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1.
Braz. J. Pharm. Sci. (Online) ; 57: e18122, 2021. tab, graf
Article in English | LILACS | ID: biblio-1339306

ABSTRACT

This study investigated the mechanism underlying the suppression of estrogen receptor-positive MCF-7 cell growth by regorafenib. MCF-7 cells were treated with regorafenib, and the effect of regorafenib on multiple cancer-associated pathways was evaluated. Although regorafenib effectively inhibited the proliferation of MCF-7 cells, it had no effect on the proliferation of the normal breast epithelial cell line MCF10A. Regorafenib suppressed MCF-7 cell migration, probably by regulating the homeostatic expression of matrix metalloproteinases and the tissue inhibitor of MMPs. Furthermore, it upregulated p21 expression, downregulated cyclin B1 and cyclin D1 expresssions, and caused cell cycle arrest. In addition, regorafenib induced apoptosis in MCF-7 cells by reducing Mcl-1 expression and activating caspase signaling. These results demonstrate that regorafenib has the potential to be an effective drug for treating breast cancer


Subject(s)
Cell Cycle/immunology , MCF-7 Cells/classification , Breast Neoplasms/pathology , Pharmaceutical Preparations , Receptors, Estrogen , Apoptosis , Cyclin D1/pharmacology , Epithelial Cells/classification , Cyclin B1/pharmacology
2.
Chinese Journal of Geriatrics ; (12): 761-765, 2021.
Article in Chinese | WPRIM | ID: wpr-910913

ABSTRACT

Objective:To analyze the dosing, efficacy and safety of Regorafenib in elderly patients with metastatic colorectal cancer.Methods:Clinical data of 40 elderly patients with advanced colorectal cancer treated with regorafenib from June 2018 to October 2019 at Beijing Hospital were collected.The dosing, effectiveness and safety of regorafenib were retrospectively analyzed.The primary endpoint was overall survival(OS).Results:A total of 40 elderly patients were enrolled in this study, including 25 males and 15 females, with a median age of 66 years.The initial dose of Regorafenib was 80 mg, and the maintenance dose was 80 mg in 14(35.0%)patients, 120 mg in 20(50.0%)patients and 160 mg in 6(15.0%)patients.Thirty-one patients were treated with Regorafenib and 9 patients were given a combination therapy including Regorafenib.The objective response rate(ORR)was 2.5%(1 case), and the disease control rate(DCR)was 45.0%(18 cases). The median progression free survival(PFS)was 2.2 months(95% CI: 2.1-4.0)and the median OS was 8.8 months(95% CI: 7.1-11.2). There was no significant difference in PFS or OS in different maintenance dose groups( P<0.05). Patients who received 120 mg Regorafenib as a maintenance dose showed longest survival with a median OS of 9.8 months(95% CI: 6.9-14.0). There was no difference in median OS between the Regorafenib group and the combination therapy group( χ2=0.1, P>0.05). Grade 3 and 4 adverse reactions occurred in 11 patients(27.5%). Common adverse reactions were hand-foot skin reaction, fatigue, hypertension, diarrhea, elevated transaminase levels and proteinuria. Conclusions:Regorafenib offers a good survival benefit for elderly patients with advanced colorectal cancer who failed to respond to standard therapy.The dosing strategy, starting with a low dose of Regorafenib and escalating gradually as tolerance builds up, is recommended for elderly patients, when both efficacy and safety are considered.The proportion of patients who can tolerate 120 mg Regorafenib as a maintenance dose is high with relatively long overall survival, indicating it is appropriate for the elderly.

3.
Journal of Clinical Hepatology ; (12): 1175-1180, 2020.
Article in Chinese | WPRIM | ID: wpr-822011

ABSTRACT

As the first-line drug for the treatment of primary liver cancer, sorafenib has been widely used in clinical practice, but its drug resistance and toxic and side effects have become increasingly apparent, along with limited efficacy. In recent years, the research on regorafenib for the treatment of hepatocellular carcinoma (HCC) has gradually become a hotspot. The RESORCE trial has shown that regorafenib can significantly extend the overall survival time of patients with failed sorafenib treatment to 10.6 months, and regorafenib was approved as a second-line drug for advanced HCC by Food and Drug Administration in 2017. This article reviews the molecular mechanism, efficacy evaluation, combination therapy, and criteria for patient selection in the treatment of HCC with regorafenib, so as to provide a direction for further research in the future.

