Oxaliplatin Combination Therapy Research Articles

Impact of oxaliplatin and trastuzumab combination therapy on tumor markers and T lymphocyte subsets for advanced gastric cancer.

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. To investigate the impact of oxaliplatin and trastuzumab combination therapy on serum markers and T cell subsets in patients with AGC. This prospective study enrolled 60 patients with AGC. All patients received oxaliplatin (130 mg/m2, 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. 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). 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.

Evaluation of oxaliplatin and tigio combination therapy in locally advanced gastric cancer.

Locally advanced gastric cancer (LAGC) is a common malignant tumor. In recent years, neoadjuvant chemotherapy has gradually become popular for the treatment of LAGC. To investigate the efficacy of oxaliplatin combined with a tigio neoadjuvant chemotherapy regimen vs a conventional chemotherapy regimen for LAGC. 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 chemotherapy. 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. 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. 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.

Abstract 3269: APE1/NF-κB/PRDX2 activated by reflux conditions mediates chemoresistance in esophageal adenocarcinoma by suppressing ferroptosis

Abstract Background: Esophageal adenocarcinoma (EAC) stands out as one of the most lethal malignancies, characterized by a discouragingly low 5-year survival rate of less than 20%. Accumulating lines of evidence indicate that ferroptosis, a novel type of cell death, can regulate drug resistance. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, plays an antioxidant protective role in the cells under stress by regulating redox homeostasis. We aimed to elucidate the role of PRDX2 in regulating reactive oxygen species (ROS), ferroptosis, and chemoresistance in EAC. Methods: In this investigation, we analyzed RNA sequencing data and public databases to uncover the aberrant overexpression and potential chemoresistance function of PRDX2 in EAC. We employed transient acidic bile salts exposure (ABS) and repeated ABS exposure (rABS) to mimic gastroesophageal reflux disease, the main risk factor for EAC, in in vitro cell models. EAC cells and 3D organotypic culture (OTC) served as platforms to delve into the anti-ferroptosis function and regulatory mechanisms of PRDX2. The findings were validated using patient-derived xenografts (PDX) and human EAC tissue microarrays (TMA). Results: Elevated PRDX2 level was observed in both EAC patients and cell lines exhibiting poor responsiveness to chemotherapy. Intrinsic overexpression of PRDX2 emerged as a crucial factor in the recovery from ABS-exposure-induced lipid peroxidation. Silencing PRDX2 heightened the sensitivity of EAC cells to Oxaliplatin by inhibiting ferroptosis in a GPX4-dependent manner. Mechanistically, we found ABS activate the APE1/redox/NF-kB signal axis, leading to the upregulation of PRDX2 transcription. The co-overexpression of APE1 and PRDX2 was identified through both immunofluorescent staining in cells/OTC and immunohistochemistry staining in TMA. Moreover, the APE1-redox-specific inhibitor, APX2009, significantly sensitized EAC cells to Oxaliplatin by repressing PRDX2 and inducing ferroptosis. Remarkably, the combination therapy of Oxaliplatin and APX2009 achieved a synergistic effect in EAC-PDX tumors. Conclusion: The study unveils a novel signaling axis, APE1/NF-kB/PRDX2, linking disease-associated ROS unbalance and ferroptosis-related chemoresistance. Targeting PRDX2 signaling by APE1-redox-specific inhibition provides a potential novel strategy for combined chemotherapies in refractory EAC. Citation Format: Lei Chen, Heng Lu, Farah Ballout, Dunfa Peng, Zheng Chen, Jianwen Que, Steven Chen, Oliver McDonald, Alexander Zaika, Wael El-Rifai. APE1/NF-κB/PRDX2 activated by reflux conditions mediates chemoresistance in esophageal adenocarcinoma by suppressing ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3269.

Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201)

BackgroundAdvanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer.MethodsThis multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma.DiscussionGEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer.Trial registrationThis study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

The potential therapeutic effect of melatonin in oxaliplatin combination therapy against chemoresistant colorectal cancer cells.

