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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 -
International Immunopharmacology Dec 2023Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used...
Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: A retrospective study.
BACKGROUND
Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used HAIC regimen is oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). However, arterial infusion of fluorouracil over 46 h was not convenient. Raltitrexed, another antimetabolic agent with a long plasma half-life, allows for shorter infusion durations. We aimed to compare the effectiveness and toxicity of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) combined with HAIC with raltitrexed plus oxaliplatin (RALOX) or FOLFOX in patients with intermediate and advanced HCC.
METHODS
This retrospective study enrolled 82 eligible patients from February 2019 to December 2021. Forty patients were treated with FOLFOX HAIC (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil bolus 400 mg/m administered on day 1, and 5-fluorouracil 2400 mg/m infusion for 46 h, every 3 weeks) combined with TKIs and ICIs. Forty-two patients received RALOX HAIC (oxaliplatin 100 mg/m and raltitrexed 3 mg/m on day 1, every 3 weeks) combined with TKIs and ICIs. We compared the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile.
RESULTS
ORR was similar between the FOLFOX HAIC and RALOX HAIC groups (42.5% vs 42.5%, P = 0.974). DCR also showed no significant difference between the two groups (87.5% vs 85.7%, P = 0.813). Median PFS was 10.7 months in the FOLFOX HAIC group versus 10.2 months in the RALOX HAIC group (P = 0.41). Median OS was 20.3 months in the FOLFOX HAIC group, compared to 17.7 months in the RALOX HAIC group (P = 0.50). Both groups had similar profiles of grade 3/4 treatment-related adverse events, including thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, and leukocytopenia.
CONCLUSION
The effectiveness and safety of HAIC with RALOX were comparable to HAIC with FOLFOX in intermediate and advanced HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Fluorouracil; Oxaliplatin; Leucovorin; Retrospective Studies; Immune Checkpoint Inhibitors; Tyrosine Kinase Inhibitors; Liver Neoplasms; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37879230
DOI: 10.1016/j.intimp.2023.111019 -
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 -
Hepatology Research : the Official... Nov 2021This study aimed to evaluate efficacy and safety of raltitrexed-based transcatheter arterial chemoembolization (TACE) for intermediate and advanced hepatocellular...
AIM
This study aimed to evaluate efficacy and safety of raltitrexed-based transcatheter arterial chemoembolization (TACE) for intermediate and advanced hepatocellular carcinoma (HCC) using real-world evidence.
METHODS
All eligible HCC cases were collected from multiple centers in Chongqing, China, from January 2013 to December 2018 and divided into the raltitrexed group (raltitrexed + lobaplatin + pirarubicin) and control group (lobaplatin + pirarubicin). Propensity score matching (PSM) with a 1:1 ratio was used to eliminate the imbalance of potential confounding factors between groups. The primary end-point was overall survival (OS) and the secondary end-points were progression-free survival (PFS) and disease control rate.
RESULTS
The median follow-up period for patients in the raltitrexed and control groups was 8.7 and 5.9 months, respectively. After PSM, median OS was 10.0 months in the raltitrexed group and 7.0 months in the control group (p = 0.002). The 6-month, 1-year, and 2-year OS rates of the raltitrexed group were significantly higher than those of the control group (78.2% vs. 60.9%, p = 0.010; 43.5% vs. 22.8%, p = 0.030; and 17.4% vs. 2.2% p = 0.001, respectively). Multivariate analysis of these propensity score-matched HCC patients revealed treatment, age, tumor size, lipiodol accumulation, and the number of TACE cycles as independent predictors of OS (all p < 0.05). The disease control rate of the raltitrexed and control groups was 87.4% and 65.8%, respectively (p < 0.001).
CONCLUSIONS
Raltitrexed-based TACE can prolong the OS of patients with intermediate and advanced HCC in a real-world clinical setting, and is safe and tolerable.
PubMed: 34492152
DOI: 10.1111/hepr.13708 -
Cancer Biotherapy & Radiopharmaceuticals Oct 2023This study investigated the loadability and releasing profiles of vinorelbine and raltitrexed from CalliSpheres Beads (CB) , and further explored the pharmacokinetic...
This study investigated the loadability and releasing profiles of vinorelbine and raltitrexed from CalliSpheres Beads (CB) , and further explored the pharmacokinetic features of vinorelbine and raltitrexed eluting CB Ten milligrams vinorelbine and 0.2 mg raltitrexed were mixed with 0.15 g CB at two sizes (100-300 and 300-500 μm) for 24 h, respectively, to measure the loadability. Then vinorelbine/raltitrexed loading CBs were placed in 20% phosphate-buffered saline for 24 h to measure the release profiles. Transcatheter arterial chemoembolization (TACE) with 1 mg vinorelbine eluting CBs (two sizes respectively) and transcatheter arterial hepatic infusion (TAI) with 1 mg vinorelbine were performed in 9 rabbits (3 rabbits in each group). The above experiments were repeated with 0.2 mg raltitrexed. Vinorelbine loading efficiency quickly reached 90% within 10 min with maximum loadability >90% by CB with both two sizes, and vinorelbine release rate gradually increased to ∼100% within 1 h. Raltitrexed loading efficiency gradually increased to >40% within 15 min, then slowly increased to >60% within 24 h, with maximum loadability <70% by CB with both sizes, and raltitrexed release rate gradually increased to >90% within 1 h. Besides, vinorelbine/raltitrexed eluting CB showed greatly decreased maximum serum concentration (Cmax) of the drug compared with TAI in rabbits with similar area under the curve (0-t), mean residence time (0-t), and half-time (T1/2). CB exhibits good loadability and an acceptable releasing profile for eluting vinorelbine and raltitrexed, and shows lower Cmax and numerically stable concentration than TAI.
