Enhanced antitumour effect for hepatocellular carcinoma in the advanced stage using a cyclodextrin-sorafenib-chaperoned inclusion complex

2019 ◽  
Vol 7 (11) ◽  
pp. 4758-4768
Author(s):  
Chiuyen Phan ◽  
Ziyang Zheng ◽  
Jianwei Wang ◽  
Qiwen Wang ◽  
Xiurong Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Inclusion Complex ◽  
Inclusion Complexes ◽  
Nude Mice ◽  
Advanced Stage ◽  
Antitumour Effect ◽  
Advanced Hcc ◽  
Tumor Bearing

We have proposed and classified the HCC tumor of HCC tumor-bearing BALB/c nude mice to four stages. Cyclodextrin-sorafenib-chaperoned inclusion complexes were prepared and applied to treat advanced HCC tumor-bearing mice.

scholarly journals Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma

Liver Cancer ◽  
2021 ◽  
pp. 1-13
Author(s):  
Kazufumi Kobayashi ◽  
Sadahisa Ogasawara ◽  
Aya Takahashi ◽  
Yuya Seko ◽  
Hidemi Unozawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Duration ◽  
Molecular Target ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Stage ◽  
First Line ◽  
Advanced Hcc ◽  
Period 2 ◽  
Study Population ◽  
The Impact

<b><i>Background and Aims:</i></b> The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. <b><i>Approach and Results:</i></b> We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009–2012, <i>n</i> = 267; period 2: 2013–2016, <i>n</i> = 352; period 3: 2017–2019, <i>n</i> = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, <i>p</i> &#x3c; 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (<i>p</i> = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; <i>p</i> &#x3c; 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. <b><i>Conclusions:</i></b> The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

scholarly journals Gemcitabine Plus Carboplatin in Patients with Advanced Hepatocellular Carcinoma: Results of a Phase II Study

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5
Author(s):  
Aly M. Azmy ◽  
Khalid E. Nasr ◽  
Nagy S. Gobran ◽  
M. Yassin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Stage ◽  
Survival Times ◽  
Advanced Hcc ◽  
Disease Stabilization ◽  
Grade 3

Objectives. Assessment of gemcitabine/carboplatin combination in patients with advanced-stage hepatocellular carcinoma (HCC) in a phase II trial for safety and efficacy. Methods. Forty patients with previously untreated advanced-stage HCC were prospectively enrolled and subjected to gemcitabine/carboplatin regimen which consisted of gemcitabine 1000 mg/m2 on days 1 and 8, and carboplatin AUC 6 on day 1. The treatment was repeated every 3 weeks until disease progression or limiting toxicity. Results. Forty patients were assessable for efficacy and toxicity. In all, 276 treatment cycles were administered. No toxic deaths occurred. Hematological grade 3-4 toxicity consisted of thrombocytopenia (27% of patients) and neutropenia (24%), including 2 febrile neutropenia and anemia (9%). Grade 3 carboplatin-induced neurotoxicity was observed in 3 (9%) patients. ORR was 23% (95% CI, 0.10–0.29) with 9 partial responses and disease stabilization was observed in 46% (95% CI, 0.22–0.42) of patients, giving a disease control rate of 69%. Median progression-free and overall survival times were, respectively, 5 months (95% CI: 3–8 months) and 8 months (95% CI: 6–18 months). Conclusion. The gemcitabine/carboplatin regimen seems to be effective, well tolerated, and active in advanced HCC.

New therapy including combination

2018 ◽  
Vol 1 (2) ◽  
pp. 33-36 ◽  
Author(s):  
Phongphob Intraprasong
Keyword(s):  
Hepatocellular Carcinoma ◽  
High Risk ◽  
Liver Function ◽  
Standard Treatment ◽  
Tumor Resection ◽  
Advanced Stage ◽  
Current Standard ◽  
Advanced Hcc ◽  
The World ◽  
Current Standard Treatment

