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 i...Objective:Paclitaxel(P)is a standard second-line chemotherapy in the treatment of advanced gastric cancer.This study compared the clinical outcome of a paclitaxel plus raltitrexed(RP)regimen as second-line treatment in metastatic gastric cancer(MGC)patients.Methods:An open,randomized,multi-center phase Ⅱ clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP[raltitrexed(3 mg/m^(2)on day 1)and paclitaxel(135 mg/m^(2)on day 1 every 3 weeks)]or P[paclitaxel(135 mg/m^(2)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.展开更多
AIM To evaluate the efficiency and safety of hepatic artery infusion chemotherapy(HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer(CRC) liver metastasis(CRCLM).METHODS A retrospective analysis of patien...AIM To evaluate the efficiency and safety of hepatic artery infusion chemotherapy(HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer(CRC) liver metastasis(CRCLM).METHODS A retrospective analysis of patients with unresectable CRCLM who failed systemic chemotherapy and were subsequently treated with HAIC at our institute from May 2013 to April 2015 was performed. A total of 24 patients were treated with 5-fluorouracil, and 18 patients were treated with raltitrexed. RESULTS The median survival time(MST) from diagnosis of CRC was 40.8 mo in the oxaliplatin plus raltitrexed(TOMOX) arm and 33.5 mo in the oxaliplatin plus 5-fluorouracil(FOLFOX) arm(P = 0.802). MST from first HAIC was 20.6 mo in the TOMOX arm and 15.4 mo in the FOLFOX arm(P = 0.734). Median progression-free survival(PFS) from first HAIC was 4.9 mo and 6.6 mo, respectively, in the TOMOX arm and FOLFOX arm(P= 0.215). Leukopenia(P = 0.026) was more common in the FOLFOX arm, and hepatic disorder(P = 0.039) was more common in the TOMOX arm. There were no treatment-related deaths in the TOMOX arm and one treatment-related death in the FOLFOX arm. Analysis of prognostic factors indicated that response to HAIC was a significant factor related to survival.CONCLUSION No significant difference in survival was observed between the TOMOX and FOLFOX arms. HAIC treatment with either TOMOX or FOLFOX was demonstrated as an efficient and safe alternative choice.展开更多
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...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 m L of glucose) was infused by pump for 4 h,followed by raltitrexed(2 mg in 100 m L of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated afterthe 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.展开更多
Objective:For locally advanced nasopharyngeal carcinoma(LA-NPC)patients,high incidences of distant metastases and severe treatment related toxicities are the main obstacles needed to be overcome.Raltitrexed,a specific...Objective:For locally advanced nasopharyngeal carcinoma(LA-NPC)patients,high incidences of distant metastases and severe treatment related toxicities are the main obstacles needed to be overcome.Raltitrexed,a specific thymidylate synthase inhibitor with a convenient administration schedule,has an acceptable and manageable toxicity,and possesses radio-sensitizing properties.To investigate the efficacy and safety of raltitrexed and cisplatin induction chemotherapy and concurrent chemoradiotherapy(IC+CCRT)in patients with LA-NPC,a phaseⅡclinical study was conducted.Methods:Sixty eligible patients with LA-NPC were enrolled into this study.A raltitrexed-cisplatin combination was used as part of an IC+CCRT regimen.Raltitrexed-cisplatin IC was given once every 3 weeks(q3 w)for two cycles,followed by raltitrexed-cisplatin based CCRT q3 w for two cycles.Intensity-modulated radiotherapy(IMRT)was given for all enrolled patients.Results:All patients were included in survival analysis according to the intent-to-treat principle.The objective response rate(ORR)3 months after treatment was 98%.The 2-year overall survival(OS)rate was 92%.The median relapse-free survival(RFS)time was 30.5[95%confidence interval(95%CI),28.4-32.3]months.The 2-year RFS rate was 85%.The 2-year local failure-free survival(LFFS)rate was 97%and the 2-year distant metastasis-free survival(DMFS)rate was 88%.Acute toxicities were mostly grade 2 and 3 reactions in bone marrow suppression,gastrointestinal side effect and oropharyngeal mucositis.Only two patients occurred grade 4 acute toxicities,one was bone marrow suppression and the other was dermatitis radiation.Conclusions:The combination of raltitrexed and cisplatin has a comparable efficacy to those in standard firstline therapy.展开更多
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 hepatocell...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.展开更多
