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Background: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. Methods: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. Results: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1–61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1–5.7) and median overall survival was 13.1 months (95% CI 12.2–15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. Conclusions: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). Trial registration: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. Methods This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. Results A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1–61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1–5.7) and median overall survival was 13.1 months (95% CI 12.2–15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. Conclusions The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). Trial registration ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.

Background: The most common loadable chemotherapeutic drugs in drug-eluting bead transarterial chemoembolization (DEB-TACE) include doxorubicin, epirubicin, etc. CalliSpheres® beads have exhibited efficient loadability and eluting characteristics for raltitrexed as well as in vitro and animal experiments. However, the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage hepatocellular carcinoma (HCC) remain unclear. Objectives: To assess the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage HCC. Design: The study was conducted as a single-arm prospective study. Methods: This study was a prospective, single-arm trial conducted between June 2019 and June 2022. CalliSpheres® beads loaded with raltitrexed were used in the DEB-TACE procedure. The follow-up lasted for at least 1 year or until death. The primary endpoint was overall survival (OS), and the secondary endpoints were time to progression (TTP), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Results: The 6-month ORR and disease control rates were 90.1% and 93.8%, respectively. The median OS was 33.0 months. The 1-, 2-, and 3-year survival rates were 95.1%, 82.1%, and 43.6%, respectively. Child–Pugh class and bilobar disease occurrence were identified as independent OS predictors. The median TTP and PFS were 22.7 and 19.8 months, respectively. Eleven (11.5%) patients experienced at least one grade 3 AE, and serious AEs were reported in five participants (5.2%). No patient experienced grade 4 or 5 AEs. Conclusion: Raltitrexed-loaded DEB-TACE is feasible, safe, and effective in patients with intermediate-stage HCC. Trial registration: This trial was registered at www.chictr.org.cn under the identifier: 1900024097 on 25 June 2019. Plain language summary: Efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage hepatocellular carcinoma The utility of raltitrexed-loaded CalliSphere® beads in drug-eluting bead transarterial chemoembolization (DEB-TACE) has been demonstrated in in vitro and animal experiments. However, its efficacy and safety in patients with intermediate-stage hepatocellular carcinoma (HCC) remain unclear. Hence, this study aimed to assess the efficacy and safety profiles of DEB-TACE for such patients. We discovered that raltitrexed-loaded DEB-TACE led to a 6-month ORR of 90.1%, a median OS of 33.0 months, a median TTP of 22.7 months, and a median PFS of 19.8 months. The 1-, 2-, and 3-year survival rates were 95.1%, 82.1%, and 43.6%, respectively. Factors such as Child-Pugh class and bilobar disease occurrence were identified as independent predictors of OS. The study also showed acceptable safety profiles, with a low incidence of grade 3 adverse events and no grade 4 or 5 adverse events. The results indicated that raltitrexed-eluting CalliSpheres® beads for TACE can be a viable option for treating patients with intermediate-stage HCC. [ABSTRACT FROM AUTHOR]

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/m2 on day 1) and paclitaxel (135 mg/m2 on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m2 on day 1 every 3 weeks)] as 2nd-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 vs. 1.7 months; P = 0.148). OS was also prolonged with RP compared to P (10.2 months vs. 6.1 months; P = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; P = 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% vs. 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 (P = 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.