Hepatocellular carcinoma (HCC) is one of the most common cancers with high mortalityrate found throughout the world especially in Southeast Asia and Thailand. Many factors determinethe outcome of the treatment for HCC including the stage of the cancer and liver function. Sorafenibis the current standard treatment for advanced HCC. Many studies have not shown any benefit of usingSorafenib after tumor resection or ablation and the combination of Sorafenib with transarterialchemoembolization. Lenvatinib, Regorafenib and Nivolumab have been studied in Advanced HCCwith preserved liver function with promising results. Surveillance for HCC in high-risk patientsremains the tools to deliver better outcomes for patient with HCC.   Keywords: HCC, advanced stage, therapy, Sorafenib, Lenvatinib, Regorafenib, Nivolumab

scholarly journals Acteoside as a potential therapeutic option for primary hepatocellular carcinoma: a preclinical study

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Di Ma ◽  
Juan Wang ◽  
Lu Liu ◽  
Meiqi Chen ◽  
Zhiyong Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Nude Mice ◽  
Colony Formation ◽  
Primary Hepatocellular Carcinoma ◽  
Mice Model ◽  
Advanced Hcc ◽  
Nude Mice Model ◽  
And Migration

Abstract Background Hepatocellular carcinoma (HCC) is a common malignant tumor with characteristics of poor prognosis, high morbidity and mortality worldwide. In particular, only a few systemic treatment options are available for advanced HCC patients, and include sorafenib and the recently described atezolizumab plus bevacizumab regimen as possible first-line treatments. We here propose acteoside, a phenylethanoid glycoside widely distributed in many medicinal plants as a potential candidate against advanced HCC. Methods Cell proliferation, colony formation and migration were analyzed in the three human HCC cell lines BEL7404, HLF and JHH-7. Angiogenesis assay was performed using HUVESs. The BEL7404 or JHH-7 xenograft nude mice model was established to analyze the possible antitumor effects of acteoside. qRT-PCR and western blotting were used to reveal the potential antitumor mechanisms of acteoside. Results Acteoside inhibited cell proliferation, colony formation and migration in all the three human HCC cell lines BEL7404, HLF and JHH-7. The prohibition of angiogenesis by acteoside was revealed by the inhibition of tube formation and cell migration of HUVECs. The combination of acteoside and sorafenib produced stronger inhibition of cell colony formation and migration of the HCC cells as well as of angiogenesis of HUVECs. The in vivo antitumor efficacy of acteoside was further demonstrated in BEL7404 or JHH-7 xenograft nude mice model, with an enhancement when combined with sorafenib in inhibiting the growth of JHH-7 xenograft. Further treatment of JHH-7 cells with acteoside revealed an increase in the level of tumor suppressor protein p53 as well as a decrease of kallikrein-related peptidase (KLK1, 2, 4, 9 and 10) gene level with no significant changes of the rest of KLK1–15 genes. Conclusions Acteoside exerts an antitumor effect possibly through its up-regulation of p53 levels as well as inhibition of KLK expression and angiogenesis. Acteoside could be useful as an adjunct in the treatment of advanced HCC in the clinic.

scholarly journals The Synergistic Antitumor Effect of Tanshinone IIA Plus Adriamycin on Human Hepatocellular Carcinoma Xenograft in BALB/C Nude Mice and Their Influences on Cytochrome P450 CYP3A4 In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Tao-Li Liu ◽  
Li-Na Zhang ◽  
Yue-Yu Gu ◽  
Mei-Gui Lin ◽  
Jun Xie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cytochrome P450 ◽  
Protein Expression ◽  
Nude Mice ◽  
Antitumor Effect ◽  
Tumor Volume ◽  
Life Quality ◽  
Tanshinone Iia ◽  
Tumor Bearing