Objective:Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer.Our research aimed to establish a library of patient-derived ...Objective:Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer.Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia;validate an index of the hyperthermia chemotherapy sensitization enhancement ratio(HCSER)to identify the chemotherapeutics most enhanced by hyperthermia;and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment.Methods:Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines.Cells from both sources were encapsulated in 3 D Matrigel droplets,which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres.The microspheres were seeded in 96-well plates,with each well containing a single microsphere that developed into an organoid after 7 days.The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37℃ as a control and 43℃ for 90 min to examine hyperthermia synergism.Cell viability was counted with 10%CCK8.Results:We successfully established a library of colorectal cancer organoids from 22 patient parental tumors.We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs.In 11 of the 22 patient organoids,raltitrexed had significant hyperthermia synergism,which was indexed as the highest HCSER score within each patient group.Conclusions:Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics.We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.展开更多
The interaction of raltitrexed（RTX） with bovine serum albumin（BSA） was investigated by steady state/lifetime fluorescence spectroscopy and circular dichroism（CD） spectroscopy under the simulative physiological c...The interaction of raltitrexed（RTX） with bovine serum albumin（BSA） was investigated by steady state/lifetime fluorescence spectroscopy and circular dichroism（CD） spectroscopy under the simulative physiological conditions.The results of fluorescence titration reveal that RTX could strongly quench the intrinsic fluorescence of BSA via a static quenching procedure.The obtained binding constant K A of RTX with BSA was 478630 and 44259 L/mol at 298 and 310 K,respectively.According to van＇t Hoff equation,the thermodynamic parameters ΔH,ΔG and ΔS were calculated,indicating that hydrophobic forces were the predominant intermolecular forces in stabilizing the complex.The binding process was a spontaneous process,in which Gibbs free energy change was negative.According to F rster＇s non-radioactive energy transfer theory,the distance r between donor（BSA） and acceptor（RTX） was 3.82 nm,suggesting that the energy transfer from BSA to RTX occurred with high probability.Displacement experiment and the number of binding sites calculation confirmed that RTX could bind to the site-I of BSA.Furthermore,the effects of pH and some metal ions on the interaction of RTX with BSA were also investigated.The results of synchronous fluorescence and CD spectra show that the RTX-BSA binding induced conformational changes in BSA.展开更多
Thymidylate synthase(TS)is a key enzyme in the de novo biosynthesis of thymidine monophosphate,serving as a well-known drug target in chemotherapy against cancers and infectious diseases.Additional to its clinical val...Thymidylate synthase(TS)is a key enzyme in the de novo biosynthesis of thymidine monophosphate,serving as a well-known drug target in chemotherapy against cancers and infectious diseases.Additional to its clinical value,TS is supposed to be a promising drug target in aquatic-disease control.To facilitate designing pathogen-specific TS inhibitors for shrimp-disease control,we report the crystal structures of TS from Litopenaeus vannamei(LvTS)in the apo form,LvTS-dUMP complex and LvTS-dUMP-raltitrexed complex at 2.27Å,1.54Å,and 1.56Åresolution,respectively.LvTS shares a similar fold with known TSs,existing as a dimer in the crystal.The apo LvTS and LvTS-dUMP take an open conformation,and raltitrexed binding induces structural changes into a closed conformation in LvTS-dUMP-raltitrexed.Compared to those in other known TS-dUMP-raltitrexed complexes with the closed conformation,the C-terminal loop in LvTS-dUMP-raltitrexed shifts its position away from the bound raltitrexed;the distance between C6 of dUMP and Sγof the catalytic cysteine is obviously longer than that in the known TS structures with closed conformations,resembling that in the TS structures with open conformations.Other species-specific interactions with dUMP and raltitrexed are also observed.Therefore,LvTS-dUMP-raltitrexed adopts a loosely closed conformation with structural features intermediate between the closed and the open conformations that were reported in other TSs.Our study provides the first crustcean TS structure,and reveals species-specific interactions between TSs and the ligands,which would facilitate designing pathogen-specific TS inhibitors for shrimp-disease control.展开更多
