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BMC Cancer Mar 2023Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC)...
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).
Topics: Humans; Esophageal Squamous Cell Carcinoma; Carcinoma, Non-Small-Cell Lung; Esophageal Neoplasms; Matrix Metalloproteinase 9; Proto-Oncogene Proteins c-akt; Lung Neoplasms; Apoptosis
PubMed: 36870981
DOI: 10.1186/s12885-023-10691-y -
Cancer Imaging : the Official... Feb 2023Raltitrexed shows therapeutic effects and safety in many types of malignant tumors. However, reports of the clinical outcomes of raltitrexed-based transarterial...
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.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Doxorubicin; Treatment Outcome; Chemoembolization, Therapeutic; Retrospective Studies
PubMed: 36814327
DOI: 10.1186/s40644-023-00534-1 -
Translational Vision Science &... Feb 2023Using previously approved medications for new indications can expedite the lengthy and expensive drug development process. We describe a bioinformatics pipeline that...
PURPOSE
Using previously approved medications for new indications can expedite the lengthy and expensive drug development process. We describe a bioinformatics pipeline that integrates genomics and proteomics platforms to identify already-approved drugs that might be useful to treat diabetic retinopathy (DR).
METHODS
Proteomics analysis of vitreous humor samples from 12 patients undergoing pars plana vitrectomy for DR and a whole genome dataset (UKBiobank TOPMed-imputed) from 1330 individuals with DR and 395,155 controls were analyzed independently to identify biological pathways associated with DR. Common biological pathways shared between both datasets were further analyzed (STRING and REACTOME analyses) to identify target proteins for probable drug modulation. Curated target proteins were subsequently analyzed by the BindingDB database to identify chemical compounds they interact with. Identified chemical compounds were further curated through the Expasy SwissSimilarity database for already-approved drugs that interact with target proteins.
RESULTS
The pathways in each dataset (proteomics and genomics) converged in the upregulation of a previously unknown pathway involved in DR (RUNX2 signaling; constituents MMP-13 and LGALS3), with an emphasis on its role in angiogenesis and blood-retina barrier. Bioinformatics analysis identified U.S. Food and Drug Administration (FDA)-approved medications (raltitrexed, pemetrexed, glyburide, probenecid, clindamycin hydrochloride, and ticagrelor) that, in theory, may modulate this pathway.
CONCLUSIONS
The bioinformatics pipeline described here identifies FDA-approved drugs that can be used for new alternative indications. These theoretical candidate drugs should be validated with experimental studies.
TRANSLATIONAL RELEVANCE
Our study suggests possible drugs for DR treatment based on an integrated proteomics and genomics pipeline. This approach can potentially expedite the drug discovery process by identifying already-approved drugs that might be used for new indications.
Topics: United States; Humans; Proteomics; Diabetic Retinopathy; Genomics; Diabetes Mellitus
PubMed: 36745438
DOI: 10.1167/tvst.12.2.8 -
Annals of Translational Medicine Dec 20225-Fluorouracil and its oral prodrug, capecitabine, are frequently used in the treatment of gastrointestinal cancers-including gastric cancer-but carry a cardiotoxicity...
BACKGROUND
5-Fluorouracil and its oral prodrug, capecitabine, are frequently used in the treatment of gastrointestinal cancers-including gastric cancer-but carry a cardiotoxicity risk. Raltitrexed (brand name Tomudex), a direct inhibitor of thymidylate synthase, has been successfully used as an alternative to fluoropyrimidines in patients with 5-fluorouracil-induced cardiac events. We report the first case, to our knowledge, of raltitrexed used with trastuzumab and platinum-based chemotherapy as a substitute for fluoropyrimidines following cardiotoxicity in a 78-year-old male patient with metastatic gastric cancer.
CASE DESCRIPTION
The patient experienced a myocardial infarction 3 days after beginning treatment with capecitabine, carboplatin, and trastuzumab for metastatic HER2 gastric adenocarcinoma. Capecitabine was replaced with raltitrexed, and the patient ultimately received seven cycles of chemotherapy, five of which included raltitrexed. There were no cardiotoxic events attributable to raltitrexed, although the patient did experience hypotensive episodes, premature ventricular contractions, myelosuppression, and anemia. Progression-free survival was 4.5 months, within the expected range achieved with the ToGA regimen (trastuzumab, cisplatin, 5-fluorouracil chemotherapy). At time of writing, the patient has been alive for 48 weeks since diagnosis.
CONCLUSIONS
In summary, raltitrexed appears to be a safe alternative to fluoropyrimidines when combined with trastuzumab and platinum, although more data is needed to determine its relative effectiveness.
PubMed: 36618781
DOI: 10.21037/atm-2022-69 -
Journal of Global Health Dec 2022China implemented the national drug price negotiation (NDPN) policy to include 17 innovative anticancer medicines in the national reimbursement drug list in 2018. We...
Impact of the national drug price negotiation policy on the utilization, cost, and accessibility of anticancer medicines in China: A controlled interrupted time series study.
BACKGROUND
China implemented the national drug price negotiation (NDPN) policy to include 17 innovative anticancer medicines in the national reimbursement drug list in 2018. We aimed to assess the impact of this policy on the utilization, cost, and accessibility of anticancer medicines.
METHODS
We obtained monthly medicine procurement data from 1039 hospitals from October 2017 to December 2019. We examined changes in availability, utilization, defined daily dose cost (DDDc), and affordability of the medicines using descriptive statistics and controlled interrupted time series analysis, measuring utilization by defined daily doses (DDDs). Cetuximab and raltitrexed were compared separately for the same indication.