4.
Article in Chinese | WPRIM | ID: wpr-699144

ABSTRACT

Hepatocellular carcinoma (HCC) is the world's fifth common malignant tumor,ranks as the second and sixth leading causes of cancer death in nale and female.In a majority of the cases,HCC is diagnosed in advanced stage of disease when curative treatment options are not applicable.In 2007,sorafenib was approved for the first-line treatment of advanced HCC.Targeted therapy,which could improve the overall survival and qualities of life,brought a new hope for patients with advanced HCC.Unfortunately,in the past 10 years,various drugs tested in numerous different trials failed to denonstrate any benefit.Recent studies have demonstrated the efficacy of two molecular targeted agents,the second-line agent regorafenib and the first-line agent lenvatinib.Furthermore,preliminary results of immune checkpoint inhibitors such as anti-PD-1/PD-L1 or CTLA-4 antibodies were quite encouraging.These new drugs brought dawn of targeted therapy of HCC.

5.
Acta Pharmaceutica Sinica ; (12): 1705-1714, 2017.
Article in Chinese | WPRIM | ID: wpr-779779

ABSTRACT

This study was designed to investigate the inhibitory effects of regorafenib (REG) on the catalytic activities of 12 kinds of human UGT isoforms and human liver microsomes (HLM) in vitro. The broader potential of REG to perpetrate drug-drug interactions (DDI) arising from UGT enzyme inhibition is predicted by in vitro-vivo extrapolation (IV-IVE). Fifty mixed HLM and 12 kinds of recombinant UGTs were utilized as enzyme sources to evaluation the inhibitory effects of REG against UGTs. 4-Methylumbelliferone (4-MU) as a nonselective substrate of UGTs except for UGT1A4, N-(3-carboxypropyl)-4-hydroxy-1,8-napht-halimide (NCHN) and N-butyl-4-(4-hydroxyphenyl)-1,8-naphthalimide (NPHN) as the specific fluorescent substrate of UGT1A1, and trifluoperazine (TFP) as the specific substrate of UGT1A4. The half maximal inhibitory concentration (IC50) was calculated via the nonlinear regression analysis using Graphpad Prism 6.0, the inhibition kinetic types were selected and evaluated based on the intersection location of Lineweaver-Burk plot and Dixon plot, and Ki values were determined by the second plot of slopes. The potential DDI risk based on UGT1A1 inhibition was also evaluated through the in vitro parameters. The results demonstrated that REG displayed strong inhibitory effects against UGT1A1, 1A7, 1A9, and 2B7. The IC50 values were from 0.15 to 6.6 μmol·L-1 and Ki values from 0.027 to 14 μmol·L-1. The REG exerted competitive inhibition against UGT1A1-mediated 4-MU-O-glucuronidation and UGT1A1-mediated NPHN-O-glucuronidation, while the inhibition of NCHN-4-O-glucuronide by REG was suited to noncompetitive inhibition in both HLM and recombinant UGT1A1. Likewise, REG exhibited a mixed efficacy in inhibition of UGT1A7-, UGT1A9-, and UGT2B7-catalyzed 4-MU-O-glucuronidation. The AUC ratio of UGT1A1 specific substrates NPHN and NCHN can be increased by 101% to 302% and 13% to 109%, respectively. These results suggest that much caution should be exercised when REG is co-administered with UGT1A1 substrates.