Objective： The aim of the study was to investigate the efficacy and safety of raltitrexed/bevacizumab in combination with irinotecan or oxaliplation for advanced colorectal cancer as the second-line and second-line a...Objective： The aim of the study was to investigate the efficacy and safety of raltitrexed/bevacizumab in combination with irinotecan or oxaliplation for advanced colorectal cancer as the second-line and second-line above treatments. Metho ods： Fifteen cases of advanced colorectal cancer were enrolled to receive regimens including raltitrexed/bevacizumab combined with irinotecan or oxaliplation. Two cases were treated with raltitrexed ＋ bavacizumab regimen, 9 cases with raltitrexed ＋ bavacizumab ＋ irinotecan regimen, and 4 cases with raltitrexed ＋ bevacizumab ＋ oxaliplation regimen. The doses of the drugs were as follows： bevacizumab 5 mg/kg ivgtt, d 1; raltitrexed 2.0 mg/m2 ivgtt 15 min, d2; irinotecan 180 mg/m2 ivgtt 1 h, d2; and oxaliplatin 85 mg/m2 ivgtt 2 h, d2. Two weeks was a cycle for each regimen. Results： The efficacy of the 15 patients could be evaluated. Two cases were in PR ,10 cases in SD, 3 cases in PD, the response rate was 13.3%, and the disease control rate was 80.0%. The median progress-free survival was 5.1 months （95% CI： 3.404-6.813 months）, and the median overall survival was 11.5 months （95% CI： 8.985-13.930 months）. The adverse effects included anorexia, nausea/vomiting, fatigue, leucopenia, thrombocytopenia, etc, and the main 3-4 grades adverse effects were anorexia, nausea/vomiting, fatigue, and thrombocytopenia. Conclusion： Raltitrexed/bevacizumab combined with irinotecan or oxaliplatin as the secondline and second-line above treatments for advanced colorectal cancer has high disease control rates, and the adverse effect is well tolerated. The combined regimen can be recommended as a phase III clinical research and second-line and secondlines above treatments for advanced colorectal cancer.展开更多
Objective:To investigate the effects of Huachansu capsules combined with raltitrexed and olisaplatin on advanced colorectal cancer immunity, tumor markers, matrix metalloproteinases and angiogenesis.Methods: Eighty-tw...Objective:To investigate the effects of Huachansu capsules combined with raltitrexed and olisaplatin on advanced colorectal cancer immunity, tumor markers, matrix metalloproteinases and angiogenesis.Methods: Eighty-two patients with advanced colorectal cancer who were treated in our hospital from August 2015 to September 2017 were randomly divided into the control group (41 cases) and the observation group (41 cases), the control group was treated with raltitrex plus oxaliplatin, on the basis of the control group, the observation group was treated with Huachansu Capsule. The levels of immune function, tumor markers, matrix metalloproteinases and angiogenic factors were compared before and after treatment in two groups of patients with advanced colorectal cancer.Results: After treatment, the levels of CD4+ and CD4+/CD8+ in the two groups were significantly higher than those before treatment (P<0.05), and the levels of CD4+ and CD4+/CD8+ in the observation group were significantly higher than those in the control group (P<0.05). the levels of CA125, CA19-9 and CEA in the two groups were significantly lower than those before treatment (P<0.05), and the levels of CA125, CA19-9 and CEA in the observation group were significantly lower than those in the control group (P<0.05);the levels of MMP-2 and MMP-9 in the two groups were significantly lower than those before treatment (P<0.05), and the levels of MMP-2 and MMP-9 in the observation group were significantly lower than those in the control group (P<0.05);the levels of VEGF, HIF-1α and TGF-β1 in the two groups were significantly lower than those before treatment (P<0.05), and the levels of VEGF, HIF-1α and TGF-β1 in the observation group were significantly lower than those in the control group (P<0.05).Conclusions: Huachansu Capsule combined with retidoxed and olixaplatin chemotherapy regimen can enhance the immune function of patients with advanced colorectal cancer, reduce the level of tumor markers in serum, inhibit the growth and metastasis of tumor cells and angiogenesis, which has clinical significance.展开更多
