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Cancer Management and Research 2019To evaluate the efficacy and safety of raltitrexed plus oxaliplatin-based transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma...
OBJECTIVE
To evaluate the efficacy and safety of raltitrexed plus oxaliplatin-based transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC).
METHODS
A total of 123 patients with unresectable HCC were recruited into the prospective cohort study. Raltitrexed plus oxaliplatin-based TACE was performed according to the traditional method at monthly intervals and was repeated for up to 4 cycles if no disease progression or intolerable toxicity occurred. The primary efficacy endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and tumor response rate. The Cox proportional-hazards regression model was used to assess the independent prognostic factors of OS. Adverse events were also observed.
RESULTS
The median OS time and PFS were 623 days (95% CI: 461, 785) and 338 days (95% CI: 302, 704), respectively. The disease control rate was 95.5% (118/123). The Cox proportional-hazards regression model indicated that age, ECOG performance status and response to TACE as independent prognostic factors of OS. No treatment-related mortality occurred within 30 days of treatment procedure. The most common complications included postembolization syndrome, liver dysfunction and hematological toxicity. Grade 3 pain, transglutaminase abnormality and thrombocytopenia were observed in 16 (13%), 15 (12.2%) and 3 (2.4%) patients, respectively. No grade 4 adverse events were observed.
CONCLUSION
Raltitrexed plus oxaliplatin-based TACE led to high tumor response rate and promising PFS and OS, and was considered safe and tolerable in patients with unresectable HCC.
PubMed: 31819623
DOI: 10.2147/CMAR.S217524 -
EBioMedicine Oct 2019Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating...
BACKGROUND
Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating gastrointestinal cancer now, but they have limited clinical benefits due to the prevalent unresponsiveness and toxicity. It is urgent to identify a predictive biomarker to guide the precise clinical use of TYMS inhibitors.
METHODS
Genome-scale CRISPR-Cas9 knockout screening was performed to identify potential therapeutic targets for treating gastrointestinal tumours as well as key regulators of raltitrexed (RTX) sensitivity. Cell-based functional assays were used to investigate how MYC regulates TYMS transcription. Cancer patient data were used to verify the correlation between drug response and MYC and/or TYMS mRNA levels. Finally, the role of NIPBL inactivation in gastrointestinal cancer was evaluated in vitro and in vivo.
FINDINGS
TYMS is essential for maintaining the viability of gastrointestinal cancer cells, and is selectively inhibited by RTX. Mechanistically, MYC presets gastrointestinal cancer sensitivity to RTX through upregulating TYMS transcription, supported by TCGA data showing that complete response cases to TYMS inhibitors had significantly higher MYC and TYMS mRNA levels than those of progressive diseases. NIPBL inactivation decreases the therapeutic responses of gastrointestinal cancer to RTX through blocking MYC.
INTERPRETATION
Our study unveils a mechanism of how TYMS is transcriptionally regulated by MYC, and provides rationales for the precise use of TYMS inhibitors in the clinic.
FUNDING
This work was financially supported by grants of NKRDP (2016YFC1302400), STCSM (16JC1406200), NSFC (81872890, 81322034, 81372346) and CAS (QYZDB-SSW-SMC034, XDA12020210).
Topics: Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance; Folic Acid Antagonists; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Thymidylate Synthase; Transcription, Genetic
PubMed: 31648989
DOI: 10.1016/j.ebiom.2019.10.003 -
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 -
Nanoscale Aug 2019Combined modality therapy incorporating raltitrexed (RTX), a thymidylate synthase inhibitor, and radiation can lead to improved outcome for rectal cancer patients. To...
Combined modality therapy incorporating raltitrexed (RTX), a thymidylate synthase inhibitor, and radiation can lead to improved outcome for rectal cancer patients. To increase delivery and treatment efficacy, we formulated a hyaluronic acid (HA) coated nanoparticle encapsulating RTX (HARPs) through layer-by-layer assembly. These particles were determined to have a diameter of ∼115 nm, with a polydispersity index of 0.112 and a zeta potential of -22 mV. Cell uptake in CT26 cells determined through flow cytometry showed a ∼5-fold increase between untargeted and HA-coated particles. Through viability and DNA damage assays, we assessed the potency of the free RTX and HARPs, and found increased DNA damage in cells treated with the RTX-loaded nanoparticles administered concurrently with radiation. In vivo efficacy through tumor growth inhibition was investigated in a syngeneic murine colorectal cancer model. Nanoparticle treatment showed no acute toxicity in vivo, and all treatments showed survival benefits for their respective groups compared to controls. HARPs alone slowed tumor growth, although not significantly. Radiation alone and in combination with the HARPs showed significant growth delay. Notably, the combination treatment significantly hindered tumor progression relative to the HARPs highlighting the benefit of this multipronged treatment. These results provide a foundation for loading RTX in a nanoparticle formulation, and establish a combined radiation and drug dosing schedule to determine optimal tumor growth delay and subsequent treatment efficacy.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; DNA Damage; Drug Carriers; Histones; Humans; Hyaluronic Acid; Kaplan-Meier Estimate; Liver; Mice; Mice, Inbred BALB C; Nanoparticles; Quinazolines; Radiation, Ionizing; Thiophenes; Transplantation, Heterologous
PubMed: 31305836
DOI: 10.1039/c9nr04320a -
Cancer Cell International 2019Radiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection. Many strategies have been...