Objective. Hepatocellular carcinoma is one of the most common diseases that seriously threaten human life and health. In this study, we evaluated the inhibitory effect of tanshinone IIA (Tan IIA) combined with adriamycin (ADM) on human hepatocellular carcinoma and developed a platform to assess the function if Chinese herbal ingredients combined with chemotherapy drugs have synergistic antitumor effects in vivo. Methods. Established animal model of human hepatocarcinoma HepG2 cell in nude mice. Mice were divided into model control group, Tan IIA group, ADM group, and Tan IIA + ADM group. The changes from general condition, weight, tumor volume, and inhibition rate were observed. The data were gathered from serum AST level and histopathological changes. The content and activity of cytochrome P450 were determined by spectrophotometric analysis. CYP3A4 protein expression was analyzed by western blotting. The binding model crystal structure of Tan IIA and ADM with pregnane X receptor (PXR) was evaluated by Discovery Studio 2.1. Results. A combination of Tan IIA with ADM could improve life quality by relieving ADM toxicity, decreasing tumor volume, declining serum AST level, and improving liner pathological section in tumor-bearing mice. The inhibitory rates of Tan IIA, ADM, and cotreatment were 32.77%, 60.96%, and 73.18%, respectively. The Tan IIA group significantly enhanced the content of cytochrome b5, P450, and erythromycin-N-demethylase activity. CYP3A4 protein expression was enhanced obviously by the Tan IIA + ADM group. Virtual molecular docking showed that both Tan IIA and ADM could be stably docked with the same binding site of PXR but different interactions. Conclusions. Tan IIA in combination with ADM could improve the life quality in tumor-bearing mice and enhance the antitumor effect. The Tan IIA group increased the concentration of cytochrome P450 enzymes and activity. Combined Tan IIA with ADM could upregulate the CYP3A4 protein expression and make relevant interaction with protein PXR by virtual docking.

Sorafenib (S) for hepatocellular carcinoma (HCC) treatment: Russian experience in cirrhotic (C) and non-cirrhotic (non-C) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14723-e14723
Author(s):  
Valeriy Vladimirovich Breder ◽  
Yulia Bisovskaya ◽  
Svetlana Victorovna Khokhlova ◽  
Vera Gorbunova
Keyword(s):  
Hepatocellular Carcinoma ◽  
Side Effects ◽  
Hepatitis B ◽  
Skin Rash ◽  
Advanced Stage ◽  
Advanced Hcc ◽  
Significant Toxicity ◽  
Significant Difference ◽  
Clinically Significant ◽  
Skin Side Effects

e14723 Background: S is the standard for HCC treatment in advanced stage. There is no date about an etiology of HCC and S efficacy/toxicity in Russian pts. Methods: 69 patients (19 f/ 50 m, average age 54 years) with advanced HCC BCLC A/B/C/D 1/30/38/0 were treated with sorafenib as a I-st line. S treatment: 400 mg bid until progression, uncontrolled toxicity, or death. S dose reduced when toxicity (NCI CTC, ver 3.0) ≥Gr 2 occured. We evaluate influences of BCLC and Child-Pugh stage, presence of C and/or viral hepatitis on S efficacy and toxicity. Results: 33 (48%) out of 69 patients had C and 36 (52%) were non-C. No hepatitis - 36 pts (C/non-C - 5/31 pts), 16 pts had HBV (C/non-C – 15/1), 17 pts had HCV (C/non-C – 15/2), 1 pt had hepatitis B+/C without C. Clinically significant toxicity (Gr 2/3) occurred in 20 (C/non-C – 9/12) pts: HFS 1/6, skin rash 3/3, diarrhea 3/2, arterial hypertension (AG) 2/0, asthenia 1/1, fever 1/0. S interrupted in 12 (C/non-C – 5/7) pts: HFS- 0/4, skin rash -1/3 diarrhea - 2/1 and AG - 2/0. Efficacy evaluated in 68 pts: PR - 5 (7,4%) pts, stable – 46 (67,6%) and disease progressed in 17 (25%) pts. All PR (OR=13,9%) observed in non-C pts: 6, 9,3, 10, 10,2 and 13+ mo). Median PFS and OS on S treatment was 5,4 and 9,3 mo respectively. No significant difference were in PFS and OS for C and non-C pts, irrespectively for HCV/HBV status and Child-Pugh stage A/B (Table). Conclusions: More than 50% of HCC pts in Russia are non-C and don’t have HBV/HCV. Clinically significant toxicity of S differs in C/non-C pts, with prevalence of skin side effects in non-C pts, AG and diarrhea in C group. Non-C HCC pts have better chance to respond to S treatment. However we didn’t find any significant difference of S treatment in terms of survival and side effects between C and non-C pts. [Table: see text]

