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Canadian Journal of Gastroenterology &... 2022Although raltitrexed shows therapeutic effects in many types of malignant tumors, the therapeutic effects and safety of drug-eluting bead transarterial chemoembolization...
OBJECTIVES
Although raltitrexed shows therapeutic effects in many types of malignant tumors, the therapeutic effects and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with raltitrexed for the treatment of hepatocellular carcinoma (HCC) are rare. This study aimed to investigate the safety and efficacy of DEB-TACE with raltitrexed-loaded CalliSpheres beads (CB) in patients with unresectable or recurrent HCC.
METHODS
Between May 2018 and October 2021, 41 patients with unresectable or recurrent HCC treated by DEB-TACE loaded with raltitrexed were retrospectively enrolled. The primary end points were overall survival and progression-free survival. The response evaluation criteria in solid tumors (RECIST) criteria and modified RECIST criteria (mRECIST) were used to assess the tumor response after the DEB-TACE procedure.
RESULTS
A total of 79 DEB-TACE procedures were successfully performed, and the technical success rate was 100%. The overall response rate and disease control rate assessed by mRECIST criteria were 76.9% and 88.5%, 62.5% and 70.8%, and 35.3% and 47.1%, respectively, at 1, 3, and 6 months postprocedure. The mean progression-free survival and overall survival were 21.6 ± 3.6 and 43.7 ± 5.8 months, respectively. The 6-, 24-, and 36-month overall survival rates were 86.8%, 62.7%, and 57.1%, respectively. Minor complications were observed in 21 patients (51.2%), with no treatment-related mortality or severe adverse events. The most common treatment-related complications were abdominal pain (48.8%) and nausea (29.3%).
CONCLUSION
DEB-TACE with raltitrexed-loaded CB suggests a feasible, safe, and efficacious palliative regimen in unresectable or recurrent HCC patients.
Topics: Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Humans; Liver Neoplasms; Quinazolines; Retrospective Studies; Thiophenes; Treatment Outcome
PubMed: 36051250
DOI: 10.1155/2022/2602121 -
BMC Pharmacology & Toxicology Aug 2022Raltitrexed is a specific inhibitor of thymidylate synthase and a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In this study, we...
BACKGROUND
Raltitrexed is a specific inhibitor of thymidylate synthase and a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In this study, we investigated the effect of raltitrexed on the proliferation of HGC-27 human gastric cancer cells and its potential underlying molecular mechanism(s).
METHODS
RT-qPCR and western blotting were used to quantify RSK4 levels. Colony formation and flow cytometry assays were used to assess HGC-27 cell proliferation, cell cycle progression, mitochondrial membrane potential, and apoptosis. The expression of cell cycle and apoptosis markers were determined by western blotting.
RESULTS
Our results demonstrate that raltitrexed upregulated RSK4 mRNA and protein levels in HGC-27 cells. Moreover, raltitrexed significantly inhibited tumor cell colony formation, arrested the cell cycle, decreased the mitochondrial membrane potential, and induced apoptosis. We observed that raltitrexed was capable of upregulating the expression of Bax, cyclin A1, and CDK3, and downregulating the expression of Bcl-2 and cleaved caspase-3. Importantly, siRNA-mediated RSK4 knockdown significantly reduced the inhibitory effect of raltitrexed on cell proliferation and its promotion of cell apoptosis. Moreover, silencing of RSK4 inhibited the raltitrexed-induced upregulation of cytochrome C. In addition, the changes in molecular markers related to the cell cycle and apoptosis induced by raltitrexed were reduced upon RSK4 depletion.
CONCLUSION
Our study shows that RSK4 is a key target of raltitrexed in the regulation of gastric cancer cell proliferation, cell cycle progression, and apoptosis.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Quinazolines; Stomach Neoplasms; Thiophenes
PubMed: 36031631
DOI: 10.1186/s40360-022-00605-2 -
Neurochemical Research Dec 2022Chemotherapeutic agents such as methotrexate (MTX), raltitrexed (RTX), 5-fluorouracil (5-FU), hydroxyurea (HU), and retinoic acid (RA), and valproic acid (VPA), an...