Objective：The aim of this study was to analysis raltitrexed by the safety and ef icacy of intra-arterial infusion chemotherapy. Methods：Forty-seven cases in dif erent parts of cancer patients, interventional methods...Objective：The aim of this study was to analysis raltitrexed by the safety and ef icacy of intra-arterial infusion chemotherapy. Methods：Forty-seven cases in dif erent parts of cancer patients, interventional methods, based on digital subtraction angiography （DSA） prompt, raltitrexed-based chemotherapy, the tumor nourish artery infusion chemotherapy. Patients with postoperative chemotherapy side ef ects and complications, and ef icacy assessments. Results：Forty-seven patients, 2 patients had II-III degree of bone marrow suppression, the rate was 4.26%, 34 cases of I to II degree gastroin-testinal reactions, 1 case of grade III gastrointestinal reactions, the incidence of 2.13%, and 1 case mild diarrhea. I degrees or more chemotherapy-related adverse reactions did not occur in this group of patients. Al patients received at least 2 times arterial infusion chemotherapy, complete remission （CR） 3 cases, partial remission （PR） 11 cases, stable disease （SD） 17 cases, disease progression （PD） 6 cases, total ef ective rate of treatment 87.23%. Conclusion：Raltitrexed for intra-arterial chemotherapy is safe and ef ective. However, due to the smal number of this group of patients, time is short, its safety, ef-ficacy and long-term ef icacy needs further observation and validation.展开更多
Background Unresectable hepatocellular carcinoma(HCC)has a poor prognosis.According to the HCC management guidelines in China,the standard treatment of Barcelona Clinic Liver Cancer(BCLC)stage B or C HCC with portal v...Background Unresectable hepatocellular carcinoma(HCC)has a poor prognosis.According to the HCC management guidelines in China,the standard treatment of Barcelona Clinic Liver Cancer(BCLC)stage B or C HCC with portal vein tumour thrombosis(PVTT)is chemoembolization.However,some patients with BCLC stage B or C HCC with PVTT respond poorly to chemoembolization.We aimed to compare tumour responses and survival benefits between patients with unresectable HCC with or without PVTT.Methods We reviewed 119 consecutive patients with unresectable HCC with PVTT(n=67)and without PVTT(n=52)who underwent hepatic arterial infusion of oxaliplatin plus raltitrexed between January 2018 and April 2021.Overall survival,progression-free survival,tumour responses,and adverse events were compared between the groups.Results There were no significant between-group differences in the objective response rates and median progression-free survival.The median overall survival was significantly longer in the group without PVTT than in that with PVTT(17.0 vs 10.4 months,respectively;P=0.024).Conclusion Hepatic arterial infusion of oxaliplatin plus raltitrexed may be efficacious in patients with unresectable HCC with or without PVTT.展开更多
文摘Objective:Paclitaxel(P)is a standard second-line chemotherapy in the treatment of advanced gastric cancer.This study compared the clinical outcome of a paclitaxel plus raltitrexed(RP)regimen as second-line treatment in metastatic gastric cancer(MGC)patients.Methods:An open,randomized,multi-center phase Ⅱ clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP[raltitrexed(3 mg/m^(2)on day 1)and paclitaxel(135 mg/m^(2)on day 1 every 3 weeks)]or P[paclitaxel(135 mg/m^(2)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.
基金Supported by Capital Medical Development and Scientific Research Fund,China,No.2014-2-2154
文摘AIM To evaluate the efficiency and safety of hepatic artery infusion chemotherapy(HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer(CRC) liver metastasis(CRCLM).METHODS A retrospective analysis of patients with unresectable CRCLM who failed systemic chemotherapy and were subsequently treated with HAIC at our institute from May 2013 to April 2015 was performed. A total of 24 patients were treated with 5-fluorouracil, and 18 patients were treated with raltitrexed. RESULTS The median survival time(MST) from diagnosis of CRC was 40.8 mo in the oxaliplatin plus raltitrexed(TOMOX) arm and 33.5 mo in the oxaliplatin plus 5-fluorouracil(FOLFOX) arm(P = 0.802). MST from first HAIC was 20.6 mo in the TOMOX arm and 15.4 mo in the FOLFOX arm(P = 0.734). Median progression-free survival(PFS) from first HAIC was 4.9 mo and 6.6 mo, respectively, in the TOMOX arm and FOLFOX arm(P= 0.215). Leukopenia(P = 0.026) was more common in the FOLFOX arm, and hepatic disorder(P = 0.039) was more common in the TOMOX arm. There were no treatment-related deaths in the TOMOX arm and one treatment-related death in the FOLFOX arm. Analysis of prognostic factors indicated that response to HAIC was a significant factor related to survival.CONCLUSION No significant difference in survival was observed between the TOMOX and FOLFOX arms. HAIC treatment with either TOMOX or FOLFOX was demonstrated as an efficient and safe alternative choice.