Oxaliplatin is one of the main therapeutics in colorectal cancer (CRC) chemotherapy. However, in light of multidrug resistance (MDR) phenotype development, the efficacy of oxaliplatin has decreased. This study aimed to assess the potential therapeutic effect of melatonin in oxaliplatin combination therapy for drug-resistant colorectal cancer cells. Initially, the oxaliplatin-resistant cell line was created of LS174T (LS174T/DR) by using the oxaliplatin IC50 concentration and resting cycles. MTT assays and flow cytometry were applied for assessing cell viability and apoptotic cells. The mRNA expression level of Bax, Bcl2, MT1, MT2, and ABCB1 as well as protein levels of ABCB1, Bcl2, BAX were measured by the qRT-PCR and western blot techniques respectively. P-gp activity was assessed by Rho123 staining. The IC50 concentration of oxaliplatin in resistant cells was increased from 500.7 ± 0.2 nM to 7119 ± 0.1 nM. Bcl2, MT1, MT2, and ABCB1 mRNA plus protein expression levels of Bcl2 and ABCB1 were significantly reduced in resistant cells, along with a marked increase in Bax mRNA and protein levels compared to parental cells. Rho 123 staining revealed a marked reduction in P-gp activities in the combination-treated group compared to the oxaliplatin-treated group. The results of cytotoxicity assays, MTT, and flow cytometry revealed that the combination of melatonin and oxaliplatin exerts synergistic effects on induction of oxaliplatin's cytotoxicity in CRC. Our research suggests that combining the treatments of melatonin and oxaliplatin may be considered as a new approach to overcoming oxaliplatin resistance in CRC patients.

183P Final analysis of phase II clinical study evaluating the safety and effectiveness of neoadjuvant S-1 + oxaliplatin combination therapy for older patients with locally advanced gastric cancer

183P Final analysis of phase II clinical study evaluating the safety and effectiveness of neoadjuvant S-1 + oxaliplatin combination therapy for older patients with locally advanced gastric cancer

N2 Lymph Node Metastasis Is a Useful Predictor of Recurrence in Patients With Stage III Rectal Cancer Undergoing Adjuvant Chemotherapy Using Tegafur-uracil/leucovorin.

Fluoropyrimidine therapy or oxaliplatin combination therapy is recommended for patients with stage III colorectal cancer as adjuvant chemotherapy (AC). However, the criterion for selecting these regimens is still unclear in patients with stage III rectal cancer (RC). In order to select an appropriate regimen of AC for such patients, it is needed to identify characteristics associated with tumor recurrence. The records of 45 patients with stage III RC undergoing AC using tegafur-uracil/leucovorin (UFT/LV) were retrospectively reviewed. The cut-off value of characteristics was determined using a receiver operating characteristic curve for recurrence. Univariate analyses using Cox-Hazard model for predicting recurrence were performed with clinical characteristics. Survival analysis was performed using Kaplan-Meier method and log-rank test. Thirty patients (66.7%) completed AC using UFT/LV. Fifteen patients (33.3%) did not complete AC because of adverse events, tumor recurrence and others. Sixteen patients (35.6%) had recurrence. Univariate analyses revealed that lymph node metastasis (N2/N1) (p=0.002) was associated with tumor recurrence. Survival analysis showed that lymph node metastasis (N2/N1) could stratify recurrence-free survival (p<0.001). N2 lymph node metastasis can predict tumor recurrence in patients with stage III RC undergoing AC using UFT/LV.

SiRNA-E6 sensitizes HPV-16-related cervical cancer through Oxaliplatin: an in vitro study on anti-cancer combination therapy

BackgroundPersistent infection with high-risk Human papillomaviruses (HPV), such as hr-HPV-16 and hr-HPV-18, lead to cervical cancer, the fourth most common cancer in the world. In the present study, we investigated the alteration of E6 oncogene expression by E6-specific short interfering RNA (siRNA) combined with Oxaliplatin.MethodsThe cervical cancer cell line, CaSki, was transfected with E6-siRNA, then treated with Oxaliplatin. The cellular genes, such as p53, MMP9, Nanog, and caspases expression, were assessed by quantitative real-time PCR. The cell death rate, cell cycle, and cell viability were assessed by Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, colony formation assay and scratch test determined the stemness ability and cell metastasis, respectively.ResultsCombination therapy increased the re-expression of genes involved in the p53-dependent apoptosis pathway (increase in apoptosis to 44.2%), and reduced stemness and metastasis ability compared to either siRNA or Oxaliplatin monotherapy. Together, our results demonstrate that E6-siRNA and Oxaliplatin combination increased the cervical cancer cells’ sensitivity to Oxaliplatin and decreased the survival rate, proliferation, and metastasis, and consequently escalated apoptosis rate, induced cell cycle arrest in the sub-G1 stage, and reduced the chemotherapy drug dosage.ConclusionInhibition of E6 oncogene expression and subsequent E6-siRNA with Oxaliplatin combination therapy could be a novel strategy for cervical cancer treatment.Graphical