Chemotherapeutic agents such as methotrexate (MTX), raltitrexed (RTX), 5-fluorouracil (5-FU), hydroxyurea (HU), and retinoic acid (RA), and valproic acid (VPA), an antiepileptic drug, all can cause malformations in the developing central nervous system (CNS), such as neural tube defects (NTDs). However, the common pathogenic mechanisms remain unclear. This study aimed to explore the mechanisms of NTDs caused by MTX, RTX, 5-FU, HU, RA, and VPA (MRFHRV), based on network pharmacology and molecular biology experiments. The MRFHRV targets were integrated with disease targets, to find the potential molecules related to MRFHRV-induced NTDs. Protein-protein interaction analysis and molecular docking were performed to analyze these common targets. Utilizing the kyoto encyclopedia of genes and genomes (KEGG) signaling pathways, we analyzed and searched the possible causative pathogenic mechanisms by crucial targets and the signaling pathway. Results showed that MRFHRV induced NTDs through several key targets (including TP53, MAPK1, HSP90AA1, ESR1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN) and multiple signaling pathways such as PI3K/Akt pathway, suggesting that abnormal proliferation and differentiation could be critical pathogenic contributors in NTDs induced by MRFHRV. These results were further validated by CCK8 assay in mouse embryonic stem cells and GFAP staining in embryonic brain tissue. This study indicated that chemotherapeutic and antiepileptic agents induced NTDs might through predicted targets TP53, MAPK1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN and multiple signaling pathways. More caution was required for the clinical administration for women with childbearing potential and pregnant.
Topics: Animals; Female; Mice; Pregnancy; Anticonvulsants; Class I Phosphatidylinositol 3-Kinases; ErbB Receptors; Fluorouracil; Hydroxyurea; Molecular Docking Simulation; Network Pharmacology; Neural Tube Defects; Phosphatidylinositol 3-Kinases; Tretinoin; Valproic Acid; Methotrexate; Antineoplastic Agents
PubMed: 35960485
DOI: 10.1007/s11064-022-03717-7 -
Frontiers in Oncology 2022We reported the long-term outcomes of transcatheter chemoembolization (TACE) for patients with late-stage or recurrent oral carcinoma.
OBJECTIVE
We reported the long-term outcomes of transcatheter chemoembolization (TACE) for patients with late-stage or recurrent oral carcinoma.
METHODS
This retrospective study enrolled 18 patients with late-stage or recurrent oral carcinoma between December 2015 and April 2021. The tumor-feeding artery was catheterized, and cisplatin/oxaliplatin and 5-FU/raltitrexed were infused with embolization using polyvinyl alcohol or gelatin sponge. Computed tomography was performed at about 1, 3, and 6 months after the procedure, and every 6 months after that. During the procedure and follow-up, procedure outcomes, complications, treatment efficacy, and overall survival were analyzed.
RESULTS
A total of 31 sessions of TACE were performed, with a technical success rate of 100%. Of 12 patients combined with oral hemorrhage, two patients showed rebleeding 35 and 37 days later, with a clinical efficiency of hemostasis of 88.9%. Mild complications were observed in 11 patients (61.1%). Severe complications or procedure-related deaths were not observed during or after the procedure. The objective response rate and disease control rate were 20.0% and 86.7%, 38.5% and 61.5%, and 25.0% and 50.0% at 1, 3, and 6 months later, respectively. Seventeen patients (94.4%) were followed up, with a median duration of 37.8 months (IQR 22.3-56.8). Nine patients died of tumor progression, one died of massive rebleeding, and one died of severe lung infection. The median overall survival was 23.8 months.
CONCLUSION
TACE is a safe and effective procedure with minimal invasiveness for treating late-stage or recurrent oral carcinoma. TACE can be recommended as a palliative treatment, particularly for patients with oral hemorrhage.
PubMed: 35936680
DOI: 10.3389/fonc.2022.831583 -
Journal of Gastrointestinal Surgery :... Nov 2022Unresectable hepatocellular carcinoma (HCC) has a poor prognosis. We aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) for...
BACKGROUND
Unresectable hepatocellular carcinoma (HCC) has a poor prognosis. We aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) for locally advanced HCC compared to transcatheter arterial chemoembolization (TACE).