基金the National Key R and D Program of China,No.2016YFC0106604the National Natural Science Foundation of China,No.81502591
文摘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 m L of glucose) was infused by pump for 4 h,followed by raltitrexed(2 mg in 100 m L of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated afterthe 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.
基金supported by The Radiation Therapy Major Project of the Ministry of Science and Technology of China(No.2016YFC0105711)supported partly by Natural Science Foundation of China(No.81401913)。
文摘Objective:For locally advanced nasopharyngeal carcinoma(LA-NPC)patients,high incidences of distant metastases and severe treatment related toxicities are the main obstacles needed to be overcome.Raltitrexed,a specific thymidylate synthase inhibitor with a convenient administration schedule,has an acceptable and manageable toxicity,and possesses radio-sensitizing properties.To investigate the efficacy and safety of raltitrexed and cisplatin induction chemotherapy and concurrent chemoradiotherapy(IC+CCRT)in patients with LA-NPC,a phaseⅡclinical study was conducted.Methods:Sixty eligible patients with LA-NPC were enrolled into this study.A raltitrexed-cisplatin combination was used as part of an IC+CCRT regimen.Raltitrexed-cisplatin IC was given once every 3 weeks(q3 w)for two cycles,followed by raltitrexed-cisplatin based CCRT q3 w for two cycles.Intensity-modulated radiotherapy(IMRT)was given for all enrolled patients.Results:All patients were included in survival analysis according to the intent-to-treat principle.The objective response rate(ORR)3 months after treatment was 98%.The 2-year overall survival(OS)rate was 92%.The median relapse-free survival(RFS)time was 30.5[95%confidence interval(95%CI),28.4-32.3]months.The 2-year RFS rate was 85%.The 2-year local failure-free survival(LFFS)rate was 97%and the 2-year distant metastasis-free survival(DMFS)rate was 88%.Acute toxicities were mostly grade 2 and 3 reactions in bone marrow suppression,gastrointestinal side effect and oropharyngeal mucositis.Only two patients occurred grade 4 acute toxicities,one was bone marrow suppression and the other was dermatitis radiation.Conclusions:The combination of raltitrexed and cisplatin has a comparable efficacy to those in standard firstline therapy.
基金supported by the National Natural Science Foundation of China(81571781).
文摘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.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81972918 and 61971255)Shenzhen Science and Technology Innovation Committee(Grant No.KQJSCX20180327143623167)+2 种基金NANJING CHIA TAI TIANQING Company,Foundation for Young Innovative Talents in Education of Guangdong(Grant No.2017KQNCX161)Natural Science Foundation of Guangdong Province(Grant No.2018A030310249)Key Clinical Technique of Guangzhou(Grant No.2019ZD16)。
文摘Objective:Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer.Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia;validate an index of the hyperthermia chemotherapy sensitization enhancement ratio(HCSER)to identify the chemotherapeutics most enhanced by hyperthermia;and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment.Methods:Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines.Cells from both sources were encapsulated in 3 D Matrigel droplets,which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres.The microspheres were seeded in 96-well plates,with each well containing a single microsphere that developed into an organoid after 7 days.The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37℃ as a control and 43℃ for 90 min to examine hyperthermia synergism.Cell viability was counted with 10%CCK8.Results:We successfully established a library of colorectal cancer organoids from 22 patient parental tumors.We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs.In 11 of the 22 patient organoids,raltitrexed had significant hyperthermia synergism,which was indexed as the highest HCSER score within each patient group.Conclusions:Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics.We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.
