminase/aspartate transaminase levels(n = 1,2.5%).There was one treatment-related death.Conclusions:The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.Trial registration:Clinical trial
