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The Oncologist Aug 2021Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for...
LESSONS LEARNED
Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer.
BACKGROUND
In patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed.
METHODS
This investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion were eligible for this trial. Anti-epidermal growth factor receptor (EGFR) (for tumors with wild-type RAS) and anti-vascular endothelial growth factor (VEGF) therapy in the first or second line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day 1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m on day 1) every 3 weeks. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.
RESULTS
From September 2015 to November 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and the disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated.
CONCLUSION
Bevacizumab combined with S-1 and raltitrexed showed promising antitumor activity and safety in refractory mCRC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Quinazolines; Thiophenes
PubMed: 33830591
DOI: 10.1002/onco.13778 -
Molecular Pharmacology Jun 2021Previous short-hairpin RNA knockdown studies have established that depletion of human uracil DNA glycosylase (hUNG) sensitizes some cell lines to 5-fluorodeoxyuridine...
Previous short-hairpin RNA knockdown studies have established that depletion of human uracil DNA glycosylase (hUNG) sensitizes some cell lines to 5-fluorodeoxyuridine (FdU). Here, we selectively inhibit the catalytic activity of hUNG by lentiviral transduction of uracil DNA glycosylase inhibitor protein into a large panel of cancer cell lines under control of a doxycycline-inducible promoter. This induced inhibition strategy better assesses the therapeutic potential of small-molecule targeting of hUNG. In total, 6 of 11 colorectal lines showed 6- to 70-fold increases in FdU potency upon hUNG inhibition ("responsive"). This hUNG-dependent response was not observed with fluorouracil (FU), indicating that FU does not operate through the same DNA repair mechanism as FdU in vitro. Potency of the thymidylate synthase inhibitor raltitrexed (RTX), which elevates deoxyuridine triphosphate levels, was only incrementally enhanced upon hUNG inhibition (<40%), suggesting that responsiveness is associated with incorporation and persistence of FdU in DNA rather than deoxyuridine. The importance of FU/A and FU/G lesions in the toxicity of FdU is supported by the observation that dT supplementation completely rescued the toxic effects of U/A lesions resulting from RTX, but dT only increased the IC for FdU, which forms both FU/A and FU/G mismatches. Contrary to previous reports, cellular responsiveness to hUNG inhibition did not correlate with p53 status or thymine DNA glycosylase expression. A model is suggested in which the persistence of FU/A and FU/G base pairs in the absence of hUNG activity elicits an apoptotic DNA damage response in both responsive and nonresponsive colorectal lines. SIGNIFICANCE STATEMENT: The pyrimidine base 5-fluorouracil is a mainstay chemotherapeutic for treatment of advanced colorectal cancer. Here, this study shows that its deoxynucleoside form, 5-fluorodeoxyuridine (FdU), operates by a distinct DNA incorporation mechanism that is strongly potentiated by inhibition of the DNA repair enzyme human uracil DNA glycosylase. The hUNG-dependent mechanism was present in over 50% of colorectal cell lines tested, suggesting that a significant fraction of human cancers may be sensitized to FdU in the presence of a small-molecule hUNG inhibitor.
Topics: Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; DNA Damage; Drug Screening Assays, Antitumor; Floxuridine; Fluorouracil; Humans; Quinazolines; Thiophenes; Uracil-DNA Glycosidase
PubMed: 33795350
DOI: 10.1124/molpharm.120.000191 -
Cancer Biology & Medicine Mar 2021Organoids have recently been used as models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer. Our research aimed to...
OBJECTIVE
Organoids have recently been used as 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 3D 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°C as a control and 43°C 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 models to evaluate hyperthermia synergistic chemotherapeutics. We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.
PubMed: 33710819
DOI: 10.20892/j.issn.2095-3941.2020.0566 -
European Journal of Hospital Pharmacy :... Mar 2021Optimise a wipe sampling procedure to evaluate the surface contamination for 23 antineoplastic drugs used in the hospital pharmacy.
PURPOSE
Optimise a wipe sampling procedure to evaluate the surface contamination for 23 antineoplastic drugs used in the hospital pharmacy.
METHODS
The influence of various parameters (ie, sampling device, sampling solution, desorption modes) was evaluated using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method able to quantify 23 antineoplastic drugs widely used in the hospital pharmacy: 5-fluorouracil, busulfan, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, etoposide phosphate, fludarabine phosphate, ganciclovir, gemcitabine, idarubicin, ifosfamide, irinotecan, methotrexate, paclitaxel, pemetrexed, raltitrexed, topotecan and vincristine. Best conditions were tested with real samples from a hospital pharmacy chemotherapy compounding unit.
RESULTS
Polyester swabs (TX714 and TX716) gave satisfactory results for the desorption step for all compounds with mean recoveries of 90% and 95%, respectively. For the wiping step, higher recoveries were obtained using TX716 and isopropanol 75% as wiping solution. As anticipated, most intense contaminations were found close to the chemotherapy production site, on surfaces the most frequently in contact with operators' hands.