基金Supported by the National Natural Science Foundation of China(No.30973659)
文摘The interaction of raltitrexed（RTX） with bovine serum albumin（BSA） was investigated by steady state/lifetime fluorescence spectroscopy and circular dichroism（CD） spectroscopy under the simulative physiological conditions.The results of fluorescence titration reveal that RTX could strongly quench the intrinsic fluorescence of BSA via a static quenching procedure.The obtained binding constant K A of RTX with BSA was 478630 and 44259 L/mol at 298 and 310 K,respectively.According to van＇t Hoff equation,the thermodynamic parameters ΔH,ΔG and ΔS were calculated,indicating that hydrophobic forces were the predominant intermolecular forces in stabilizing the complex.The binding process was a spontaneous process,in which Gibbs free energy change was negative.According to F rster＇s non-radioactive energy transfer theory,the distance r between donor（BSA） and acceptor（RTX） was 3.82 nm,suggesting that the energy transfer from BSA to RTX occurred with high probability.Displacement experiment and the number of binding sites calculation confirmed that RTX could bind to the site-I of BSA.Furthermore,the effects of pH and some metal ions on the interaction of RTX with BSA were also investigated.The results of synchronous fluorescence and CD spectra show that the RTX-BSA binding induced conformational changes in BSA.
基金Supported by the National Natural Science Foundation of China(Nos.31572660,31872600)the“1000 Talents Program”,and the Qingdao Innovation Leadership Project(No.18-1-2-12-zhc)。
文摘Thymidylate synthase(TS)is a key enzyme in the de novo biosynthesis of thymidine monophosphate,serving as a well-known drug target in chemotherapy against cancers and infectious diseases.Additional to its clinical value,TS is supposed to be a promising drug target in aquatic-disease control.To facilitate designing pathogen-specific TS inhibitors for shrimp-disease control,we report the crystal structures of TS from Litopenaeus vannamei(LvTS)in the apo form,LvTS-dUMP complex and LvTS-dUMP-raltitrexed complex at 2.27Å,1.54Å,and 1.56Åresolution,respectively.LvTS shares a similar fold with known TSs,existing as a dimer in the crystal.The apo LvTS and LvTS-dUMP take an open conformation,and raltitrexed binding induces structural changes into a closed conformation in LvTS-dUMP-raltitrexed.Compared to those in other known TS-dUMP-raltitrexed complexes with the closed conformation,the C-terminal loop in LvTS-dUMP-raltitrexed shifts its position away from the bound raltitrexed;the distance between C6 of dUMP and Sγof the catalytic cysteine is obviously longer than that in the known TS structures with closed conformations,resembling that in the TS structures with open conformations.Other species-specific interactions with dUMP and raltitrexed are also observed.Therefore,LvTS-dUMP-raltitrexed adopts a loosely closed conformation with structural features intermediate between the closed and the open conformations that were reported in other TSs.Our study provides the first crustcean TS structure,and reveals species-specific interactions between TSs and the ligands,which would facilitate designing pathogen-specific TS inhibitors for shrimp-disease control.
文摘Objective： The aim of the study was to investigate the efficacy and safety of raltitrexed/bevacizumab in combination with irinotecan or oxaliplation for advanced colorectal cancer as the second-line and second-line above treatments. Metho ods： Fifteen cases of advanced colorectal cancer were enrolled to receive regimens including raltitrexed/bevacizumab combined with irinotecan or oxaliplation. Two cases were treated with raltitrexed ＋ bavacizumab regimen, 9 cases with raltitrexed ＋ bavacizumab ＋ irinotecan regimen, and 4 cases with raltitrexed ＋ bevacizumab ＋ oxaliplation regimen. The doses of the drugs were as follows： bevacizumab 5 mg/kg ivgtt, d 1; raltitrexed 2.0 mg/m2 ivgtt 15 min, d2; irinotecan 180 mg/m2 ivgtt 1 h, d2; and oxaliplatin 85 mg/m2 ivgtt 2 h, d2. Two weeks was a cycle for each regimen. Results： The efficacy of the 15 patients could be evaluated. Two cases were in PR ,10 cases in SD, 3 cases in PD, the response rate was 13.3%, and the disease control rate was 80.0%. The median progress-free survival was 5.1 months （95% CI： 3.404-6.813 months）, and the median overall survival was 11.5 months （95% CI： 8.985-13.930 months）. The adverse effects included anorexia, nausea/vomiting, fatigue, leucopenia, thrombocytopenia, etc, and the main 3-4 grades adverse effects were anorexia, nausea/vomiting, fatigue, and thrombocytopenia. Conclusion： Raltitrexed/bevacizumab combined with irinotecan or oxaliplatin as the secondline and second-line above treatments for advanced colorectal cancer has high disease control rates, and the adverse effect is well tolerated. The combined regimen can be recommended as a phase III clinical research and second-line and secondlines above treatments for advanced colorectal cancer.