Modified chitosan nanogel-polymersomes for oral co-delivery of oxaliplatin and rapamycin for synergistic chemotherapy

Oxaliplatin (OXA) and rapamycin (RAPA) combination therapy have shown the advantages of synergistically inhibiting the growth of cancer cells by enhancing apoptosis in cancerous cell lines. However, drug resistance and the lack of an orally administered formulation which exhibited the best clinical dosing compliance limited the clinical application of this regimen. Here, we report a nanogel-polymersomes drug delivery system (i.e.TMOR-CDAN) based on modified chitosan, chitosan diacetate (CDA), methoxy-poly-(ethylene glycol)-b-poly (lactide) (MPP), and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) with permeation-glycoprotein (P-gp) inhibition capability for enhancing the oral chemotherapy efficacy of erroneously soluble RAPA and its synergistic chemotherapy with OXA. Hydrophilic OXA and hydrophobic RAPA were co-loaded using MPP and TPGS-based polymer capsules (i.e. TMOR), which were further coated by chitosan-modified gel to form TMOR-CDAN. The TMOR-CDAN displayed higher stability in both acidic and basic pH than free OXA and RAPA and could withstand the harsh gastric environmental conditions, preventing the burst drugs release while releasing the co-loaded drugs in a sustained and controlled manner. The dual-drug-loaded TMOR-CDAN provides a bifunctional platform for synergistic tumor therapy. Compared with the single drug OXA, RAPA, or the OXA and RAPA mixtures (OR), the TMOR-CDAN showed more outstanding in vitro cytotoxicity and in vivo antitumor chemotherapeutic efficacy, endowing the TMOR-CDAN with a prodigious potential for futuristic cancer chemotherapy.

Safety and efficacy of S-IROX (S-1, irinotecan and oxaliplatin combination therapy) in patients with advanced pancreatic cancer: A multicenter phase 1b dose-escalation and dose-expansion clinical trial

BackgroundThis phase 1b trial evaluated the toxicity and efficacy of S-1, irinotecan, and oxaliplatin combination therapy (S-IROX) as first-line chemotherapy in patients with advanced pancreatic cancer (APC). MethodsPatients aged 20–75 years with APC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible to receive escalating doses of S-1 (60 or 80 mg m2·day) on days 1–7, fixed doses of oxaliplatin (85 mg/m2) biweekly, and escalating doses of irinotecan (150, 165, or 180 mg/m2) once every 2 weeks. In the dose-escalation cohort, a 3 + 3 design was used to determine the maximum-tolerated dose (MTD) and explore the recommended dose (RD). A dose-expansion cohort was added to further evaluate the safety and efficacy of the combination. This trial was registered at UMIN-CTR (UMIN000012054). ResultsApproximately 47 patients were enrolled, of whom 45 were eligible for the analysis. The MTD was not determined, but the RD was determined to be dose level 1 based on a review of data from each level. Among the 45 patients, the ORR was 51.1% [95% confidence interval (CI), 35.8–66.3%]. The median progression-free survival and median overall survival was 6.9 months (95% CI, 5.1–8.8 months) and 15.8 months (95% CI, 9.8–20.8 months), respectively. Common adverse events included neutropenia, elevated liver enzyme levels, diarrhoea, and nausea. ConclusionsThe S-IROX regimen showed promising efficacy with manageable toxicities in Japanese patients with APC. A randomised phase 2/3 trial comparing S-IROX, mFOLFIRINOX, and gemcitabine plus nab-paclitaxel is currently ongoing (jRCTs031190009).

Impact of previous adjuvant oxaliplatin combination therapy on survival in elderly colorectal cancer patients with recurrence.