Topics: Animals; Rabbits; Vinorelbine; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic
PubMed: 32614660
DOI: 10.1089/cbr.2019.3360 -
Clinical Colorectal Cancer Jun 2021Use of fluoropyrimidine-based therapy in patients with metastatic colorectal cancer is associated with significant toxicities. This study aimed to assess the safety and...
BACKGROUND
Use of fluoropyrimidine-based therapy in patients with metastatic colorectal cancer is associated with significant toxicities. This study aimed to assess the safety and efficacy of raltitrexed use in patients with metastatic colorectal cancer who developed significant toxicities after fluoropyrimidine-based treatment.
PATIENTS AND METHODS
We identified patients with metastatic colorectal cancer who were treated with raltitrexed-based systemic therapy after developing serious adverse events with fluoropyrimidine-based treatment in a large Canadian province from 2004 to 2018. Demographic, tumor, and treatment characteristics were retrieved from the electronic medical records. Progression-free and overall survival were assessed from the start of raltitrexed-based therapy.
RESULTS
A total of 86 patients were identified for the study. The median age was 66.5 years, and 58.1% of patients were men. The primary cancer site was right, left, and transverse colon in 38.4%, 27.9%, and 9.3%, respectively. The remaining 24.4% had rectal cancer. Among all patients, 43.0% had received more than 2 prior systemic therapies, and 37.6% had developed previous cardiotoxicity to fluoropyrimidine-based treatment. The median progression-free and overall survival were 8.5 and 10.2 months, respectively. On multivariable Cox regression model, patients with left-sided colon cancer (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.12-0.97; P = .044) and the Eastern Cooperative Oncology Group performance status of 0/1 (HR, 0.10; 95% CI, 0.01-0.82; P = .032) had a longer progression-free survival, whereas left-sidedness of colon cancer was the only factor that predicted overall survival (HR, 0.30; 95% CI, 0.10-0.88; P = .029). Raltitrexed was well-tolerated with common adverse events that included anemia in 41.7% of patients and chemotherapy-induced nausea and vomiting in 27.4%. Most toxicities were grade 1/2, but 16.7% of patients experienced grade 3. There were no cardiac events and treatment-related deaths.
CONCLUSIONS
Raltitrexed in patients with colorectal cancer who were previously treated with fluoropyrimidine-based systemic therapy is effective and well-tolerated.
Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Canada; Colorectal Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Quinazolines; Thiophenes; Treatment Outcome
PubMed: 33268287
DOI: 10.1016/j.clcc.2020.09.006 -
Repurposing of Raltitrexed as an Effective G9a/EHMT2 Inhibitor and Promising Anti-Alzheimer's Agent.ACS Medicinal Chemistry Letters Nov 2023Herein, we report for the first time the G9a/EHMT2 inhibition and anti-Alzheimer's activities of the drug raltitrexed. G9a is a lysine methyltransferase that mainly...
Herein, we report for the first time the G9a/EHMT2 inhibition and anti-Alzheimer's activities of the drug raltitrexed. G9a is a lysine methyltransferase that mainly dimethylates the H3K9 of chromatin, which triggers the repression of genes epigenetically, leading to various diseased conditions, including Alzheimer's disease (AD). First, we demonstrate that raltitrexed inhibits G9a at 120 nM. Moreover, raltitrexed lowers the total H3K9me2/H3K9 levels in AD transgenic CL2006 worms, indicating that raltitrexed targets G9a directly. As toxicity is the bottleneck in G9a drug discovery, we conducted detailed toxicity (TOPKAT) analyses of raltitrexed and measured the food consumption by , demonstrating that raltitrexed's toxicity/function range is safe for the worm's growth. Moreover, we demonstrate that raltitrexed enhances the locomotive function of worms dose-dependently. Finally, we show that raltitrexed reduced the Aβ aggregates in worms up to 47%, highlighting the potential of raltitrexed in AD treatment.
PubMed: 37974951
DOI: 10.1021/acsmedchemlett.3c00344 -
Science Advances Mar 2024There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a...
