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International Immunopharmacology Dec 2023Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used...
Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: A retrospective study.
BACKGROUND
Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used HAIC regimen is oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). However, arterial infusion of fluorouracil over 46 h was not convenient. Raltitrexed, another antimetabolic agent with a long plasma half-life, allows for shorter infusion durations. We aimed to compare the effectiveness and toxicity of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) combined with HAIC with raltitrexed plus oxaliplatin (RALOX) or FOLFOX in patients with intermediate and advanced HCC.
METHODS
This retrospective study enrolled 82 eligible patients from February 2019 to December 2021. Forty patients were treated with FOLFOX HAIC (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil bolus 400 mg/m administered on day 1, and 5-fluorouracil 2400 mg/m infusion for 46 h, every 3 weeks) combined with TKIs and ICIs. Forty-two patients received RALOX HAIC (oxaliplatin 100 mg/m and raltitrexed 3 mg/m on day 1, every 3 weeks) combined with TKIs and ICIs. We compared the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile.
RESULTS
ORR was similar between the FOLFOX HAIC and RALOX HAIC groups (42.5% vs 42.5%, P = 0.974). DCR also showed no significant difference between the two groups (87.5% vs 85.7%, P = 0.813). Median PFS was 10.7 months in the FOLFOX HAIC group versus 10.2 months in the RALOX HAIC group (P = 0.41). Median OS was 20.3 months in the FOLFOX HAIC group, compared to 17.7 months in the RALOX HAIC group (P = 0.50). Both groups had similar profiles of grade 3/4 treatment-related adverse events, including thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, and leukocytopenia.
CONCLUSION
The effectiveness and safety of HAIC with RALOX were comparable to HAIC with FOLFOX in intermediate and advanced HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Fluorouracil; Oxaliplatin; Leucovorin; Retrospective Studies; Immune Checkpoint Inhibitors; Tyrosine Kinase Inhibitors; Liver Neoplasms; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37879230
DOI: 10.1016/j.intimp.2023.111019 -
Science Advances Mar 2024There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a...
There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported. While trying unsuccessfully to improve raltitrexed's ability to kill and remove its ability to kill human cells, we learned three lessons that may help others developing antibiotics. First, binding of raltitrexed substantially changed the configuration of the PptT active site, complicating molecular modeling of analogs based on the unliganded crystal structure or the structure of cocrystals with inhibitors of another class. Second, minor changes in the raltitrexed molecule changed its target in from PptT to dihydrofolate reductase (DHFR). Third, the structure-activity relationship for over 800 raltitrexed analogs only became interpretable when we quantified and characterized the compounds' intrabacterial accumulation and transformation.
Topics: Humans; Mycobacterium tuberculosis; Thymidylate Synthase; Bacterial Proteins; Neoplasms; Quinazolines; Thiophenes; Transferases (Other Substituted Phosphate Groups)
PubMed: 38489355
DOI: 10.1126/sciadv.adj6406 -
Cancer Biology & Medicine Aug 2023Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparing effectiveness and safety of paclitaxel plus raltitrexed paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial.
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 on day 1) and paclitaxel (135 mg/m on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m on day 1 every 3 weeks)] as 2-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 1.7 months; = 0.148). OS was also prolonged with RP compared to P (10.2 months 6.1 months; = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; = 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% 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 ( = 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.
Topics: Humans; Paclitaxel; Stomach Neoplasms; Ascites; Adenocarcinoma
PubMed: 37653589
DOI: 10.20892/j.issn.2095-3941.2023.0112 -
Cancer Medicine Aug 2023Esophageal squamous cell cancer (ESCC) accounts for approximately 90% of esophageal cancer cases in China. There are no standard regimens for second or third-line... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of irinotecan combined with raltitrexed or irinotecan monotherapy for salvage chemotherapy of esophageal squamous cell cancer: A prospective, open label, randomized phase II study.
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.
Topics: Humans; Irinotecan; Carcinoma, Squamous Cell; Prospective Studies; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37325938
DOI: 10.1002/cam4.6264 -
BMJ Open Oct 2023Organ preservation is now considered an acceptable alternative option in distal rectal cancer patients with clinical complete response (cCR) after neoadjuvant...
INTRODUCTION
Organ preservation is now considered an acceptable alternative option in distal rectal cancer patients with clinical complete response (cCR) after neoadjuvant chemoradiation (CRT). But the cCR rate is low and about one-third of tumour will regrow, which requires more effective local treatment. CRT combined with intra-arterial chemotherapy (IAC) might be a promising approach. Additionally, total neoadjuvant therapy using FOLFIRINOX induction chemotherapy improved survival while consolidation chemotherapy improved organ preservation. We assess whether IAC plus CRT and FOLFIRINOX consolidation chemotherapy can improve the chance of organ preservation and survival in distal rectal cancer.