48 Background: The benefit of adjuvant chemotherapy with oxaliplatin for elderly patients with colorectal cancer (CRC) remains controversial. Our study could not demonstrate the benefit of adding oxaliplatin for elderly CRC patients aged over 70 years as with the previous clinical trials. Here, we evaluated the prognosis after recurrence in the elderly patients who received adjuvant chemotherapy. Methods: This retrospective study included patients aged over 70 years who were diagnosed with high-risk stage II and stage III CRC and received adjuvant chemotherapy in our two hospitals (The Jikei University Hospital and Katsushika Medical Center) between January 2010 and December 2019. The patients were divided into two groups; patients who received fluoropyrimidine monotherapy were included in Fp group and those who received fluoropyrimidine plus oxaliplatin were included in Fp+OX group. Moreover, we evaluated patient characteristics, treatment, and survival in the patients with recurrence and compared them between two groups. Results: A total of 127 patients received adjuvant chemotherapy; 75 patients in Fp group and 52 patients in Fp+OX group. With a median follow-up time of 64.5 months, the 5-years disease-free survival and 5-years overall survival in Fp group/Fp+OX group were 70.6/67.1% (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.61–1.98) and 89.0/71.8% (HR 1.48, 95% CI 0.76–2.88), respectively. The benefit of adding oxaliplatin was not observed. Among them, 15 patients in Fp group and 14 patients in Fp+OX group were relapsed; median age was 78 (range: 72-83) and 78 (range: 72-86) years, male was 67% and 64%, PS of 0/1 was 67/33% and 86/14%, primary tumor site of right/left was 47/53% and 57/43%, and RAS mutation was 20% and 29%, respectively. Median relapse-free survival was 17.7 and 14.3 months (p = 0.453). There were no significant differences in treatment after recurrence; aggressive treatment (surgery/chemotherapy) was 73% (33/40%) and 86% (21/65%), best supportive care was 7% each, and unknown was 20% and 7%, respectively. However, the median overall survival from the date of relapse was significantly worse in Fp+OX group than Fp group (45.0 and 14.4 months, p = 0.011). Conclusions: Recurrence after receiving adjuvant oxaliplatin combination therapy was considered as one of the poor prognostic factors. It might attenuate the benefit of adding oxaliplatin in adjuvant setting in elderly patients.

Safety and Efficacy of S-IROX (S-1, Irinotecan&amp;nbsp;And Oxaliplatin Combination Therapy) in Patients with Advanced Pancreatic Cancer: A Multicenter Phase 1b Dose-Escalation and Dose-Expansion Clinical Trial

Safety and Efficacy of S-IROX (S-1, Irinotecan&amp;nbsp;And Oxaliplatin Combination Therapy) in Patients with Advanced Pancreatic Cancer: A Multicenter Phase 1b Dose-Escalation and Dose-Expansion Clinical Trial

Combination therapy of vanillic acid and oxaliplatin co-loaded in polysaccharide based functionalized polymeric micelles could offer effective treatment for colon cancer: A hypothesis

Colon cancer is characterised by the persistent change in bowel habits due to the formation of polyps (cancerous) in the inner lining of the colon. Clinically, there are several anticancer drugs available to treat colon cancer. Oxaliplatin (third generation platinum drug) is widely prescribed anticancer drug due to its broad range anticancer properties and low toxicities over cisplatin and carboplatin. Currently, use of oxaliplatin as adjuvant chemotherapy represents a standard care for the treatment of advanced colon cancer. Despite this, its rapid degradation in systemic circulations upon administration, lack of tumor specificity, and low bioavailability limits its anticancer potential. On the other hand, vanillic acid (VA) has shown anticancer potential in colon cancer by targeting mTOR/Ras pathway, HIF-1α inhibition, NF-ĸB, and Nrf2 that regulate cell growth, cell survival, proliferation and adaptation to cancer microenvironment. Normal oral delivery of these two drugs offers non-specific drug release in gastrointestinal tract that leads to unwanted toxicity and very less amount of drug become available for colonic site. Therefore, loading of these two drugs in polysaccharide based functionalized polymeric micelles (FPMs) can offer selective targeting at colonic site and could offer better therapeutic efficacy at much lesser doses of drugs. Therefore, a new hypothesis has been proposed that the combination of vanillic acid with oxaliplatin co-loaded in FPMs could provide colon targeting ability with enhanced potency and safety profile by targeting multiple pathways than current adjuvant chemotherapies available in the market for the treatment of colon cancer.

Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first\u2010line treatment for metastatic colorectal cancer: Safety lead\u2010in results from the QUATTRO-II study

SummaryBackground FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

The Combination Therapy of Fluorouracil and Oxaliplatin Suppress the Progression of Colon Cancer Through miR-183-5p/SOCS3 Axis and Downregulating PD-L1

