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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 -
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 -
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 -
Cancer Control : Journal of the Moffitt... 2022Irinotecan-based doublet chemotherapy strategy was standard second-line backbone for patients with oxaliplatin-refractory metastatic colorectal cancer. The aim of this... (Clinical Trial)
Clinical Trial
OBJECTIVE
Irinotecan-based doublet chemotherapy strategy was standard second-line backbone for patients with oxaliplatin-refractory metastatic colorectal cancer. The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.
METHODS
The study was a prospective, single-center, non-randomized, open-label phase II clinical trial. Patients with mCRC after failure with oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m) and raltitrexed (2.5 mg/m) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AEs).
RESULTS
Between December 2012 and October 2016, 33 and 35 patients enrolled were assessed for response and safety, respectively. The ORR was 8.6%, and the DCR was 71.4%. The median PFS was 4.5 months (95% CI 3.8-5.2). The median OS was 12.0 months (95% CI 8.5-15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 AEs were anorexia (14.3%), vomiting (14.3%), nausea (11.4%), fatigue (8.6%), and leukopenia (8.6%). No one died from treatment-related events. The incidence and severity of toxicity were irrelevant to UGT1A1 status.
CONCLUSIONS
The combination of irinotecan with raltitrexed is an efficient, convenient, and acceptable toxic regimen for second-line treatment for mCRC patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Irinotecan; Prospective Studies; Quinazolines; Thiophenes
PubMed: 35343258
DOI: 10.1177/10732748221080332 -
Annals of Oncology : Official Journal... Apr 2002Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC),... (Review)
Review
Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC), and has single-agent activity in a variety of advanced solid tumours. Although both raltitrexed and 5-FU are thymidylate synthase inhibitors, raltitrexed has a specific mode of action and a toxicity profile distinct from 5-FU. The mechanism of action of raltitrexed is also completely different from that of oxaliplatin, irinotecan and other drugs with which it has been combined. These properties, together with preclinical data, suggested that combinations of raltitrexed with 5-FU, other chemotherapeutic agents, or radiotherapy could result in improved therapies for a variety of advanced solid tumours, including advanced CRC. This review outlines the appropriate management of patients treated with raltitrexed, whether as monotherapy or in combination, and discusses the preliminary results of combination studies with raltitrexed in a range of tumour types including advanced CRC, malignant mesothelioma, gastric, pancreatic, head and neck, and non-small-cell lung cancers. Of particular interest is the combination of raltitrexed and oxaliplatin, which has shown promising antitumour effects in first-line treatment of advanced CRC and malignant mesothelioma, a disease that is refractory to chemotherapy.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Mesothelioma; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Thiophenes
PubMed: 12056700
DOI: 10.1093/annonc/mdf054 -
Medicine Jan 2020The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable,... (Clinical Trial)
Clinical Trial
BACKGROUND
The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC).
METHODS
Eligible patients were adults with newly diagnosed untreated, unresectable esophageal cancer in stages I to IV with lymph node metastases or cervical esophageal cancer. Patients received nedaplatin 25 mg/m per day on day 1-3, raltitrexed 3 mg/m on days 1 repeated every 21 days for 2 cycles, and combined concurrent radiotherapy (2 Gy/fraction, total dose of 60 Gy).
RESULT
Thirty patients were included with squamous cell carcinoma. The median follow-up duration was 24 months. The overall response rate was 90%. The 1-year and 2-year overall survival rates for all patients were 70.4% and 55.7% with a median survival time of 30 months, and the median progression free survival was 20 month. The major toxicities were leukopenia and thrombopenia, with grade 3 to 4 leukopenia and thrombopenia were 50% and 30% of patients.
CONCLUSION
Concurrent chemoradiotherapy with raltitrexed and nedaplatin agents frequently caused myelosuppression but was highly active and suggested to be a promising treatment option for locally advanced ESCC.
Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Dose-Response Relationship, Radiation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Humans; Longitudinal Studies; Male; Middle Aged; Organoplatinum Compounds; Quinazolines; Retrospective Studies; Thiophenes; Treatment Outcome
PubMed: 31977864
DOI: 10.1097/MD.0000000000018732 -
Journal of Gastrointestinal Oncology Feb 2023Patients with metastatic colorectal cancer (mCRC) beyond second line treatment have a poor prognosis. Fruquintinib, regorafenib, trifluridine/tipiracil (TAS-102),...