METHODS
A propensity score-matched cohort study was performed in patients with locally advanced HCC with ≥ 4 tumors or portal vein tumor thrombosis (PVTT) who underwent either HAIC using oxaliplatin plus raltitrexed or TACE at three institutions between June 2015 and December 2021. Overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and adverse events (AEs) were compared between the groups.
RESULTS
After propensity score matching, 62 pairs of patients were evaluated. The HAIC group had longer OS (15.0 [95% CI: 12.1-17.9] vs. 9.0 [95% CI: 5.1-12.9] months; P = 0.034), better PFS (6.7 [95% CI: 5.1-8.3] vs. 4.0 [95% CI: 2.6-5.4] months; P = 0.020), and a higher ORR (RECIST 1.1: 54.8% vs. 11.3%; P < 0.001) than the TACE group in the intention-to-treat population. Compared with the TACE group, Grade 1-2 nausea and vomiting occurred significantly more frequently in the HAIC group.
CONCLUSION
Compared to TACE, HAIC significantly increased the ORR of locally advanced HCC with multiple tumors or portal invasion and prolonged survival without causing a significant increase in severe AEs.
Topics: Humans; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Liver Neoplasms; Retrospective Studies; Cohort Studies; Antineoplastic Combined Chemotherapy Protocols; Hepatic Artery; Venous Thrombosis; Treatment Outcome
PubMed: 35920966
DOI: 10.1007/s11605-022-05421-x -
Cancer Medicine Feb 2023Although the understanding of resistance to oxaliplatin (OXA) chemotherapy in colorectal cancer (CRC) has been sought for many years, drug tolerance remains a major...
BACKGROUND
Although the understanding of resistance to oxaliplatin (OXA) chemotherapy in colorectal cancer (CRC) has been sought for many years, drug tolerance remains a major challenge for cancer therapy. Revealing the molecular mechanism of OXA resistance could help to explain the poor prognosis of patients.
METHODS
Gene expression omnibus (GEO) database was searched, GSE83129, which contains RNA profiling in metastatic CRC patients treated first-line with OXA, was chosen for the following analysis. Differential expressed genes (DEGs) between the adenocarcinoma and adjacent_normal team, respectively, in the OXA responders and no-responders were analyzed. The Gene Ontology (GO) and hub genes in the protein-protein interaction (PPI) network were used for the molecular mechanism of OXA resistance. Tumor-related databases were used for the clinical relevance of the structural maintenance of chromosomes 5 (SMC5) in CRC. The in vitro assays were used to detect the molecular function of SMC5 in CRC cells. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect the expression of the structural maintenance of chromosomes 5/6 (SMC5/6) complex components upon OXA and raltitrexed (RTX) treatment. CCK-8 was used to detect the cell viability of cells with different treatment.
RESULTS
SMC5 was downregulated in CRC tissues of OXA no-response patients. Lower expression of SMC5 was correlated with a poor prognosis in CRC patients, improved this gene expression, inhibited the CRC cell growth and invasion in vitro. Furthermore, SMC5 was downregulated upon OXA treatment in CRC cells, while RTX would reverse its expression, and the combination of these two drugs restored the SMC5 level to the normal situation. Finally, RTX treatment enhanced the OXA cytotoxicity.
CONCLUSION
SMC5 is a tumor suppressor, that low expression of this gene is benefit for the development of CRC. Combination treatment with RTX and OXA may be more suitable for those OXA no-responders with lower SMC5.
Topics: Humans; Biomarkers; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Oxaliplatin; Chromosomal Proteins, Non-Histone; Cell Cycle Proteins
PubMed: 35894836
DOI: 10.1002/cam4.5074 -
Journal of Surgical Oncology Dec 2022About 55% of hepatocellular carcinoma (HCC) cases in China are advanced HCC at the initial diagnosis. We aimed to evaluate the efficacy and safety of hepatic arterial...
Hepatic arterial infusion oxaliplatin plus raltitrexed and chemoembolization in hepatocellular carcinoma with portal vein invasion: A propensity score-matching cohort study.
BACKGROUND
About 55% of hepatocellular carcinoma (HCC) cases in China are advanced HCC at the initial diagnosis. We aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) for HCC with portal vein tumor thrombosis (PVTT) compared to transcatheter arterial chemoembolization (TACE) after propensity score matching (PSM).