CONCLUSION
Wipe sampling method was successfully developed and applied to real samples to determine surface contamination with 23 antineoplastic agents in trace amounts.
Topics: Antineoplastic Agents; Chromatography, Liquid; Ifosfamide; Pharmacy Service, Hospital; Tandem Mass Spectrometry
PubMed: 33608437
DOI: 10.1136/ejhpharm-2019-001983 -
Asia-Pacific Journal of Clinical... Dec 2021A third-line chemotherapy regimen for metastatic colorectal cancer (mCRC) is not available in China. Studies have shown that raltitrexed or S-1 has no complete...
AIM
A third-line chemotherapy regimen for metastatic colorectal cancer (mCRC) is not available in China. Studies have shown that raltitrexed or S-1 has no complete cross-resistance with fluorouracil (5-FU). In this phase II study, we prospectively analyzed the efficacy and safety of raltitrexed combined with S-1 (RS regimen) in the treatment of mCRC after the failure of conventional chemotherapy.
METHODS
A total of 105 patients with mCRC with progression following treatment with 5-FU, oxaliplatin, and irinotecan were enrolled between November 2015 and May 2019. Patients received intravenous infusion of raltitrexed (3 mg/m from day 1 every 3 weeks) and oral S-1 (80-120 mg for 14 days every 3 weeks). Tumor evaluations were performed every two cycles according to the RECIST 1.1 guidelines.
RESULTS
In the intention-to-treat patients, the objective response and disease control rates were 7.62% and 48.57%, respectively. The median progression-free survival and median overall survival were 2.5 and 8.0 months, respectively. Common adverse events included neutropenia, anemia, thrombocytopenia, and nausea, while neutropenia, anemia, thrombocytopenia nausea, diarrhea, skin eruption, and oral ulceration had grade 3 or higher adverse events. Subgroup analysis revealed that primary site or gene mutation status had little influence on the RS regimen efficacy, while the baseline albumin level, 5-FU administration in second-line therapy, and number of previous treatment regimens affected the efficacy.
CONCLUSION
The RS regimen demonstrated favorable effects in patients with mCRC following failure of standard chemotherapy, and could be a new choice for third-line treatment, and must be verified in future randomized clinical trials (Clinical trial: NCT02618356).
Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Prospective Studies; Quinazolines; Salvage Therapy; Thiophenes; Treatment Outcome
PubMed: 33567129
DOI: 10.1111/ajco.13511 -
Materials (Basel, Switzerland) Jan 2021Two different raltitrexed gold and silver nanoparticles for the delivery of an antitumoral drug into cancer cells were synthesized and characterized. A cysteine linker...
Two different raltitrexed gold and silver nanoparticles for the delivery of an antitumoral drug into cancer cells were synthesized and characterized. A cysteine linker was used for the covalent bonding of raltitrexed to the surface of nanoparticles. To evaluate the efficacy of the antifolate-derivative nanoparticles, their cytotoxicity was assayed in vitro with A549 human lung adenocarcinoma and HCT-116 colorectal carcinoma human cells. Modified nanoparticles are a biocompatible material, and administration of silver raltitrexed nanoparticles strongly inhibited the viability of the cancer cells; gold raltitrexed nanoparticles do not show any type of cytotoxic effect. The results suggest that silver raltitrexed nanoparticles could be a potential delivery system for certain cancer cells.
PubMed: 33499297
DOI: 10.3390/ma14030534 -
BMC Cancer Jan 2021This study aimed to evaluate the impact of postoperative complications on long-term survival in patients with peritoneal metastasis (PM) arising from colorectal cancer...
High-grade postoperative complications affect survival outcomes of patients with colorectal Cancer peritoneal metastases treated with Cytoreductive surgery and Hyperthermic Intraperitoneal chemotherapy.
BACKGROUND
This study aimed to evaluate the impact of postoperative complications on long-term survival in patients with peritoneal metastasis (PM) arising from colorectal cancer (CRC) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
METHODS
Patients with PM arising from CRC treated with CRS and HIPEC were systematically reviewed at the China National Cancer Center and Huanxing Cancer Hospital from June 2017 to June 2019. High-grade complications that occurred within 30 days were defined as grade 3 to 4 events according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. Univariate and multivariable Cox regression models for overall survival were created. Predictors of high-grade postoperative complications were evaluated with univariate and multivariate logistic regression analyses.
RESULTS
In all, 86 consecutive cases were included in this study. Forty-one patients (47.7%) developed postoperative complications, while 22 patients (25.6%) experienced high-grade complications. No mortality occurred during the postoperative period. The median survival of all patients was 25 months, and the estimated 3-year overall survival (OS) rate was 35.0%. In the multivariable Cox regression analysis, a high peritoneal carcinomatosis index (PCI) score (HR, 1.07, 95% CI, 1.01-1.14; P=0.015) and grade 3-4 postoperative complications (HR, 1.86, 95% CI, 1.22-3.51; P=0.044) correlated with worse overall survival. High estimated blood loss (OR, 1.01, 95% CI, 1.01-1.02; P< 0.001) was identified as an independent risk factor for developing high-grade complications.