6.
China Pharmacist ; (12): 348-350, 2017.
Article in Chinese | WPRIM | ID: wpr-507558

ABSTRACT

Objective: To establish an LC-MS/MS method for the determination of 4-( 4-amino-3-fluorophenoxy )-N-methylpyri-dine-2-carboxamide ( AFP-PMA) as a genotoxic impurity in regorafenib. Methods: The content of AFP-PMA was determined by an LC-MS/MS method. A Waters XBridge Shield RP18 column was adopted to separate the samples and the column temperature was 50℃. The mobile phase consisted of 5 mmol·L-1ammonium acetate aqueous (A)-acetonitrile (B) with gradient elution (0~9 min, 5%B→90%B) at a flow rate of 1. 0 ml·min-1. An electrospray ionization source (ESI) was used in a positive-ion and multiple reactions monitoring mode. The ion channel was m/z 262. 2→244. 1. Results:The standard curve was linear within the range of 2. 41-980. 90 ng·ml-1(r=0. 9998) and the limit of quantification was 8. 02 ng·ml-1. The limit of detection was 2. 41 ng·ml-1, which was e-quivalent to 0.000241% for the concentration of regorafenib. The average recovery was 100.95% and RSD was 2.37% (n=9). Conclusion:The method has good specificity, promising accuracy and high sensitivity, which can be used for determining the trace genotoxic impurity AFP-PMA in regorafenib.

7.
Article in English | WPRIM | ID: wpr-101947

ABSTRACT

PURPOSE: The aim of this study was to confirm the efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors (GISTs) reported in the GRID phase III trial in Korean patients. MATERIALS AND METHODS: Fifty-seven Korean patientswith advanced GISTwho experienced both imatinib and sunitinib failure were enrolled in the management access program between December 2012 and November 2013 and treated with regorafenib (160 mg orally once daily in a 3 weeks on/1 week off). RESULTS: None of the patients achieved a complete or partial response while 25 patients (44%) showed stable disease for ≥ 12 weeks. With a median follow-up of 12.7 months (range, 0.2 to 27.6 months), the median progression-free survival and overall survival were 4.5 months (95% confidence interval [CI], 3.8 to 5.3) and 12.9 months (95% CI, 8.1 to 17.7), respectively. Interestingly, 15 patients (26%) experienced an exacerbation of their cancer-related symptoms (abdominal pain in eight and abdominal distension in five) during the rest period for regorafenib, but all were ameliorated upon the resumption of regorafenib. The most common grade 3 or 4 adverse event was a hand-foot skin reaction (25%). The regorafenib dose was reduced in 44 patients (77%) due to toxicity, which manifested mainly as a hand-foot skin reaction (n=31). CONCLUSION: This study confirmed the efficacy and safety of regorafenib for advanced GIST after imatinib and sunitinib failure in Korean patients. Considering the exacerbation of the cancer-related symptoms observed during the rest periods, further exploration of the continuous dosing schedule of regorafenib is warranted in future clinical trials.


Subject(s)
Appointments and Schedules , Disease-Free Survival , Follow-Up Studies , Gastrointestinal Stromal Tumors , Humans , Imatinib Mesylate , Skin
8.
China Pharmacy ; (12): 3431-3433,3434, 2016.
Article in Chinese | WPRIM | ID: wpr-605793

ABSTRACT

OBJECTIVE:To establish a method for the determination of related substances in regorafenib. METHODS:Gradi-ent elution HPLC was performed on the column of Waters Atlantis T3 C18 with mobile phase A of 0.1%Trifluoroacetic acid solution and B of acetonitrile(gradient elution)at a flow rate of 1.0 ml/min,the detection wavelength was 232 nm and column temperature was 35 ℃,injection volume was 10 μl. RESULTS:AFP-PMA urease(impurity A),FP- dimethyl pyridine carboxamide(impurity B),3,4-bis-CTF-aminoformamido-PMA(impurity C),regorafenib and other impurities were well separated;the linear range was 0.511-5.108 μg/ml for impurity A(r=0.999 9),0.287-2.869 μg/ml for impurity B(r=0.999 5),0.360-3.604 μg/ml for impurity C (r=0.999 9)and 1.444-14.442 μg/ml for regorafenib(r=0.999 8);the detection limit were 0.052,0.022,0.084 and 0.071 μg/ml, respectively;RSDs of precision,stability and reproducibility tests were lower than 3%;recoveries of impurity A,B and C were 102.7%-106.3%(RSD=1.09%,n=9),98.2%-102.9%(RSD=1.83%,n=9)and 98.6%-104.3%(RSD=1.57%,n=9). CON-CLUSIONS:The method is sensitive,rapid,accurate and reliable,and can be used for the determination of related substances in regorafenib.

