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Clinical Breast Cancer Oct 2022The tubulin inhibitor, eribulin, improves survival for previously treated advanced breast cancer (ABC) compared to chemotherapy of physician's choice, including...
INTRODUCTION
The tubulin inhibitor, eribulin, improves survival for previously treated advanced breast cancer (ABC) compared to chemotherapy of physician's choice, including vinorelbine, an older anti-tubulin. Vinorelbine is commonly still used after eribulin, but potentially risks cross-resistance and its efficacy in this setting is unproven.
MATERIALS AND METHODS
A retrospective analysis of all patients who received vinorelbine after prior eribulin (VAE) 2011-2015 and a parallel cohort of consecutive patients who received vinorelbine without prior eribulin (VWE) for previously treated ABC between 2005 and 2011. Patient demographics, histopathological features, treatment duration and responses were recorded. The primary endpoint was progression-free survival from date of first vinorelbine for each cohort. Secondary endpoints included radiological response rate, and overall survival (OS).
RESULTS
Thirty-five VAE and 103 VWE patients were identified, all female, 71.4% and 78.6% were ER positive/HER2 negative, 8.6% and 6.8% HER2 positive, and 20.0% and 14.6% triple negative for VAE and VWE cohorts, respectively. The median number of lines of chemotherapy lines prior to vinorelbine was 4 (range 2-6) and 2 (range 0-4), respectively. Fifteen VAE patients (42.9%) received ≥1 line of chemotherapy between eribulin and vinorelbine. VAE and WWE Patients received a median of 3 cycles of vinorelbine (range 1-9 and 1-12, respectively). The median progression-free survival for VAE patients was 2.1 months and 2.0 months for VWE patients. No VAE patients were progression-free at 24 weeks, compared to 15.5% of VWE patients. Median OS from commencing vinorelbine was 4.3 months for VAE and 6.4 months for VWE patients.
CONCLUSION
Vinorelbine was of limited benefit after prior eribulin in our study, suggesting cross-resistance. Even without prior eribulin, only 15% of patients experienced clinical benefit from vinorelbine monotherapy.
Topics: Antineoplastic Agents; Breast Neoplasms; Female; Furans; Humans; Ketones; Retrospective Studies; Tubulin Modulators; Vinorelbine
PubMed: 35840514
DOI: 10.1016/j.clbc.2022.05.008 -
Journal of Chemotherapy (Florence,... Jul 2018Vinorelbine is a very potent chemotherapeutic agent which is used to treat a number of cancers including breast and non-small cell lung tumors. Vinorelbine mainly acts... (Review)
Review
Vinorelbine's anti-tumor actions may depend on the mitotic apoptosis, autophagy and inflammation: hypotheses with implications for chemo-immunotherapy of advanced cancers and pediatric gliomas.
Vinorelbine is a very potent chemotherapeutic agent which is used to treat a number of cancers including breast and non-small cell lung tumors. Vinorelbine mainly acts via blocking microtubules and induces a specific type of cell death called 'mitotic catastrophe/apoptosis' subsequent to mitotic slippage, which is the failure of cells to stay in a mitotic arrested state and replicating their DNA without cytokinesis. Glial tumor cells are especially sensitive to mitotic slippage. In recent years, vinorelbine demonstrated potency in pediatric optic and pontine gliomas. In this manuscript, we propose that vinorelbine's anti-tumor actions involve mitotic apoptosis, autophagy and inflammation. Intravenous infusion of vinorelbine induces a peculiar severe pain in the tumor site and patients with highly vascularized, oedematous and necrotic tumors are particularly vulnerable to this pain. Severe pain is a sign of robust inflammation and anti-inflammatory agents are used in treatment of this side effect. However, no one has questioned whether inflammation contributes to anti-tumor effects of vinorelbine, despite the existing data that vinorelbine induces Toll-Like Receptor-4 (TLR4), cytokines and cell death in endothelial cells especially under hypoxia. Robust inflammation may contribute to tumor necrosis such as seen during immunotherapy with lipopolysaccharides (LPS). Evidence also emerges that enhanced cyclooxygenase activity may increase cancer cell death in certain contexts. There are data indicating that non-steroidal anti-inflammatory drugs (NSAIDs) could block anti-tumor efficacy of taxanes, which also work mainly via anti-microtubule actions. Further, combining vinorelbine with immunostimulant cytokines provided encouraging results in far advanced melanoma and renal cell carcinoma, which are highly antigenic tumors. Vinorelbine also showed potential in treatment of inflammatory breast cancer. Finally, pontine gliomas - where partial activity of vinorelbine is shown by some studies - are also tumors which partially respond to immune stimulation. Animal experiments shall be conducted whether TLR4-activating molecules or immune-checkpoint inhibitors could augment anti-tumor actions of vinorelbine. Noteworthy, TLR4-activation seems as the most promising way of cancer immunotherapy, as a high percentage of molecules which demonstrated clinical benefits in cancer treatment are activators of TLR4, including BCG vaccine, monophosphoryl lipid A and picibanil (OKT-432). The provided data would be meaningful for the oncological practice.