PurposeThe purpose of this study was to investigate the mechanism of combination of fluorouracil (FU) and oxaliplatin (OXA) on the progression of colon cancer via miR-183-5p/SOCS3 axis and regulating PD-L1.MethodsHCT116 cells were treated with 4 μM OXA and 10.5 μM FU, or exogenous regulation of the expression of miR-183-5p, SOCS3 and PD-L1 in HCT116 cells. CCK-8 assay was employed to detect cell viability of HCT116 cells. Flow cytometry was performed to assess the apoptosis and cell cycle. The expression level of SOCS3, PD-L1, chemokines (CCL1, CCL4 and CCL7) and immune escapes related proteins (EGFR, STARD1 and STARD3) in HCT116 cells were assessed by Western blotting. In addition, dual-luciferase reporter gene was carried out to verify the targeted relationship between miR-183-5p with SOCS3.ResultsOur study demonstrated that the combination of OXA and FU remarkably suppressed proliferation, promoted apoptosis and arrest cells in G0/G1 phrase of HCT116 cells, and observably downregulated the expression of PD-L1, CCL1, CCL4, CCL7, EGFR, STARD1 and STARD3. Meanwhile, the combination of OXA and FU significantly downregulated miR-183-5p expression. Knockdown of miR-183-5p also repressed the proliferation, promoted apoptosis and arrest cells in G0/G1 phrase of HCT116 cells, and downregulated the expression of PD-L1, CCL1, CCL4, CCL7, EGFR, STARD1 and STARD3. In addition, our study proved that miR-183-5p upregulated PD-L1 by targeting downregulated SOCS3 expression. Finally, we demonstrated that the combination therapy of OXA and FU inhibited the proliferation, promote apoptosis and arrest cells in G0/G1 phrase by downregulating PD-L1 via miR-183-5p/SOCS3 axis.ConclusionThe combination therapy of OXA and FU could suppress the malignant biological behavior, and the mechanism was realized by inhibiting PD-L1 through miR-183-5p/SOCS3 axis.

The failure of DAC to induce OCT2 expression and its remission by hemoglobin-based nanocarriers under hypoxia in renal cell carcinoma.

Background: Human organic cation transporter 2 (OCT2) is the most abundant and important uptake transporter involved in the renal excretion of cationic drugs. Abnormal hypermethylation- mediated silencing of OCT2 results in oxaliplatin resistance in renal cell carcinoma (RCC). The epigenetic activation of OCT2 by decitabine (DAC) reversed this resistance in normoxic conditions. Given the hypoxic characteristic of RCC, it is still unclear whether hypoxia promotes DAC resistance and is involved in the regulation of OCT2.Methods: The mRNA and protein expression of OCT2 was determined by qRT-PCR and Western blotting. MSRE-qPCR and BSP were used to examine methylation modifications at the OCT2 promoter. The ChIP-qPCR analysis was performed to detect the abundance of histone modification and HIF-1α. The accumulation of DAC and 5-mC were detected using LC-MS, and the amount of 5-hmC was determined by dot blot analysis. To understand the role of hypoxia in the regulation of equilibrative nucleoside transporter 1 (ENT1) expression, the HIF-1α KO cell model was constructed. The re-emulsion method was used for the construction of H-NPs, an oxygen nanocarrier based on hemoglobin, to alleviate the drug resistance of DAC under hypoxia.Results: DAC was unable to upregulate OCT2 expression in hypoxic conditions because of the hypermethylation and low H3K4me3 modification in its promoter region. Hypoxia-mediated repression of human ENT1, which was markedly suppressed in RCC, resulted in a decrease in the cellular accumulation of DAC. Besides, hypoxia-induced upregulation of histone deacetylase HDAC9, which impaired the enrichment of H3K27ac modification in the OCT2 promoter, led to the transcriptional repression of OCT2. H-NPs could attenuate the hypoxia-induced loss of DAC activity and sensitize RCC cells to the sequential combination therapy of DAC and oxaliplatin.Conclusions: Hypoxia-mediated repression of ENT1 led to the inability of DAC to upregulate the expression of OCT2 under hypoxia. H-NPs could alleviate resistance to oxaliplatin and DAC in RCC cells under hypoxia and may have potential clinical applications.

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

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

A case of chemotherapy for unresectable sigmoid colon cancer with severe cardiac dysfunction