METHODS AND ANALYSIS
This prospective, monocentric, open-label, single-arm phase II study will include 32 patients with cT3-4NanyM0 distal rectal adenocarcinoma. All patients will receive one cycle of IAC (irinotecan, raltitrexed and oxaliplatin), followed by CRT (50 Gy/25 fractions with concomitant capecitabine) and then with six cycles of FOLFIRINOX (leucovorin, 5-fluorouracil, oxaliplatin and irinotecan). After final evaluation, patients with cCR will receive non-operative management or surgery at their own discretion and others are mandatorily referred to surgery. Adjuvant chemotherapy with six cycles of mFOLFOX6 (leucovorin, 5-fluorouracil and oxaliplatin) will be used for patients with adverse pathological features. The primary endpoint is the rate of complete response (CR; pathological CR or sustained cCR≥2 years). The main secondary endpoints are toxicity, compliance, short-term and long-term oncological outcomes, surgical morbidity and quality of life. This protocol has been designed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials 2013 guidelines.
ETHICS AND DISSEMINATION
This study was approved by the Academic and Ethics Committee of The Affiliated Hospital of Youjiang Medical University for Nationalities in March 2023. Trial results will be published in peer-reviewed international journals and on the ChiCTR website.
PROTOCOL VERSION
Registered on 18 April 2023; version #1.
TRIAL REGISTRATION NUMBER
ChiCTR2300070620.
Topics: Humans; Neoadjuvant Therapy; Antineoplastic Combined Chemotherapy Protocols; Irinotecan; Oxaliplatin; Leucovorin; Quality of Life; Prospective Studies; Pancreatic Neoplasms; Rectal Neoplasms; Fluorouracil; Chemoradiotherapy; Neoplasm Staging; Clinical Trials, Phase II as Topic
PubMed: 37798027
DOI: 10.1136/bmjopen-2023-075023 -
ACS Omega Oct 2023Stearoyl chitosan (SC), derived from the acylation of chitosan, contributes to the efficiency of drug delivery systems because of its structure, which accommodates the...
Stearoyl chitosan (SC), derived from the acylation of chitosan, contributes to the efficiency of drug delivery systems because of its structure, which accommodates the drug in a particle. Nonetheless, its role in chemotherapy has been largely unexplored. The present study involves the synthesis of stearoyl chitosan through the reaction of depolymerized chitosan with stearoyl chloride under mild reaction conditions. The resulting compound was subjected to structural analysis utilizing Fourier-transform infrared (FTIR) spectroscopy, H NMR, and X-ray diffraction (XRD) spectroscopy. The dispersion of SC molecules in phosphate-buffered saline (PBS) forms SC nanoparticles. The best dispersion of SC in the solution was achieved at a 1:60 chitosan-to-stearoyl chloride weight ratio. Three antimetabolite drugs, methotrexate, pemetrexed, and raltitrexed, were selected to examine the loading efficacy of SC. Pemetrexed had the highest drug-loading value of 36.8% among the three antimetabolites incorporated into SC, along with an encapsulation efficiency of 85.1%. The size of SC loaded with antimetabolites ranged from 225 to 369 nm, and their spherical form was verified via a transmission electron microscope. The in vitro release study showed that SC demonstrated controlled drug release, suggesting that SC nanoparticles have significant promise as a delivery strategy for chemotherapy.
PubMed: 37929136
DOI: 10.1021/acsomega.3c05108 -
Bioinformation 2023Myeloid leukemia 1 (MCL-1), a BCL-2 protein family member, acts as an anti-apoptotic protein by interacting with pro-apoptotic BCL-2 proteins. Its overexpression is...
Myeloid leukemia 1 (MCL-1), a BCL-2 protein family member, acts as an anti-apoptotic protein by interacting with pro-apoptotic BCL-2 proteins. Its overexpression is frequently observed in numerous cancer types including breast cancer, and is closely linked to the initiation and progression of tumors as well as poor prognosis and resistance to therapeutic interventions. Here, a database of 3402 chemicals with established therapeutic activity against various diseases was chosen and systematically screened against the MCL-1 protein. Visual inspection and binding energy analysis revealed that the compounds OSU-03012, Raltitrexed, Ostarine (MK-2866), Dovitinib (TKI-258), and Varespladib (LY315920) had strong binding affinity for the MCL-1 protein. Notably, their binding affinity was higher than that of the control compounds. These compounds exhibited strong interactions with critical amino acid residues of the MCL-1 protein. Furthermore, these compounds shared several common amino acid residue interactions with the control compounds. These findings suggest that these compounds may be useful as MCL-1 inhibitors in the treatment of breast cancer. However, additional experimental validation is required to confirm these findings.