Abstract Background: Esophageal squamous cell cancer (ESCC) accounts for approximately 90% of esophageal cancer cases in China. There are no standard regimens for second or third–line chemotherapy of metastatic squamous esophageal cancer. The objective of this study was to investigate the security and effectiveness of irinotecan combined with raltitrexed or irinotecan monotherapy for salvage chemotherapy of ESCC. Methods: One hundred and twenty–eight patients with metastatic ESCC confirmed by histopathology were enrolled into this study. These patients had failure of the first–line chemotherapy combination of fluorouracil or platinum or paclitaxel and had not undergone chemotherapy with irinotecan or raltitrexed previously. Patients were randomly divided into irinotecan combined with raltitrexed group (experiment group) and irinotecan monotherapy group (control group). Overall survival (OS) and progression–free survival (PFS) were the primary endpoint. Results: In the control group, the median PFS (mPFS) and median OS (mOS) of patients were 3.37 and 5.3 months. In the experiment group, mPFS and mOS were 3.91 and 7.0 months. There was statistical significance of PFS and OS between two groups (PFS P = 0.002, OS P = 0.01). In subgroup analysis, in the second–line treatment, the mPFS of control and experiment group, was 3.90 and 4.60 months, mOS was 6.95 and 8.5 months, which was statistically significant differences between the two groups. (PFS P = 0.001, OS P = 0.005), In the third–line and beyond treatment, mPFS of control and experiment group was 2.80 and 3.19 months, mOS were 4.5 and 4.8 months. But there was no significant difference of PFS or OS between the two groups (PFS P = 0.19, OS P = 0.31). There was no statistical significance of toxicity side effects between two groups. Conclusions: The PFS and OS of irinotecan plus raltitrexed may be better than that of irinotecan monotherapy, especially in second line treatment, which should be confirmed with a phase III study including much more patients.

Abstract Background Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC) and soft tissue sarcoma. Raltitrexed is well known to be effective in the treatment of colorectal cancer in China. The present study aims to investigate the combinatory antitumor effect of anlotinib and raltitrexed on human esophageal squamous carcinoma cells and further explore the molecular mechanisms in vitro. Methods Human esophageal squamous cell lines KYSE-30 and TE-1 were treated with anlotinib or raltitrexed, or both, then cell proliferation was measured by MTS and colony formation assay; cell migration and invasion were detected by wound-healing and transwell assays; cell apoptosis rate was studied by flow cytometry and the transcription of apoptosis-associated proteins were monitored by quantitative polymerase chain reaction (qPCR) analysis. Finally, western blot was performed to check phosphorylation of apoptotic proteins after treatment. Results Treatment with raltitrexed and anlotinib showed enhanced inhibitory effects on cell proliferation, migration and invasiveness compared with raltitrexed or anlotinib monotherapy. Meanwhile, raltitrexed combined with anlotinib strongly increased cell apoptosis percentage. Moreover, the combined treatment down-regulated mRNA level of the anti-apoptotic protein Bcl-2 and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9), while up-regulated pro-apoptotic Bax and caspase-3 transcription. Western blotting showed that the combination of raltitrexed and anlotinib could inhibit the expression of phosphorylated Akt (p-Akt), Erk (p-Erk) and MMP-9. Conclusions This study indicated that raltitrexed enhanced the antitumor effects of anlotinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, providing a novel treatment option for patients with esophageal squamous cell carcinoma (ESCC).

Background: Esophageal squamous cell cancer (ESCC) accounts for approximately 90% of esophageal cancer cases in China. There are no standard regimens for second or third–line chemotherapy of metastatic squamous esophageal cancer. The objective of this study was to investigate the security and effectiveness of irinotecan combined with raltitrexed or irinotecan monotherapy for salvage chemotherapy of ESCC. Methods: One hundred and twenty–eight patients with metastatic ESCC confirmed by histopathology were enrolled into this study. These patients had failure of the first–line chemotherapy combination of fluorouracil or platinum or paclitaxel and had not undergone chemotherapy with irinotecan or raltitrexed previously. Patients were randomly divided into irinotecan combined with raltitrexed group (experiment group) and irinotecan monotherapy group (control group). Overall survival (OS) and progression–free survival (PFS) were the primary endpoint. Results: In the control group, the median PFS (mPFS) and median OS (mOS) of patients were 3.37 and 5.3 months. In the experiment group, mPFS and mOS were 3.91 and 7.0 months. There was statistical significance of PFS and OS between two groups (PFS P = 0.002, OS P = 0.01). In subgroup analysis, in the second–line treatment, the mPFS of control and experiment group, was 3.90 and 4.60 months, mOS was 6.95 and 8.5 months, which was statistically significant differences between the two groups. (PFS P = 0.001, OS P = 0.005), In the third–line and beyond treatment, mPFS of control and experiment group was 2.80 and 3.19 months, mOS were 4.5 and 4.8 months. But there was no significant difference of PFS or OS between the two groups (PFS P = 0.19, OS P = 0.31). There was no statistical significance of toxicity side effects between two groups. Conclusions: The PFS and OS of irinotecan plus raltitrexed may be better than that of irinotecan monotherapy, especially in second line treatment, which should be confirmed with a phase III study including much more patients. [ABSTRACT FROM AUTHOR]