There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported. While trying unsuccessfully to improve raltitrexed's ability to kill and remove its ability to kill human cells, we learned three lessons that may help others developing antibiotics. First, binding of raltitrexed substantially changed the configuration of the PptT active site, complicating molecular modeling of analogs based on the unliganded crystal structure or the structure of cocrystals with inhibitors of another class. Second, minor changes in the raltitrexed molecule changed its target in from PptT to dihydrofolate reductase (DHFR). Third, the structure-activity relationship for over 800 raltitrexed analogs only became interpretable when we quantified and characterized the compounds' intrabacterial accumulation and transformation.
Topics: Humans; Mycobacterium tuberculosis; Thymidylate Synthase; Bacterial Proteins; Neoplasms; Quinazolines; Thiophenes; Transferases (Other Substituted Phosphate Groups)
PubMed: 38489355
DOI: 10.1126/sciadv.adj6406 -
Cancer Biology & Medicine Aug 2023Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparing effectiveness and safety of paclitaxel plus raltitrexed paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial.
OBJECTIVE
Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus raltitrexed (RP) regimen as second-line treatment in metastatic gastric cancer (MGC) patients.
METHODS
An open, randomized, multi-center phase II clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP [raltitrexed (3 mg/m on day 1) and paclitaxel (135 mg/m on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m on day 1 every 3 weeks)] as 2-line chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), and safety.
RESULTS
PFS had a tendency to be prolonged with RP compared to P (2.7 months 1.7 months; = 0.148). OS was also prolonged with RP compared to P (10.2 months 6.1 months; = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; = 0.72). The disease control rate (DCR) in the RP and P groups was 56.2% and 36.0%, respectively. Grade 3-4 treatment-related adverse events occurred in 36.2% (RP) and 28.2% (P) of patients. Frequent grade 3-4 toxicities for RP and P were neutropenia (11.0% and 4.0%), anemia (1.4% and 4.0%), and thrombocytopenia (1.4% and 5.3%), and all grades of peripheral neurotoxicity (12.3% 17.3%). All grades of hepatic toxicity were demonstrated for the RP and P groups based on elevated aminotransferase levels (27.4% and 14.1%). Subgroup analysis shows if MGC was combined with ascites or peritoneal involvement, the OS of the RP regimen was longer ( = 0.05).
CONCLUSIONS
Second-line palliative chemotherapy with RP was shown to prolong the PFS and OS, especially among patients with ascites or peritoneal involvement, which warrants confirmation using larger sample studies.
Topics: Humans; Paclitaxel; Stomach Neoplasms; Ascites; Adenocarcinoma
PubMed: 37653589
DOI: 10.20892/j.issn.2095-3941.2023.0112 -
Frontiers in Immunology 2023Esophageal cancer (EC) is an aggressive neoplasm of the gastrointestinal tract that is usually treated with a combination of chemotherapy, radiotherapy (RT), and/or...
BACKGROUND
Esophageal cancer (EC) is an aggressive neoplasm of the gastrointestinal tract that is usually treated with a combination of chemotherapy, radiotherapy (RT), and/or surgery, according to disease status. Despite the availability of multimodal therapeutic strategies, local recurrence is frequently observed. However, there is no standard treatment or promising therapeutic approach for local recurrence or metastatic esophageal carcinoma after the RT. This study tended to investigate the efficacy and safety of sintilimab maintenance after concurrent chemoradiotherapy (CCRT) for local/regional recurrent esophageal squamous carcinoma.
METHODS
This study was a single-arm, phase Ib/II trial conducted in a single site in China. Patients previously radically treated (surgery or CCRT), histologically confirmed, local or regional recurrence esophageal squamous carcinoma, qualified for the study design, were treated with 25-28 times radiotherapy plus raltitrexed once every 3 weeks for up to two cycles. Patients who have not progressed after CCRT received sintilimab as maintenance once every 3 weeks up to 1 year. Primary endpoints were overall survival (OS) and safety. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR).
RESULTS
Between September 2019 and March 2022, in a total of 36 enrolled patients, 34 pts completed CCRT. Three patients excluded due to violation of the exclusion criteria (1 pt) and consent withdrawal (2 pts). Finally, 33 pts were included in the final analysis, in which 3 pts had disease progression, and the remaining 30 entered maintenance therapy with sintilimab. The median follow-up time was 12.3 months. Median OS was 20.6 months (95%CI 10.5-NA) and the 1-year OS rate was 64%. Median PFS was 11.5 months (95%CI 5.29-21.3) and the 1-year PFS rate was 43.6%. The ORR was 63.6% (95%CI 44.6-77.8), including 2 cases of CR and 19 cases of PR. The DCR was 19.9%, the median DOR was 19.5 months, and the median TTR was 2.4 months. The rate of any grade TRAEs was 96.7%; ≥Grade 3 TRAE was 23.4%. The incidence of immune-related AE was 60%, most of which were grade 1-2, and only one case of thyroid-stimulating hormone increased was irAE with grade 3 or above.
CONCLUSION
Sintilimab has shown promising clinical efficacy and a manageable safety profile as maintenance therapy after CCRT for local/regional recurrent esophageal squamous carcinoma. In addition, further confirmation from a large-scale real-world study is still needed.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma
PubMed: 37325650
DOI: 10.3389/fimmu.2023.1193394