METHODS
A propensity score-matched cohort study was performed in patients with advanced HCC with PVTT who underwent either HAIC using oxaliplatin plus raltitrexed or TACE at three institutions between January 2016 and January 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events were compared between the groups.
RESULTS
After PSM, 44 pairs of patients were assessed. The HAIC group had longer OS (11.2 [95% confidence interval [CI]: 9.9-12.5] vs. 9.0 [95% CI: 5.3-12.7] months; p = 0.010), better PFS (5.6 [95% CI: 3.7-7.9] vs. 2.0 [95% CI: 1.3-2.7] months; p = 0.006), and a higher ORR (Response Evaluation Criteria in Solid Tumors [version 1.1]: 56.8% vs. 18.2%; p < 0.001) than the TACE group. In multivariate analysis, HAIC was identified as an independent favorable prognostic factor for survival.
CONCLUSIONS
Compared to TACE, HAIC significantly increased the ORR of HCC with portal invasion and prolonged survival without causing a significant increase in severe adverse events.
Topics: Humans; Carcinoma, Hepatocellular; Portal Vein; Oxaliplatin; Chemoembolization, Therapeutic; Liver Neoplasms; Propensity Score; Cohort Studies; Antineoplastic Combined Chemotherapy Protocols; Venous Thrombosis; Treatment Outcome
PubMed: 35856502
DOI: 10.1002/jso.27023 -
Journal of Gastrointestinal Oncology Jun 2022Local recurrence of colorectal cancer is associated with poor prognosis and quality of life. For patients not eligible for curative surgery, chemoradiation could be a...
BACKGROUND
Local recurrence of colorectal cancer is associated with poor prognosis and quality of life. For patients not eligible for curative surgery, chemoradiation could be a promising therapeutic option, but there is no consensus yet for the concurrent chemotherapy regimen. This study evaluated the effects and safety of intensity-modulated radiation therapy (IMRT) when administered concurrently with raltitrexed and irinotecan to patients with unresectable recurrent colorectal cancer.
METHODS
Eligible patients developed unresectable recurrent colorectal cancer, and were refractory to, or intolerant of, chemotherapy with fluoropyrimidine and oxaliplatin. IMRT was delivered (total dose: 50-60 Gy in 25-30 fractions) concurrently with irinotecan and raltitrexed (200 and 3 mg/m, respectively, on days 1 and 22). After treatment completion, patients underwent surgery or continued the same regimen of chemotherapy and were assessed by a multidisciplinary team. The primary endpoint was the objective response rate, defined as the proportion of patients with a confirmed complete response or partial response, assessed by radiologist and investigator after the completion of radiotherapy and reconfirmed a month later, in accordance with the Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS
All 30 patients enrolled in this study between January 2019 and July 2020 completed radiotherapy and received a median of five chemotherapy cycles (range, 2-10 cycles). Twelve patients (40.0%) experienced an objective response (two complete responses and ten partial responses) and 17 patients exhibited stable disease [disease control rate (DCR): 96.7%]. The median follow-up was 22 months (range, 4-35 months), by the end of follow-up, six (20.0%) patients had local failure in the irradiation field, four (13.3%) had regional progression outside the irradiation field, 13 (43.3%) had distant metastasis or metastatic progression and nine (30.0%) died. The median progression-free survival (PFS) and local PFS (LPFS) were 13.5 and 23 months, respectively. The incidence of grade 3 or 4 adverse events was 26.7%, the most common of which was neutropenia (13.3%).
CONCLUSIONS
IMRT with concurrent raltitrexed and irinotecan is a feasible treatment for unresectable recurrent colorectal cancer, which allows good tumor response and local control with acceptable toxicity profile.
PubMed: 35837190
DOI: 10.21037/jgo-22-308 -
Frontiers in Genetics 2022This study aimed to screen potential drugs targeting a new prognostic gene signature associated with proliferation in hepatocellular carcinoma (HCC). CRISPR Library...