9.
China Pharmacist ; (12): 1059-1063, 2016.
Article in Chinese | WPRIM | ID: wpr-493275

ABSTRACT

Objective:To optimize the formula of regorafenib solid dispersion .Methods: On the basis of preliminary studies on the carrier and drug/carrier ratio, an orthogonal test was used to study the formula of regorafenib solid dispersion .The orthogonal table of L9 (34 ) was designed to study the drug/carrier ratio, ultrasound time and bath temperature .Results: Regorafenib solid dispersion was prepared by a solvent method with polyvinylpyrrolidone K 30 as the carrier.The drug/carrier ratio was 1 ∶7, the ultrasound time was 4min, and the bath temperature was 30℃.Regorafenib solid dispersion showed good stability confirmed by differential scanning calorimetry and X-ray diffraction .The dissolution in 30 min reached above 90 %.Conclusion: The preparation process is stable and reproducible , which can be used to prepare regorafenib solid dispersion .

10.
Cancer Research and Treatment ; : 1155-1166, 2016.
Article in English | WPRIM | ID: wpr-98818

ABSTRACT

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors originating in the gastrointestinal tract. With the introduction of molecular-targeted therapy for GISTs which has yielded remarkable outcomes, these tumors have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those published by the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), the clinical situations in Asian countries are different from those in Western countries in terms of diagnostic methods, surgical approach, and availability of new targeted agents. Accordingly, we have reviewed current versions of several GIST guidelines published by Asian countries (Japan, Korea, China, and Taiwan) and the NCCN and ESMO and discussed the areas of dissensus. We here present the first version of the Asian GIST consensus guidelines that were prepared through a series of meetings involving multidisciplinary experts in the four countries. These guidelines provide an optimal approach to the diagnosis and management of GIST patients in Asian countries.


Subject(s)
Asians , China , Consensus , Diagnosis , Gastrointestinal Stromal Tumors , Gastrointestinal Tract , Humans , Imatinib Mesylate , Korea , Medical Oncology
11.
Indian J Cancer ; 2015 July-Sept; 52(3): 257-260
Article in English | IMSEAR | ID: sea-173741

ABSTRACT

Regorafenib is a novel oral multitargeted tyrosine kinase inhibitor having both antitumor and anti‑angiogenic activities. Regorafenib was recently approved by US Food and Drug Administration in February 25, 2013 in the treatment for patients with advanced gastrointestinal stromal tumor and for the treatment of patients with metastatic colorectal carcinoma after disease progression or intolerance to imatinib mesylate and sunitinib therapy. Oral regorafenib demonstrates a high level of efficacy with acceptable tolerability with the 160 mg daily for 3 weeks followed by 1 week off schedule; a continuous schedule could be of interest. Hypertension, mucositis, hand foot skin reaction, diarrhea and asthenia are the most common side‑effects. Regardless of these encouraging results, studies investigating, adjuvant and neoadjuvant settings are awaited, as well as trials using regorafenib in combination with chemotherapy or other targeted therapies. Clinical trials investigating regorafenib in other tumor types are ongoing.

12.
Article in Chinese | WPRIM | ID: wpr-464987

ABSTRACT

Angiogenesis plays a vital role in carcinogenesis and development of colorectal cancer. Treatment targeting VEGF signaling pathway acquires important survival prolong for advanced colorectal cancer patients. For advanced colorectal cancer patients,bevacizumab could furtherly prolongs survival time in the setting of first line,second line and continuing therapy after first-progression therapy combined with chemothe-rapy. Aflibercept used in combination with irinotecan-containing regimen improves the survival of advanced colorectal cancer patients in second-line setting. Regorafenib also improves the survival of advanced colorectal cancer patients who have progressed after all line treatment. Considering these suivival benefit and their favora-ble safety,anti-angiogenic agents should be taken into all lines of therapy in the management of advanced colo-rectal cancer.