BACKGROUND
Radiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection. Many strategies have been developed to increase the radiosensitivity of esophageal cancer, with some success.
METHODS
This study was conducted to determine whether raltitrexed can enhance radiosensitivity of esophageal squamous cell carcinoma (ESCC). ESCC cell lines 24 h were incubated with raltitrexed or DMSO with or without subsequent irradiation. Cell Counting Kit assay-8 assay and clonogenic survival assay were used to measure the cell proliferation and radiosensitization, respectively. Flow cytometry was utilized to examine cell apoptosis and cell cycle distribution in different groups. Immunofluorescence analysis was performed to detect deoxyribonucleic acid (DNA) double-strand breaks. In addition, the expression levels of proteins that are involved in radiation induced signal transduction including Bax, Cyclin B1, Cdc2/pCdc2, and Cdc25C/pCdc25C were examined by western blot analysis.
RESULTS
The results indicated that raltitrexed enhanced radiosensitivity of ESCC cells with increased DNA double-strand breaks, the G2/M arrest, and the apoptosis of ESCC cells induced by radiation. The sensitization enhancement ratio of 1.23-2.10 was detected for ESCC cells with raltitrexed treatment in TE-13 cell line. In vitro, raltitrexed also increased the therapeutic effect of radiation in nude mice.
CONCLUSION
Raltitrexed increases the radiosensitivity of ESCC. This antimetabolite drug is promising for future clinical trials with concurrent radiation in esophageal cancer.
PubMed: 30820189
DOI: 10.1186/s12935-019-0752-y -
The Oncologist May 2019The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic...
LESSONS LEARNED
The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (mCRC) after long exposure to 5-FU.S-1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third- or later-line therapy in mCRC.
BACKGROUND
5-fluorouracil (5-FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5-FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5-FU. To evaluate the efficacy and safety of S-1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one-center, single-arm, prospective phase II trial was conducted.
METHODS
Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S-1 (80-120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.
RESULTS
In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention-to-treat population ( = 46), the ORR was 13.0% and disease control rate was 54.3%. Median PFS and median OS were 107 days (95% confidence interval [CI], 96.3-117.7) and 373 days (95% CI, 226.2-519.8), respectively. Most of the adverse effects were mild to moderate.
CONCLUSION
S-1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third- or later-line therapy in mCRC.
Topics: Adult; Aged; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Quinazolines; Tegafur; Thiophenes
PubMed: 30651398
DOI: 10.1634/theoncologist.2018-0901 -
World Journal of Gastroenterology Jun 2018To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in...
Transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed for hepatocellular carcinoma with major portal vein tumor thrombus.
AIM
To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in hepatocellular carcinoma (HCC) with major portal vein tumor thrombus (MPVTT).
METHODS
Eighty-six patients with MPVTT accepted routine embolization. The catheter was kept in the hepatic artery and oxaliplatin (50 mg in 250 mL of glucose) was infused by pump for 4 h, followed by raltitrexed (2 mg in 100 mL of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated after the transarterial chemoembolization (TACE).
RESULTS
Full or partial embolization was achieved in 86 cases, where all the cases received low dose continuous hepatic arterial infusion chemotherapy. Complete responses (CRs), partial responses (PRs), stable disease (SD), and disease progression (PD) for intrahepatic disease were observed in 0, 45, 20, and 21 patients, respectively. The 1-, 2-and 3-year overall survival rates of the 86 patients were 40.7%, 22.1%, and 8.1% respectively, and the median survival time was 8.7 mo. Complication was limited.