BACKGROUND
Patients with metastatic colorectal cancer (mCRC) beyond second line treatment have a poor prognosis. Fruquintinib, regorafenib, trifluridine/tipiracil (TAS-102), panitumumab and cetuximab combined with single-agent chemotherapy regimens are currently recommended as third-line therapies for patients exhibiting disease progression. Effective late-line therapies for mCRC are urgently needed. The FRESCO randomized clinical trial (RCT) prompts fruquintinib as a third-line treatment in advanced colorectal cancer (CRC). A phase II study in our center reported the efficacy and safety of S-1 plus raltitrexed for the treatment of chemo-refractory mCRC. The combination of the fruquintinib, raltitrexed, and S-1 has not been reported in mCRC.
CASE DESCRIPTION
This case report presents a patient with mCRC who received third-line treatment with fruquintinib, raltitrexed, and S-1. A 54-year-old male presenting with hematochezia was admitted to West China Hospital of Sichuan University in June 2017 and underwent surgery for a tumor between the rectum and sigmoid colon. Postoperative pathology identified adenocarcinoma (wild-type RAS/RAF, no PIK3CA mutation), and the patient was diagnosed with mCRC (pathological stage, pT3pN1apM0). The mFOLFOX6 regimen was administered. The patient was subsequently diagnosed with Hodgkin lymphoma in May 2018 and treated with the ABVD regimen after multidisciplinary discussions. Liver metastases (intestinal-type adenocarcinoma) were detected in November 2018, and second-line therapy with the FOLFIRI regimen was initiated in January 2019. Lung metastases were identified in September 2019, so the patient was treated with a combination of raltitrexed, S-1, and fruquintinib. A partial response (PR) was detected in November 2019, and the patient underwent resection of the hepatic lesion on November 5, 2020. Computed tomography (CT) images in November 2021 revealed a stable disease; thus, raltitrexed was discontinued, and S-1 and fruquintinib were maintained. The treatment is still responding until the last follow-up (December 2022).
CONCLUSIONS
The case was characterized by the simultaneous existence of mCRC and Hodgkin lymphoma, which required management by a multidisciplinary team. Third-line therapy with fruquintinib, raltitrexed, and S-1 achieved a PR that permitted surgical resection and enabled a relatively long progression-free survival. The findings suggest that the three agents regimen might be clinically effective as late-line therapy for mCRC.
PubMed: 36915460
DOI: 10.21037/jgo-23-39 -
American Journal of Translational... 2021To investigate the short-term efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with epirubicin and raltitrexed in the treatment of...
OBJECTIVE
To investigate the short-term efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with epirubicin and raltitrexed in the treatment of intermediate and advanced primary hepatocellular carcinoma (PHC).
METHODS
One hundred patients with intermediate or advanced PHC were randomly divided into a control group (the CG, n=50) and an observation group (the OG, n=50). The CG was treated with conventional TACE (cTACE), and the OG was treated with DEB-TACE loaded with epirubicin and raltitrexed. The overall efficiency, the liver function indices, the tumor markers, the macrophage migration inhibitory factor (MIF) levels , the lesion diameters, the Child-Pugh scores, the adverse reactions, the median times to disease progression, the 1-year and 2-year recurrence rates, and the survival rates were compared between the two groups.
RESULTS
At 6 months after the surgery, the overall response rate in the OG (82.00%) was higher than it was in the CG (62.00%) (<0.05). The serum alanine aminotransferase, total bilirubin, and aspartate aminotransferase levels were elevated in both groups after the intervention, but they were lower in the OG than they were in the CG (<0.05). The serum alpha-fetoprotein, carcinoembryonic antigen, and MIF levels, and the lesion diameters were lower in both groups at one month after the intervention, and they were lower in the OG than they were in the CG (<0.05). The incidence of abnormal blood test results in the OG was lower than it was in the CG (<0.05). The OG also exhibited a longer median time to disease progression, lower 1-year and 2-year recurrence rates, and higher 1- and 2-year survival rates than the CG (<0.05).
CONCLUSION
DEB-TACE loaded with epirubicin and raltitrexed improves the short-term outcomes, reduces the tumor load, decreases the incidence of adverse events, and improves the survival rate in patients with intermediate and advanced PHC.
PubMed: 34540079
DOI: No ID Found -
Journal of Interventional Medicine May 2019To investigate the safety, efficacy, and prognostic factors of hepatic arterial infusion chemotherapy (HAIC) with raltitrexed and oxaliplatin post-transarterial...
Safety and efficacy of hepatic arterial infusion chemotherapy with raltitrexed and oxaliplatin post-transarterial chemoembolization for unresectable hepatocellular carcinoma.