Abstract Background In the treatment of advanced cancer patients with severe cardiac dysfunction, there is a risk that the side effects of the chemotherapy may lead to a serious situation, and it is necessary to carefully judge the indications. There were only a few reported cases of chemotherapy for such patients. Here we report our experience with a patient who had continued chemotherapy for more than a year and a half for advanced sigmoid colon cancer with severe cardiac dysfunction. Case presentation A 73-year-old man came to our hospital because positive fecal occult blood was pointed out in a medical examination in March 2017. He had been diagnosed dilated cardiomyopathy at the age of sixty, and his LVEF was about 25% by the recent echocardiogram. A colonoscopy was performed in May, sigmoid colon cancer was found, and further CT examination was revealed multiple liver metastases. We determined that surgery was not a possible treatment option for him, and we decided to perform chemotherapy. In June we introduced to the patient S-1 plus oxaliplatin combination therapy. We changed to S-1 plus irinotecan combination therapy because of becoming PD from November in the same year. After that SD was maintained for a while, but it became PD by December 2018, and we changed to FTD/TPI as the third line chemotherapy from January 2019. Discussion Median survival of BSC follow-up for unresectable advanced recurrent colorectal cancer was reported to be 6 to 8 months. This case has survived more than a year and a half after starting chemotherapy, suggesting that chemotherapy should be performed as much as possible even for cancer patients with severe cardiac dysfunction. However, there are few such case reports, and it is necessary to accumulate and study more cases from now on.

Assembly simulation and synergistic chemotherapy of TPGS derivative functionalized polymersomes in hepatocellular carcinoma.

Aim: Multidrug resistance and severe side effects lead to poor therapeutic efficacy of monotherapy against hepatocellular carcinoma. Here, a targeting codelivery nanocomposite system is constructed to reverse tumor multidrug resistance and realize a combination therapy of doxorubicin and oxaliplatin. Methods & materials: We simulate the composited structure ofTPGS-lactobionic acid conjugate (TLA) modified methyl poly(ethylene glycol)-polylactide(mPP) polymersomes using dissipative particle dynamics. Cellular uptake and drug retention, cytotoxicity, in vivo antitumor efficacy and toxicity were evaluated. Results: TLA/mPP composited polymersomes improved intracellular accumulation of coloaded drugs via active targeting ability and P-gp efflux inhibition, leading to strong cytotoxicity against HepG2/ADR cells and potent tumor inhibition (93.5%) for HepG2/ADR tumor. Conclusion: TLA/mPP composited polymersomes represent a promising multifunctional nanoplatform against hepatocellular carcinoma.

OXALIPLATIN RE-INTRODUCTION THERAPY AMONG PATIENTS WITH ADVANCE STAGE COLORECTAL CANCER

Background: : Retreating with prior chemotherapeutic regimens is a possible option for palliative treatment for patients with advanced stage colorectal cancer (CRC). Objective: This study aimed to examine the feasibility and clinical outcomes of oxaliplatin re-introduction therapy.&#x0D; Methods: The present study was a prospective case series of patients with advanced stage colorectal adenocarcinoma who were previously treated and re-treated with oxaliplatin combination therapy at Phramongkutklao Hospital between April 1st, 2011 and March 30th, 2014. Treatment regimens are described below. First, FOLFOX4 (14-day cycles of oxaliplatin 85 mg/m2, folinic acid 200 mg/m2) was given days 1-2 plus fluorouracil 400 mg/m2 (bolus) and 600 mg/m2 (continuous 22 hours infusion). Second, modificd FOLFOX6 (oxaliplatin 85 mg/m2) was given day I with calcium folinate 400 mg/m2 as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m2 and a 46-hour infusion of 5-fluorouracil 2,400 mg/m2). Similarly, XELOX (130 mg/m2 intravenous oxaliplatin) was provided for 2 hours day 1 plus oral capecitabine 1,000 mg m2 twice daily for 2 weeks from day 1. Treatment was continued until disease progression (PD), intolerability to therapy, poor performance status, withdrawal of consent or death occurred. Authors evaluated tolerability, feasibility, types and rate of untoward medical occurrences due to adverse reactions of PD.&#x0D; Results: Thirteen patients with CRC were recruited in the study. The median cycles (range) of receiving oxaliplatin-based chemotherapy before re-introduction therapy was 8 (3-15) cycles. The median age (range) was 50 (27-78) years. Etiologies of treatment cessation were recorded by number of patients as follows: tumor progression (6), lost to follow-up (1), refused to receive further treatment (1), allergic reaction (2) and physical deterioration (2). Eflicacy of the treatment was assessed in 10 of 13 patients. Of 10 patients, 2 developed drug allergies and 1 was lost to follow-up. Six patients (60%) had PD while 4 patients (40%) had stabilized disease measured by the Response Evaluation Criteria in Solid Tumors (RECIST).&#x0D; Conclusion: Reintroducing oxaliplatin combination chemotherapy is one of the treatments in advanced stage CRC. In this study, physical deterioration and tumor progression were the main etiologies of treatment cessation.