Topics: Adjuvants, Immunologic; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cytokines; Glioma; Humans; Inflammatory Breast Neoplasms; Toll-Like Receptor 4; Vinorelbine
PubMed: 30025492
DOI: 10.1080/1120009X.2018.1487149 -
Musculoskeletal Surgery Mar 2023Approximately 80% of desmoid tumors (DTs) show spontaneous regression or disease stabilization during first-line active surveillance. Medical treatment can be considered... (Review)
Review
Approximately 80% of desmoid tumors (DTs) show spontaneous regression or disease stabilization during first-line active surveillance. Medical treatment can be considered in cases of disease progression. This systematic review aimed to evaluate the effectiveness and toxicity of each medical treatment by reviewing only the studies that included progressive disease as the inclusion criterion. We searched the EMBASE, PubMed, and CENTRAL databases to identify published studies for progressive DTs. The disease control rates of the medical treatments, such as low-dose chemotherapy with methotrexate plus vinblastine or vinorelbine, imatinib, sorafenib, pazopanib, nilotinib, anlotinib, doxorubicin-based agents, liposomal doxorubicin, hydroxyurea, and oral vinorelbine for progressive DTs were 71-100%, 78-92%, 67-96%, 84%, 88%, 86%, 89-100%, 90-100%, 75%, and 64%, respectively. Low-dose chemotherapy, sorafenib, pazopanib, nilotinib, anlotinib, and liposomal doxorubicin had similar toxicities. Sorafenib and pazopanib were less toxic than imatinib. Doxorubicin-based chemotherapy was associated with the highest toxicity. Hydroxyurea and oral vinorelbine exhibited the lowest toxicity. Stepwise therapy escalation from an initial, less toxic treatment to more toxic agents is recommended for progressive DTs. Sorafenib and pazopanib had limited on-treatment side effects but had the possibility to induce long-term treatment-related side effects. In contrast, low-dose chemotherapy has some on-treatment side effects and is known to have very low long-term toxicity. Thus, for progressive DTs following active surveillance, low-dose chemotherapy is recommended in young patients as long-term side effects are minor, whereas therapies such as sorafenib and pazopanib is recommended for older patients as early side effects are minor.
Topics: Humans; Vinorelbine; Sorafenib; Imatinib Mesylate; Hydroxyurea; Fibromatosis, Aggressive; Watchful Waiting; Methotrexate; Doxorubicin
PubMed: 35150408
DOI: 10.1007/s12306-022-00738-x -
Biomedicine & Pharmacotherapy =... Jun 2023Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary...
Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary to find drugs that could improve immune function and synergistically enhance the anti-tumor effect of vinorelbine. Thymosin is reported to inhibit tumor growth as an immunomodulator. Herein, to study the synergistic anti-cancer and attenuation effects of thymosin on vinorelbine, human lung cancer A549 cells that were labeled with CM-DiI were transplanted into zebrafish to establish the lung cancer xenotransplanted model. After treatment of vinorelbine and different concentrations of thymosin, the fluorescence intensity of CM-DiI-labeled A549 cells and the number of apoptotic muscle cells in the tumor-bearing zebrafish were detected. Besides, effects of thymosin on vinorelbine-reduced macrophages and T cells were identified in the transgenic zebrafish (Tg:zlyz-EGFP and Tg:rag2-DsRed). Then, the qRT-PCR was used to determine the alterations of the immune-related factors at the transcription level. Thymosin showed a marked synergistic anti-cancer effect with vinorelbine for the xenograft human lung cancer A549 cells, and the synergistic effect enhanced in a dose-dependent manner. Moreover, thymosin alleviated vinorelbine-induced muscle cell apoptosis, macrophage reduction, and T cell suppression. Compared with the vinorelbine group, co-administration with thymosin raised the mRNA levels of TNF-α, TNF-β, INF-γ, and GM-CSF. Thus, thymosin possesses synergistic anti-cancer effect on vinorelbine, and has protective effect on vinorelbine-induced immunosuppression. Thymosin, as an adjuvant immunomodulatory therapy, has great potential in enhancing the clinical application of vinorelbine.