Abstract Purpose Raltitrexed shows therapeutic effects and safety in many types of malignant tumors. However, reports of the clinical outcomes of raltitrexed-based transarterial chemoembolization (TACE) or drug-eluting beads TACE (DEB-TACE) in the treatment of hepatocellular carcinoma (HCC) are rare. We aim to report the preliminary outcomes of DEB-TACE loaded with raltitrexed in patients with unresectable or recurrent HCC. Methods From June 2018 to March 2020, 29 patients with unresectable or recurrent HCC were recruited from our department and treated by DEB-TACE loaded with raltitrexed. Overall survival and progression-free survival were the primary end points. Tumor response was investigated by using the modified response evaluation criteria in solid tumors (mRECIST) criteria. Results A total of 49 sessions of DEB-TACE were performed, with a technique success rate of 100%. The overall response rate and disease control rate at 1, 3, and 6 months after DEB-TACE were 72.0% and 96.0%, 57.1% and 85.7%, 47.6% and 66.7% respectively. The median progression-free survival and overall survival was 25.7 and 33.9 months, respectively. The 6-, 24- and 36-month overall survival rates were 88.4%, 66.3% and 46.3%, respectively. Minor complications were observed in 17 patients (58.6%), with no treatment-related mortality or severe adverse events. The most common treatment-related complications were abdominal pain (41.4%) and elevated ALT/AST (27.6%). Conclusion DEB-TACE loaded with raltitrexed is suggested as a safe, feasible, efficacious palliative regimen in unresectable or recurrent HCC patients.

Abstract 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.

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Background: Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC) and soft tissue sarcoma. Raltitrexed is well known to be effective in the treatment of colorectal cancer in China. The present study aims to investigate the combinatory antitumor effect of anlotinib and raltitrexed on human esophageal squamous carcinoma cells and further explore the molecular mechanisms in vitro. Methods: Human esophageal squamous cell lines KYSE-30 and TE-1 were treated with anlotinib or raltitrexed, or both, then cell proliferation was measured by MTS and colony formation assay; cell migration and invasion were detected by wound-healing and transwell assays; cell apoptosis rate was studied by flow cytometry and the transcription of apoptosis-associated proteins were monitored by quantitative polymerase chain reaction (qPCR) analysis. Finally, western blot was performed to check phosphorylation of apoptotic proteins after treatment. Results: Treatment with raltitrexed and anlotinib showed enhanced inhibitory effects on cell proliferation, migration and invasiveness compared with raltitrexed or anlotinib monotherapy. Meanwhile, raltitrexed combined with anlotinib strongly increased cell apoptosis percentage. Moreover, the combined treatment down-regulated mRNA level of the anti-apoptotic protein Bcl-2 and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9), while up-regulated pro-apoptotic Bax and caspase-3 transcription. Western blotting showed that the combination of raltitrexed and anlotinib could inhibit the expression of phosphorylated Akt (p-Akt), Erk (p-Erk) and MMP-9. Conclusions: This study indicated that raltitrexed enhanced the antitumor effects of anlotinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, providing a novel treatment option for patients with esophageal squamous cell carcinoma (ESCC). [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