PubMed: 37885779
DOI: 10.6026/97320630019707 -
Therapeutic Advances in Medical Oncology 2024The most common loadable chemotherapeutic drugs in drug-eluting bead transarterial chemoembolization (DEB-TACE) include doxorubicin, epirubicin, etc. CalliSpheres beads...
Efficacy and safety of raltitrexed-eluting CalliSpheres bead transarterial chemoembolization in patients with intermediate-stage hepatocellular carcinoma: a single-arm, prospective study.
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 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.
PubMed: 38362379
DOI: 10.1177/17588359241229661 -
Journal of Gastrointestinal Oncology Apr 2024After the failure of standard first- and second-line treatments, including oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) combined with targeted drugs, the currently...
BACKGROUND
After the failure of standard first- and second-line treatments, including oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) combined with targeted drugs, the currently recommended third-line regimens for metastatic colorectal cancer (mCRC) include TAS-102, regorafenib, and fruquintinib. However, these regimens have the drawbacks of mediocre efficacy, substantive side effects, and high cost. Therefore, more effective, economical regimens with fewer side effects are needed in clinical practice. In this study, we assessed the efficacy and safety of gemcitabine plus raltitrexed or S-1 as a third- or later-line treatment in comparison to those of standard third-line therapies for patients with mCRC.
METHODS
Patients with previous failures of at least two lines of standard therapy with oxaliplatin, 5-FU, irinotecan, or capecitabine combined with targeted drugs were included. The participants received standard third-line therapies (including TAS-102, regorafenib, and fruquintinib) or gemcitabine plus raltitrexed or S-1 until disease progression, death, or intolerable toxicity arose. Imaging follow-up was performed every 3 months during their treatment. Progression-free survival (PFS) and overall survival (OS) were recorded. Cox regression analysis was used to investigate the potential predictors of survival.
RESULTS
From April 2018 to October 2022, 60 patients with mCRC were enrolled in our study. The numbers of patients in the chemotherapy, fruquintinib, regorafenib, and TAS-102 groups were 13, 15, 17, and 15, respectively; the median OS of the four groups was 7.4, 6.1, 8.3, and 6.7 months (P=0.384), respectively; the median PFS was 4.1, 3.4, 4.4, and 2.3 months (P=0.656), respectively; the overall response rate was 7.69%, 6.67%, 0.00%, and 13.33%, respectively; and the disease control rate was 61.54%, 60.00%, 70.59%, and 60.00%, respectively. Additionally, multivariate analysis revealed that primary lesion located in the rectum was adverse independent prognostic factors for OS. A typical case is presented in this article.
CONCLUSIONS
The gemcitabine plus raltitrexed or S-1 regimen is a potential regimen with tolerable adverse reactions and low cost for patients with mCRC.
PubMed: 38756629
DOI: 10.21037/jgo-24-76 -
Frontiers in Oncology 2023Breast and vulvar metastases from rectal signet ring cell carcinoma (SRCC) represent a rare and obscure clinical entity associated with poor survival. Managing patients...
BACKGROUND
Breast and vulvar metastases from rectal signet ring cell carcinoma (SRCC) represent a rare and obscure clinical entity associated with poor survival. Managing patients with metastatic rectal SRCC is extremely challenging due to the absence of high-quality evidence.
CASE PRESENTATION
A 26-year-old woman presented with progressively worsening anal pain, constipation, and hematochezia for approximately two years. Following the diagnosis of locally advanced rectal cancer (TNM), she received neoadjuvant chemotherapy with modified FOLFOX6 regimen and underwent laparoscopic abdominoperineal resection. Metastases to the breast and vulva developed during postoperative chemotherapy. Genetic testing revealed RAS/BRAF wild-type and microsatellite instability (MSI)-low status. Though sequential administration of irinotecan plus tegafur and tegafur plus raltitrexed-based chemotherapy in combination with bevacizumab, the disease progressed rapidly. Sadly, the patient passed away 15 months after initial diagnosis due to rapidly progressive disease.
CONCLUSION
Rectal SRCC is associated with younger on-set, aggressive behaviors, and worse survival outcomes. Due to poor cohesiveness, SRCC tends to develop metastases. A patient's medical history and immunohistochemical staining (such as CK20, CK7, and CDX-2) can aid in identifying the tumor origin of breast and vulvar metastases. Mutations and signaling pathways predominant in the tumorigenesis of SRCC remains unveiled. There is poor effect of conventional chemotherapies, targeted and immunotherapies for colorectal adenocarcinoma on SRCC, so novel therapies are needed to treat this patient population.
PubMed: 37483522
DOI: 10.3389/fonc.2023.1213888