OBJECTIVE
To investigate the safety, efficacy, and prognostic factors of hepatic arterial infusion chemotherapy (HAIC) with raltitrexed and oxaliplatin post-transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (uHCC).
METHODS
Thirty-seven patients with uHCC who received HAIC with raltitrexed and oxaliplatin post-TACE between June 2014 and December 2016 at our hospital were recruited. The primary endpoint was overall survival (OS), and secondary endpoint was progression-free survival (PFS). The overall response rate (ORR) was evaluated using the modified Response Evaluation Criteria in Solid Tumors. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (v4.0). The OS and prognostic factors were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression models.
RESULTS
Three (8.1%) patients achieved complete response, 17 (46.0%) patients achieved partial response, and the ORR was54.0%.The median OS and median PFS were 19.0 months and 12.0 months, respectively. The common toxicities included grade 3-4 increased aspartate aminotransferase levels (8/37,21.6%), grade 1-2 hyperbilirubinemia (75.7%, 28/37), nonspecific abdominal pain and fever, and grade 2-3 thrombocytopenia (18.9%, 7/37); no patients developed grade 3-4 neutropenia. Univariate analysis showed that the tumor diameter (≤50 mm, p = 0.028), Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.012), hepatitis B virus DNA level (p = 0.033), and derived neutrophil-to-lymphocyte ratio (dNLR; derived neutrophils/leukocytes minus neutrophils) (p = 0.003) were predictive factors for prognosis. Multivariate analysis showed that patients with BCLC stage B disease (p = 0.029) and dNLR≤2 before therapy (p = 0.004) had better prognosis.
CONCLUSIONS
HAIC with raltitrexed and oxaliplatin post-TACE is a safe and efficacious therapy for patients with uHCC; in particular, those with BCLC stage B and dNLR≤2 have better prognosis.
PubMed: 34805879
DOI: 10.1016/j.jimed.2019.07.006 -
Therapeutic Advances in Gastroenterology 2022Raltitrexed plus S-1 (RS) and regorafenib both showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. This study aims to compare the...
BACKGROUND
Raltitrexed plus S-1 (RS) and regorafenib both showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. This study aims to compare the effectiveness and safety of two different regimens in patients with refractory mCRC.
METHODS
This retrospective cohort study included mCRC patients who were treated with RS or regorafenib from February 2017 to June 2021. A propensity score matching (PSM) analysis was conducted to balance the baseline characteristics of all patients. Progression-free survival (PFS), overall survival (OS), tumor response, and safety of two regimens were evaluated.
RESULTS
A total of 187 patients were included in our study, with 107 patients in the RS group and 80 patients in the regorafenib group. After PSM, 78 pairs were recognized. Patients treated with RS had a semblable PFS compared to those treated with regorafenib before PSM (4.8 months 5.5 months, = 0.400) and after PSM (4.7 months 5.4 months, = 0.430). Patients in the RS group were associated with a longer OS than those in the regorafenib group (13.4 months 10.1 months, = 0.010). A similar trend of OS was also obtained in the matched cohort (13.3 months 10.0 months, = 0.024). Both objective response rate (12.8% 5.1%, = 0.093) and disease control rate (53.8% 46.2%, = 0.337) in the RS cohort were higher than those in the regorafenib group, without significant differences. Adverse events (AEs) of each group were well tolerated.
CONCLUSION
Patients treated with RS demonstrated a longer OS than those treated with regorafenib and had manageable AEs, which could be recognized as a primary choice for refractory mCRC.
PLAIN LANGUAGE SUMMARY
-Both raltitrexed plus S-1 (RS) and regorafenib showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. No study has compared the two regimens yet. Therefore, we compare the efficacy and safety between RS and regorafenib to provide an optimal treatment option. We retrospectively included patients with mCRC who failed at least two standard treatments. All enrolled patients received RS or regorafenib treatments. We conducted a propensity score matching to eliminate differences in the enrolled patients. After the analysis, we found no significant differences in progression-free survival in patients between the two groups. However, patients treated with RS had a longer OS than those treated with regorafenib, whether before matching (13.4 months 10.1 months, = 0.010) or after matching (13.3 months 10.0 months, = 0.024). In addition, the adverse effects caused by cancer-related therapy were tolerable for the patient. Certainly, this is a non-randomized retrospective study with a small sample size, so we conducted a propensity score matching to minimize potential bias. Importantly, this is the first research comparing the two treatments, and we believe that the results of this article could present a primary choice for clinical doctors dealing with patients with standard treatments that failed mCRC.
PubMed: 35601804
DOI: 10.1177/17562848221098246