CONCLUSION
TACE with low dose continuous hepatic arterial infusion of oxaliplatin and raltitrexed could be an option in MPVTT patient; it was shown to be effective in patients with advanced HCC with MPVTT with less toxicity.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Catheters; Chemoembolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Portal Vein; Quinazolines; Retrospective Studies; Survival Rate; Thiophenes; Thrombosis; Treatment Outcome
PubMed: 29930471
DOI: 10.3748/wjg.v24.i23.2501 -
PloS One 2018Filariasis is a tropical disease caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. Known inhibitors of dihydrofolate reductase (DHFR) have been... (Comparative Study)
Comparative Study
Filariasis is a tropical disease caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. Known inhibitors of dihydrofolate reductase (DHFR) have been previously shown to kill Brugia malayi nematodes and to inhibit Brugia malayi DHFR (BmDHFR) at nanomolar concentrations. These data suggest that BmDHFR is a potential target for the treatment of filariasis. Here, protocols for cloning, expression and purification of Wuchereria bancrofti DHFR (WbDHFR) were developed. The Uniprot entry J9F199-1 predicts a 172 amino acid protein for WbDHFR but alignment of this sequence to the previously described BmDHFR shows that this WbDHFR sequence lacks a crucial, conserved 13 amino acid loop. The presence of the loop in WbDHFR is supported by a noncanonical splicing event and the loop sequence was therefore included in the gene design. Subsequently, the KM for dihydrofolate (3.7 ± 2 μM), kcat (7.4 ± 0.6 s-1), and pH dependence of activity were determined. IC50 values of methotrexate, trimethoprim, pyrimethamine, raltitrexed, aminopterin, (-)-epicatechin gallate, (-)-epicatechin, and vitexin were measured for WbDHFR and BmDHFR. Methotrexate and structurally related aminopterin were found to be effective inhibitors of WbDHFR, with an KI of 1.2 ± 0.2 nM and 2.1 ± 0.5 nM, respectively, suggesting that repurposing of known antifolate compound may be an effective strategy to treating filariasis. Most compounds showed similar inhibition profiles toward both enzymes, suggesting that the two enzymes have important similarities in their active site environments and can be targeted with the same compound, once a successful inhibitor is identified.
Topics: Amino Acid Sequence; Animals; Brugia malayi; Cloning, Molecular; Enzyme Inhibitors; Flavonoids; Gene Expression Regulation, Enzymologic; Sequence Alignment; Tetrahydrofolate Dehydrogenase; Wuchereria bancrofti
PubMed: 29787565
DOI: 10.1371/journal.pone.0197173 -
PloS One 2018Thymidylate synthase (TS) is a well-validated target for the therapy of adult cancers. Propane-1,3-diphosphonic acid (PDPA) has significant inhibitory properties against...
Thymidylate synthase (TS) is a well-validated target for the therapy of adult cancers. Propane-1,3-diphosphonic acid (PDPA) has significant inhibitory properties against human thymidylate synthase (hTS) relative to mouse TS which is not predicted to adopt an inactive conformer. The current research aims to identify novel, lead inhibitors of hTS and examine the prediction that they bind selectively to hTS enzymes existing in different conformational equilibria. Conformer-selectivity was evaluated through performing activity inhibition studies, as well as intrinsic fluorescence (IF) studies in comparison to the known orthosteric inhibitor raltitrexed (RTX). Human TS was isolated from recombinant bacteria expressing either native hTS, capable of conformational switching, or an actively stabilized mutant (R163K-hTS). The examined test compounds were rationally or virtually predicted to have inhibitory activity against hTS. Among these compounds, glutarate, N-(4-carboxyphenyl) succinamic acid, and diglycolic anhydride showed higher selectivity towards native hTS as compared to R163K-hTS. The active site inhibitor RTX showed significantly higher inhibition of R163K-hTS relative to hTS. Targeting hTS via conformational selectivity represents a future approach for overcoming reported resistance towards active-state TS analogs.
Topics: Antineoplastic Agents; Catalytic Domain; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Escherichia coli; Humans; Molecular Docking Simulation; Mutation; Pregnadienes; Protein Conformation; Quinazolines; Thiophenes; Thymidylate Synthase
PubMed: 29538414
DOI: 10.1371/journal.pone.0193810 -
Journal of Thoracic Disease Jan 2018Malignant pleural mesothelioma (MPM) is a rare neoplasm that typically arises from mesothelial surfaces of the pleural cavity. Despite treatment improvements, it carries... (Review)
Review
Malignant pleural mesothelioma (MPM) is a rare neoplasm that typically arises from mesothelial surfaces of the pleural cavity. Despite treatment improvements, it carries a dismal prognosis. The majority of patients either have unresectable disease or are not candidates for surgery due to medical comorbidities or old age. For such patients, chemotherapy (CT) represents the gold-standard treatment. To date, combination CT with cisplatin plus pemetrexed represents the most widely used regimen in first-line setting for patients with unresectable MPM. Other first-line options are currently available, including the use of raltitrexed instead of pemetrexed combined with platinum. In this review, we discuss the role of CT in MPM mainly focusing on the results of the trials conducted in first-line setting.
PubMed: 29507800
DOI: 10.21037/jtd.2017.10.19