This study aimed to screen potential drugs targeting a new prognostic gene signature associated with proliferation in hepatocellular carcinoma (HCC). CRISPR Library and TCGA datasets were used to explore differentially expressed genes (DEGs) related to the proliferation of HCC cells. Differential gene expression analysis, univariate COX regression analysis, random forest algorithm and multiple combinatorial screening were used to construct a prognostic gene signature. Then the predictive power of the gene signature was validated in the TCGA and ICGC datasets. Furthermore, potential drugs targeting this gene signature were screened. A total of 640 DEGs related to HCC proliferation were identified. Using univariate Cox analysis and random forest algorithm, 10 hub genes were screened. Subsequently, using multiplex combinatorial screening, five hub genes (FARSB, NOP58, CCT4, DHX37 and YARS) were identified. Taking the median risk score as a cutoff value, HCC patients were divided into high- and low-risk groups. Kaplan-Meier analysis performed in the training set showed that the overall survival of the high-risk group was worse than that of the low-risk group ( < 0.001). The ROC curve showed a good predictive efficiency of the risk score (AUC > 0.699). The risk score was related to gene mutation, cancer cell stemness and immune function changes. Prediction of immunotherapy suggetsted the IC50s of immune checkpoint inhibitors including A-443654, ABT-888, AG-014699, ATRA, AUY-922, and AZ-628 in the high-risk group were lower than those in the low-risk group, while the IC50s of AMG-706, A-770041, AICAR, AKT inhibitor VIII, Axitinib, and AZD-0530 in the high-risk group were higher than those in the low-risk group. Drug sensitivity analysis indicated that FARSB was positively correlated with Hydroxyurea, Vorinostat, Nelarabine, and Lomustine, while negatively correlated with JNJ-42756493. DHX37 was positively correlated with Raltitrexed, Cytarabine, Cisplatin, Tiotepa, and Triethylene Melamine. YARS was positively correlated with Axitinib, Fluphenazine and Megestrol acetate. NOP58 was positively correlated with Vorinostat and 6-thioguanine. CCT4 was positively correlated with Nerabine. The five-gene signature associated with proliferation can be used for survival prediction and risk stratification for HCC patients. Potential drugs targeting this gene signature deserve further attention in the treatment of HCC.
PubMed: 35836576
DOI: 10.3389/fgene.2022.900380 -
World Journal of Surgical Oncology Jul 2022Drug-eluting bead transarterial chemoembolization (DEB-TACE) with Callispheres® beads (CB) is currently used in the treatment of hepatocellular carcinoma. However,...
BACKGROUND
Drug-eluting bead transarterial chemoembolization (DEB-TACE) with Callispheres® beads (CB) is currently used in the treatment of hepatocellular carcinoma. However, clinical data regarding DEB-TACE using raltitrexed-eluting CB for gastrointestinal adenocarcinoma liver metastases (GALM) treatment is limited. We aimed to report the preliminary outcomes of DEB-TACE using CB in unresectable GALM patients.
METHODS
This retrospective study enrolled unresectable GALM patients who were treated with DEB-TACE using raltitrexed-eluting CB from October 2018 to October 2021. Totally, 25 patients, 18 males and 7 females, mean age 66.8±9.5 years, were continuously enrolled. Postoperative treatment response, survival rates, and complication were calculated during the procedure and follow-up.
RESULTS
Twenty-four patients were technically successful, with a technical success rate of 96.0%. The 3-month overall response rate and disease control rate were 21.7% and 73.9%, and 6-month overall response rate and disease control rate were 30.0% and 65.0%. The median survival time from diagnosis of GALM was 31.3 months. The median survival time and median PFS from first DEB-TACE was 21.3 months (95% confidence interval 9.1-33.5) and 10.7 months (3.7-17.7), respectively. Main adverse events included abdominal pain (36.0%), fever (12.0%), and nausea/vomiting (28.0%) after DEB-TACE. No treatment-related deaths and grade 3 or grade 4 adverse events were observed.
CONCLUSIONS
DEB-TACE using raltitrexed eluting CB was demonstrated as a safe and efficient alternative choice for GALM.
Topics: Aged; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Female; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Male; Microspheres; Middle Aged; Quinazolines; Retrospective Studies; Thiophenes; Treatment Outcome
PubMed: 35821043
DOI: 10.1186/s12957-022-02696-x