The present study evaluated the efficiency, prognostic factors for and the safety of irinotecan combined with raltitrexed (TOMIRI) in patients with metastatic colorectal cancer (CRC). Outcome data of patients who received TOMIRI as first-, second- and third- or later-line treatment regimens were assessed to compare the efficacy of this regimen. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were evaluated for each group. Kaplan-Meier curves and univariate and multivariate analyses were performed to evaluate efficacy. From January 2017 to December 2019, TOMIRI was administered as a first-line treatment in 23 patients, second-line treatment in 164 patients and third- or later-line treatment in 18 patients. Irinotecan and 5-fluorouracil (FOLFIRI) was administered to another 50 patients, who served as the control group. The median PFS was 9, 7 and 6 months and the median OS was 37, 21 and 17 months for first-, second- and third- or later-line treatments, respectively. The ORRs of the included patients were 21.7, 13.4 and 11.1%, respectively, and the DCRs were 91.3, 81.7 and 66.7%, respectively. Compared with FOLFIRI, TOMIRI as a second-line chemotherapy treatment was associated with longer survival of the patients with CRC. Further analysis demonstrated that pathologic tumor-node-metastasis category, carcinoembryonic antigen, carbohydrate antigen 19-9, treatment cycles, targeted therapy, treatment of local metastases and first-line PFS were prognostic factors for second-line treatment. Among these, the number of treatment cycles was of vital importance. Hepatic dysfunction was the most commonly reported grade 1–2 (55.1%) and grade 3–4 (7.3%) adverse event. Neutropenia (12.2%), thrombocytopenia (10.2%), anemia (27.3%), proteinuria (38.1%) and hematuria (21.0%) were also common grade 1–2 adverse events. In conclusion, TOMIRI may be recommended as an effective and safe second-line treatment for metastatic CRC in the clinic. [ABSTRACT FROM AUTHOR]

Raltitrexed is a classical antifolate drug with antimetabolite and anticancer properties. In this research, we provide its detailed antitrypanosomal inhibition against six Trypanosoma species and investigate its potential mode of action. Molecular dynamics (MD) simulations and in silico analyses were used to track the binding strength and stability. Raltitrexed showed broad-spectrum trypanocidal actions against Trypanosoma brucei brucei GUTat3.1, T. b. rhodesiense IL1501, T. b. gambiense IL1922, T. evansi Tansui, T. equiperdum IVM-t1 and T. congolense IL3000. The estimated IC50 was found to be in the range of 5.18–24.13 µg/mL, indicating inhibition of Trypanosoma in the low micromolar range. Although the co-crystallized ligand had robust hydrogen bonding and lipophilic characteristics, its docking score was only −4.6 compared to raltitrexed's −7.78, indicating strong binding with T. brucei dihydrofolate reductase-thymidylate synthase (TbDHFR-TS). MD simulations support the strong binding of raltitrexed with TbDHFR-TS evidenced by low root mean square deviation (RMSD), low residues fluctuations, a tight radius of gyration (ROG) and an average of 3.38 ± 1.3 hydrogen bonds during 50 ns MD simulation. The prospective extended spectrum of raltitrexed against Trypanosoma species grants further research for the synthesis of raltitrexed derivatives and repurposing against other protozoa. [ABSTRACT FROM AUTHOR]

Background: The purpose was to compare the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin plus raltitrexed (TOMOX) to those of oxaliplatin plus 5-fluorouracil (FOLFOX) for unresectable colorectal cancer liver metastases (CRCLM). Methods: Patients with unresectable CRCLM were randomly assigned to receive HAI of TOMOX or FOLFOX. The primary end points were progression-free survival (PFS) measured from the date of randomisation until the date of disease progression and objective response rate (ORR). The secondary end points were overall survival (OS) measured from the date of randomisation until the date of death from any cause, disease control rate (DCR), and adverse events. Results: 113 patients were randomly assigned. With a median follow-up of 39.5 months, the PFS was 5.8 months [95% CI, 4.838-6.762]) and 4.6 months [95% CI, 3.419-5.781; P = 0.840], and the median OS was 17.6 months [95% CI, 13.828-21.372] and 13.1 months [95% CI, 11.215-14.985; P = 0.178] for the FOLFOX and TOMOX arm, respectively. The ORR were 26.1% vs 22.4% and DCR were 80.4% vs 71.4% in the FOLFOX and TOMOX arms. The most common severe adverse event was elevation of liver enzymes and pain, which did not differ in the two arms. Conclusion: HAI chemotherapy was effective for unresectable CRCLM. HAI of FOLFOX has similar efficacy to TOMOX, and HAI of TOMOX had shorter arterial infusion time. [ABSTRACT FROM AUTHOR]