RESULTS
The mean availability of 17 negotiated anticancer medicines was 28.78% after the NDPN, amounting to an increase of 25.22%. The availability increased by 7.88% (95% confidence interval (CI) = 4.31%, 11.45%, P < 0.001) immediately and by 1.23% (95% CI = 0.81%, 1.64%, P < 0.001) per month after policy implementation. Compared with the control group, the utilization of the medicines increased by 11.44 DDDs (95% CI = 2.42, 20.46, P = 0.014) immediately and by 3.54 DDDs (95% CI = 2.47, 4.60, P < 0.001) per month after policy implementation, while the DDDc decreased by US$109.09 (95% CI = 68.14, 150.05, P < 0.001) immediately and remained stable thereafter. The results on cetuximab and raltitrexed were similar. Availability and utilization differed among regions in east, middle, and west China. Out-of-pocket costs decreased by 17.35 times the catastrophic health expenditures to 1.99 times, but the affordability ratio for 14 negotiated medicines was still greater than 1.
CONCLUSIONS
The NDPN policy improved the availability, utilization, and affordability of anticancer medicines. China's experience in NDPN provides a reference for other countries. However, the availability and affordability of anticancer medicines still need further improvement.
Topics: Humans; Interrupted Time Series Analysis; Negotiating; Cetuximab; Antineoplastic Agents; Public Policy; China; Health Services Accessibility
PubMed: 36527382
DOI: 10.7189/jogh.12.11016 -
Medicina (Kaunas, Lithuania) Sep 2022: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin plus raltitrexed (HAICROX) as an alternative treatment option for...
Hepatic Arterial Infusion Chemotherapy with Oxaliplatin Plus Raltitrexed as an Alternative Option in Advanced Hepatocellular Carcinoma Patients with Failure of, or Unsuitability for, Transarterial Chemoembolization.
: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin plus raltitrexed (HAICROX) as an alternative treatment option for advanced hepatocellular carcinoma (HCC) patients who are ineligible for, or failed, the transarterial chemoembolization (TACE) treatment. : From July 2020 to November 2021, a total of 35 HCC patients were enrolled and received HAIC with oxaliplatin plus raltitrexed. The overall survival (OS) and time to progression (TTP) were primary and secondary endpoints, respectively. The tumor response was assessed by the modified response evaluation criteria in solid tumors (mRECIST), and the adverse events were investigated using the common terminology criteria for adverse events version 5.0 (CTCAE 5.0). : The median OS and TTP were 10 months (95% confidence interval (CI): 5.5-14.6) and 3.5 months (95% CI: 2.3-4.7), respectively. By means of multivariate analysis, anti-programmed cell death protein 1 (anti-PD-1) immunotherapy was found to be an independent prognostic factor for better survival. No patients experienced toxicity-related death. Thrombocytopenia, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) elevation were the most common toxicities. No grade 3 or higher adverse events related to HAICROX were observed. : HAICROX showed valuable efficacy and tolerable toxicity in advanced HCC patients who progressed on TACE or were ineligible for TACE. HAICROX is a promising treatment for advanced-stage HCC patients with TACE failure or ineligibility.
Topics: Humans; Carcinoma, Hepatocellular; Oxaliplatin; Chemoembolization, Therapeutic; Liver Neoplasms; Alanine Transaminase; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Treatment Outcome
PubMed: 36295504
DOI: 10.3390/medicina58101343 -
Molecules (Basel, Switzerland) Sep 2022Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common... (Review)
Review
Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.
Topics: Antimetabolites; Folic Acid; Folic Acid Antagonists; Methotrexate; Pemetrexed; Quinazolines; Thiophenes
PubMed: 36234766
DOI: 10.3390/molecules27196229 -
Frontiers in Oncology 2022The 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...
A randomized phase II trial of hepatic arterial infusion of oxaliplatin plus raltitrexed versus oxaliplatin plus 5-fluorouracil for unresectable colorectal cancer liver metastases.
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.
CLINICAL TRIAL REGISTRATION
https://clinicaltrials.gov/, identifier NCT02557490.
PubMed: 36212504
DOI: 10.3389/fonc.2022.913017 -
Scientific Data Oct 2022Viruses are genetically and structurally diverse, and outnumber cells by orders of magnitude. They can cause acute and chronic infections, suppress, or exacerbate...
Viruses are genetically and structurally diverse, and outnumber cells by orders of magnitude. They can cause acute and chronic infections, suppress, or exacerbate immunity, or dysregulate survival and growth of cells. To identify chemical agents with pro- or antiviral effects we conducted arrayed high-content image-based multi-cycle infection screens of 1,280 mainly FDA-approved compounds with three human viruses, rhinovirus (RV), influenza A virus (IAV), and herpes simplex virus (HSV) differing in genome organization, composition, presence of an envelope, and tropism. Based on Z'-factors assessing screening quality and Z-scores ranking individual compounds, we identified potent inhibitors and enhancers of infection: the RNA mutagen 5-Azacytidine against RV-A16; the broad-spectrum antimycotic drug Clotrimazole inhibiting IAV-WSN; the chemotherapeutic agent Raltitrexed blocking HSV-1; and Clobetasol enhancing HSV-1. Remarkably, the topical antiseptic compound Aminacrine, which is clinically used against bacterial and fungal agents, inhibited all three viruses. Our data underscore the versatility and potency of image-based, full cycle virus propagation assays in cell-based screenings for antiviral agents.
Topics: Aminacrine; Anti-Infective Agents, Local; Antiviral Agents; Azacitidine; Clobetasol; Clotrimazole; Herpes Simplex; Humans; Influenza A virus; Mutagens; Rhinovirus
PubMed: 36209289
DOI: 10.1038/s41597-022-01733-4