Approaching the tumor microenvironment in patients with advanced hepatocellular carcinoma using needle biopsy samples.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 334-334
Author(s):  
Hiroaki Kanzaki ◽  
Sadahisa Ogasawara ◽  
Keisuke Koroki ◽  
Kazufumi Kobayashi ◽  
Soichiro Kiyono ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Hepatic Resection ◽  
Systemic Therapy ◽  
Needle Biopsy ◽  
Early Stage ◽  
Pathological Examination ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Stage ◽  
Advanced Hcc

334 Background: Currently, combined immunotherapy of atezolizumab (anti-PD-L1 antibody) plus bevacizumab (a humanized anti-VEGF monoclonal antibody) is the standard first-line treatment in patients with advanced hepatocellular carcinoma (HCC). At the threshold of this new era, there is limited information about tumor microenvironment (TME) in advanced HCC. Several studies on TME in HCC have analyzed samples obtained via hepatic resection. In general, hepatic resection is indicated for patients with limited size and number of intrahepatic nodules, i.e., early stage HCC. In contrast, most patients who have an indication for systemic therapy have developed macroscopic vascular invasion (MVI) or/and extrahepatic metastasis, namely in advanced stage HCC. Progression from an early stage HCC to an advanced stage HCC involves a lengthy clinical course, therefore, the TME at the time of initial diagnosis may differ from that at the time of systemic therapy indication. The present study was aimed to analyze the TME by using needle biopsy samples obtained prior to initiation of systemic therapy in patients with advanced HCC. Methods: Between March 2019 and May 2020, 80 patients underwent liver tumor biopsy at the time of indication for systemic chemotherapy. HCC was confirmed via pathological examination in 70 patients and their samples were analyzed. Microsatellite instability (MSI) was evaluated using polymerase chain reaction. Programed death-ligand 1 (PD-L1) expression and the levels of tumor-infiltrating lymphocytes (TIL) were evaluated using immunohistochemical staining. PD-L1 expression was defined as per the tumor proportion score (TPS; the number of PD-L1-positive cells/total number of tumor cells) and was classified as low (TPS < 1%) or high (TPS >1%). Levels of TIL were defined as the mean number of CD8-positive lymphocytes in the tumor per 1 mm2 and classified as low or high using the median value. Results: Out of the 70 tumors, one was MSI-high and 69 were MSI-negative. The PD-L1 expression was < 1% in 50 samples, 1%–10% in 12, 11%–20% in 7, and 21%–30% in 1. The median level of TIL was 266/mm2. PD-L1highTILhighwas present in 20.0%, PD-L1lowTILlowin 38.5%, PD-L1highTILlowin 8.6%, and PD-L1lowTILhighin 32.9%. In the MSI-high tumor, PD-L1 expression was < 1% and the level of TIL was 142/mm2. High PD-L1 expression and high levels of TIL were associated with hepatitis C virus infection, high alpha-fetoprotein levels, and presence of MVI respectively. We are currently performing RNA-sequencing in order to obtain more details about TME in patients with advanced HCC. Conclusions: MSI-high advanced HCC was detected in 1.4% patients and was not necessarily associated with a “hot” immune microenvironment. PD-L1 expression and levels of TIL were associated with some clinical parameters. In the present study, we also reported the changes in the TME over time.

NMR Studies of the Inclusion Complexes Between Ezetimibe and Cyclodextrins

2018 ◽  
Vol 69 (7) ◽  
pp. 1838-1841
Author(s):  
Hajnal Kelemen ◽  
Angella Csillag ◽  
Bela Noszal ◽  
Gabor Orgovan
Keyword(s):  
Inclusion Complex ◽  
Inclusion Complexes ◽  
Water Solubility ◽  
Solution Nmr ◽  
Spectroscopic Techniques ◽  
Nmr Studies ◽  
The Poor ◽  
Poor Water Solubility

Ezetimibe, the antihyperlipidemic drug of poor bioavailability was complexed with native and derivatized cyclodextrins.The complexes were characterized in terms stability, stoichiometry and structure using various 1D and 2D solution NMR spectroscopic techniques. The complexes were found to be of moderate stability (logK[3). The least stable inclusion complex is formed with b-cyclodextrin, while the ezetimibe-methylated-b--cyclodextrin has a 7-fold higher stability. The results can be useful to improve the poor water-solubility and the concomitant bioavailability of ezetimibe.

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