13.
Article in English | WPRIM | ID: wpr-90561

ABSTRACT

PURPOSE: Regorafenib, an oral multi-targeted tyrosine kinase inhibitor, is considered the new standard of care in patients with chemotherapy-refractory colorectal cancers (CRCs). However, there are no data on this drug in Korean patients. MATERIALS AND METHODS: We evaluated patients who received oral regorafenib 160 mg once daily during the first 3 weeks of each 4-week cycle between August 2013 and September 2013. All patients had previously progressed fluorouracil, irinotecan, and oxaliplatin with or without biologic agents such as cetuximab or bevacizumab. RESULTS: Thirty-two patients were enrolled (median age, 57 years; male:female ratio, 20:12; Eastern Cooperative Oncology Group performance status [0-1:2], 31:1; colon:rectum, 21:11). The overall response rate was 3.1% and the disease control rate was 50.0% (95% confidence interval [CI]) with one partial response and 15 patients with stable disease. The median progression-free survival was 4.2 months (95% CI, 3.1 to 5.2 months) and the median overall survival has not yet been reached. The most common adverse events of grade two or higher related to regorafenib were hand-foot skin reaction (25%), mucositis (19%), abdominal pain (9%), and liver function test (LFT) abnormalities (9%). Grade 3 or 4 toxicities included LFT abnormalities (9%), abdominal pain (9%), rash (6%), anemia (3%), leukopenia (3%), neutropenic fever (3%), and fatigue (3%). There was no treatment-related death. CONCLUSION: Regorafenib appears to have promising activity and tolerable toxicity profiles in Korean patients with refractory CRC, consistent with the CORRECT trial findings.


Subject(s)
Abdominal Pain , Anemia , Biological Factors , Colorectal Neoplasms , Disease-Free Survival , Exanthema , Fatigue , Fever , Fluorouracil , Humans , Korea , Leukopenia , Liver Function Tests , Mucositis , Protein-Tyrosine Kinases , Skin , Standard of Care
14.
Korean Journal of Medicine ; : 341-353, 2013.
Article in Korean | WPRIM | ID: wpr-142792

ABSTRACT

Gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the gastrointestinal tract, have represented an important advance in oncology field with the success of molecular targeted therapy. Since the approval of the tyrosine kinase inhibitor (imatinib) in 2002, the survival of patients with advanced GISTs has significantly increased. Accurate histopathologic diagnosis of GISTs and multidisciplinary approach has become more important for successful management of GISTs. Recently, imatinib has become a standard treatment even in adjuvant setting, and regorafenib has been approved for advanced GIST after failure of imatinib and sunitinib. This review presents here the updated results of relevant clinical studies for the further revision to the guideline of Korean GIST study group. We hope this review will help enhance the quality of diagnosis, treatment, and care of patients with GIST in Korea.


Subject(s)
Benzamides , Gastrointestinal Stromal Tumors , Gastrointestinal Tract , Humans , Indoles , Korea , Molecular Targeted Therapy , Phenylurea Compounds , Piperazines , Protein-Tyrosine Kinases , Pyridines , Pyrimidines , Pyrroles , Imatinib Mesylate
15.
Korean Journal of Medicine ; : 341-353, 2013.
Article in Korean | WPRIM | ID: wpr-142789

ABSTRACT

Gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the gastrointestinal tract, have represented an important advance in oncology field with the success of molecular targeted therapy. Since the approval of the tyrosine kinase inhibitor (imatinib) in 2002, the survival of patients with advanced GISTs has significantly increased. Accurate histopathologic diagnosis of GISTs and multidisciplinary approach has become more important for successful management of GISTs. Recently, imatinib has become a standard treatment even in adjuvant setting, and regorafenib has been approved for advanced GIST after failure of imatinib and sunitinib. This review presents here the updated results of relevant clinical studies for the further revision to the guideline of Korean GIST study group. We hope this review will help enhance the quality of diagnosis, treatment, and care of patients with GIST in Korea.


Subject(s)
Benzamides , Gastrointestinal Stromal Tumors , Gastrointestinal Tract , Humans , Indoles , Korea , Molecular Targeted Therapy , Phenylurea Compounds , Piperazines , Protein-Tyrosine Kinases , Pyridines , Pyrimidines , Pyrroles , Imatinib Mesylate
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