文摘Objective:To investigate the effects of Huachansu capsules combined with raltitrexed and olisaplatin on advanced colorectal cancer immunity, tumor markers, matrix metalloproteinases and angiogenesis.Methods: Eighty-two patients with advanced colorectal cancer who were treated in our hospital from August 2015 to September 2017 were randomly divided into the control group (41 cases) and the observation group (41 cases), the control group was treated with raltitrex plus oxaliplatin, on the basis of the control group, the observation group was treated with Huachansu Capsule. The levels of immune function, tumor markers, matrix metalloproteinases and angiogenic factors were compared before and after treatment in two groups of patients with advanced colorectal cancer.Results: After treatment, the levels of CD4+ and CD4+/CD8+ in the two groups were significantly higher than those before treatment (P<0.05), and the levels of CD4+ and CD4+/CD8+ in the observation group were significantly higher than those in the control group (P<0.05). the levels of CA125, CA19-9 and CEA in the two groups were significantly lower than those before treatment (P<0.05), and the levels of CA125, CA19-9 and CEA in the observation group were significantly lower than those in the control group (P<0.05);the levels of MMP-2 and MMP-9 in the two groups were significantly lower than those before treatment (P<0.05), and the levels of MMP-2 and MMP-9 in the observation group were significantly lower than those in the control group (P<0.05);the levels of VEGF, HIF-1α and TGF-β1 in the two groups were significantly lower than those before treatment (P<0.05), and the levels of VEGF, HIF-1α and TGF-β1 in the observation group were significantly lower than those in the control group (P<0.05).Conclusions: Huachansu Capsule combined with retidoxed and olixaplatin chemotherapy regimen can enhance the immune function of patients with advanced colorectal cancer, reduce the level of tumor markers in serum, inhibit the growth and metastasis of tumor cells and angiogenesis, which has clinical significance.
文摘Objective：The aim of this study was to analysis raltitrexed by the safety and ef icacy of intra-arterial infusion chemotherapy. Methods：Forty-seven cases in dif erent parts of cancer patients, interventional methods, based on digital subtraction angiography （DSA） prompt, raltitrexed-based chemotherapy, the tumor nourish artery infusion chemotherapy. Patients with postoperative chemotherapy side ef ects and complications, and ef icacy assessments. Results：Forty-seven patients, 2 patients had II-III degree of bone marrow suppression, the rate was 4.26%, 34 cases of I to II degree gastroin-testinal reactions, 1 case of grade III gastrointestinal reactions, the incidence of 2.13%, and 1 case mild diarrhea. I degrees or more chemotherapy-related adverse reactions did not occur in this group of patients. Al patients received at least 2 times arterial infusion chemotherapy, complete remission （CR） 3 cases, partial remission （PR） 11 cases, stable disease （SD） 17 cases, disease progression （PD） 6 cases, total ef ective rate of treatment 87.23%. Conclusion：Raltitrexed for intra-arterial chemotherapy is safe and ef ective. However, due to the smal number of this group of patients, time is short, its safety, ef-ficacy and long-term ef icacy needs further observation and validation.
基金supported by the Guiding Project of Science and Technology Program of Fujian Province,China[grant number:2019Y0060].
文摘Background Unresectable hepatocellular carcinoma(HCC)has a poor prognosis.According to the HCC management guidelines in China,the standard treatment of Barcelona Clinic Liver Cancer(BCLC)stage B or C HCC with portal vein tumour thrombosis(PVTT)is chemoembolization.However,some patients with BCLC stage B or C HCC with PVTT respond poorly to chemoembolization.We aimed to compare tumour responses and survival benefits between patients with unresectable HCC with or without PVTT.Methods We reviewed 119 consecutive patients with unresectable HCC with PVTT(n=67)and without PVTT(n=52)who underwent hepatic arterial infusion of oxaliplatin plus raltitrexed between January 2018 and April 2021.Overall survival,progression-free survival,tumour responses,and adverse events were compared between the groups.Results There were no significant between-group differences in the objective response rates and median progression-free survival.The median overall survival was significantly longer in the group without PVTT than in that with PVTT(17.0 vs 10.4 months,respectively;P=0.024).Conclusion Hepatic arterial infusion of oxaliplatin plus raltitrexed may be efficacious in patients with unresectable HCC with or without PVTT.