CONCLUSION
Careful patient selection, high levels of technical skill and improved perioperative management are crucial to ensure patient survival benefits after CRS+HIPEC.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Hyperthermic Intraperitoneal Chemotherapy; Male; Middle Aged; Peritoneal Neoplasms; Postoperative Complications; Prognosis; Retrospective Studies; Survival Rate
PubMed: 33413223
DOI: 10.1186/s12885-020-07756-7 -
OncoTargets and Therapy 2020Apatinib has been proved effective in the treatment of advanced gastric cancer and a variety of solid tumors. Raltitrexed is emerging as a promising alternative for...
OBJECTIVE
Apatinib has been proved effective in the treatment of advanced gastric cancer and a variety of solid tumors. Raltitrexed is emerging as a promising alternative for treating advanced colorectal cancer in China. This work aims to study the combinatory antitumor effect of apatinib and raltitrexed on human esophageal squamous carcinoma cells (ESCC).
MATERIALS AND METHODS
Two VEGFR-2-positive human ESCC lines, KYSE-30 and TE-1, were treated with apatinib or raltitrexed, or both, then the cell proliferation rate was measured by MTS assay; cell migration and invasion were studied by transwell assays; cell apoptosis rate was determined by flow cytometry; cellular autophagy level affected was analyzed by Western blot analysis; finally, quantitative polymerase chain reaction (qPCR) was used to monitor transcription and Western blot was performed to check phosphorylation of apoptotic proteins after treatment.
RESULTS
Both apatinib and raltitrexed significantly inhibited KYSE-30 and TE-1 cell proliferation in a dose-dependent manner. Treatment with both drugs showed enhanced inhibitory effects on cell proliferation, migration, and invasiveness compared with apatinib monotherapy. Apoptosis percentages in both cell lines were also remarkably increased by the combined treatment. Moreover, the combination of apatinib and raltitrexed down-regulated mRNA level of the anti-apoptotic protein Bcl-2, while up-regulated pro-apoptotic protein PARP, Bax, and caspase-3 transcription. Western blot analysis showed that phosphorylation levels of Erk, Akt, and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9) were decreased in the combination group.
CONCLUSION
Taken together, these results indicate that raltitrexed enhances the antitumor effects of apatinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, implying a combination of raltitrexed and apatinib might be an effective option for treating esophageal squamous cell carcinoma patients.
PubMed: 33293826
DOI: 10.2147/OTT.S276125 -
Chinese Journal of Cancer Research =... Oct 2020For locally advanced nasopharyngeal carcinoma (LA-NPC) patients, high incidences of distant metastases and severe treatment related toxicities are the main obstacles...
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 phase II clinical 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 (q3w) for two cycles, followed by raltitrexed-cisplatin based CCRT q3w 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 first-line therapy.
PubMed: 33223761
DOI: 10.21147/j.issn.1000-9604.2020.05.11 -
3 Biotech Nov 2020Malaria remains the leading cause of deaths globally, despite significant advancement towards understanding its epidemiology and availability of multiple therapeutic...
Malaria remains the leading cause of deaths globally, despite significant advancement towards understanding its epidemiology and availability of multiple therapeutic interventions. Poor efficacy of the approved vaccine, and the rapid emergence of antimalarial drug resistance, warrants an urgent need to expedite the process of development of new lead molecules targeting malaria. Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes crucial for ribosomal protein synthesis and are valid antimalarial targets. This study explores the prospects of (re-)positioning the repertoire of approved drugs and natural products as potential malarial aaRS inhibitors. Molecular docking of these two sets of small-molecules to lysyl-, prolyl-, and tyrosyl- synthetases from followed by a comparison of the top-ranking docked compounds against human homologs facilitated identification of promising molecular scaffolds. Raltitrexed and Cefprozil, an anticancer drug and an antibiotic, respectively, showed stronger binding to aaRSs compared to human homologs with > 4 kcal/mol difference in the docking scores. Similarly, a difference of ~ 3 kcal/mol in Glide scores was observed for docked Calcipotriol, a drug used for psoriasis treatment, against the two lysyl-tRNA synthetases. Natural products such as Dihydroxanthohumol and Betmidin, having aromatic rings as a substructure, showed preferential docking to the purine binding pocket in tyrosyl-tRNA synthetase as evident from the calculated change in binding free energies. We present detailed analyses of the calculated intermolecular interaction for all top-scoring docked poses. Overall, this study provides a compelling foundation to design and develop specific antimalarials.
PubMed: 33088666
DOI: 10.1007/s13205-020-02460-6