Topics: Animals; Humans; Vinorelbine; Zebrafish; Thymosin; Cell Line, Tumor; Lung Neoplasms
PubMed: 37018994
DOI: 10.1016/j.biopha.2023.114633 -
Biomedicine & Pharmacotherapy =... Feb 2021Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients...
Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutation. However, some lung cancer patients fail to respond and eventually develop drug resistance. Therefore, new therapeutic strategies are needed to improve the outcomes for substantial clinical benefit. Here we aimed to explore the combination of vinorelbine with the second EGFR-TKI afatinib in NSCLC cells with or without EGFR mutation. The three cells of H1975, HCC827, and H460 were assessed for the combination of vinorelbine and afatinib. Vinorelbine combined with afatinib synergistically inhibited the three lung cancer cells growth without aggravating adverse effect on the normal lung cells. The combination of low doses of vinorelbine and afatinib suppressed the cancer cell proliferation by cell colony formation assay and significantly induced cell apoptosis. The anti-apoptotic proteins Bcl-xL and Bcl-2 showed significant reduction after the drug combination treatment, while the pro-apoptotic protein Bax as well as apoptosis indicators cytochrome C and cleaved PARP were observed a notable increasing. EGFR downstream pathways including AKT, ERK, JNK, and p38 were highly active and p53 was inactive in the three lung cancer cells, favoring tumor growth. The low doses of vinorelbine plus afatinib blocked the phosphorylation of AKT, ERK, JNK, and p38, but restored the expression of p53. Our findings suggested that the combination of vinorelbine and afatinib could be recommended as a therapeutic regimen for treatment of NSCLC with or without EGFR mutation.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; ErbB Receptors; Humans; Lung Neoplasms; Signal Transduction; Tumor Suppressor Protein p53; Vinorelbine
PubMed: 33360044
DOI: 10.1016/j.biopha.2020.111144 -
Cancer Chemotherapy and Pharmacology Aug 2019Pharmacokinetics of vinorelbine is mainly known from studies conducted in European patients. Interethnic differences in drug disposition may, however, induce interethnic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pharmacokinetics of vinorelbine is mainly known from studies conducted in European patients. Interethnic differences in drug disposition may, however, induce interethnic variation in drug exposure. This paper aimed to evaluate the effect of ethnicity on the bioavailability and clearance of oral and intravenous vinorelbine.
METHODS
Oral and intravenous vinorelbine pharmacokinetics data in Asian patients were pooled from two-phase II studies of patients with non-small-cell lung cancer or advanced breast cancer in China. Blood vinorelbine and its active metabolite, 4'-O-deacetylvinorelbine, were quantified using liquid chromatography-tandem mass spectrometry. Bayesian pharmacokinetic parameters were calculated and vinorelbine monotherapy results (intravenous 25 mg/m; oral 60 mg/m) of the Asian data set were compared to a reference European data set (intravenous 30 mg/m; oral 80 mg/m). Subsequently, a population pharmacokinetics analysis was conducted in a combined cohort (Asian data set + historical vinorelbine pharmacokinetics database) to investigate for a potential effect of ethnicity.
RESULTS
Pharmacokinetics data from the Asian data set (oral: n = 47; intravenous: n = 34) was compared to the European reference data set (oral: n = 48; intravenous: n = 48). Mean apparent clearance of oral vinorelbine and mean absolute clearance of intravenous vinorelbine was comparable between the Asian and reference European data set. A population pharmacokinetic analysis (oral: n = 222; intravenous: n = 111) demonstrated no influence of ethnicity on oral and intravenous vinorelbine bioavailability and clearance.
CONCLUSION
Vinorelbine pharmacokinetics were found to be comparable between Asian and European patients. No relevant influence of ethnicity on vinorelbine bioavailability and clearance for oral and intravenous routes of administration was observed.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Ethnicity; Female; Humans; Male; Middle Aged; Prospective Studies; Vinorelbine
PubMed: 31134323
DOI: 10.1007/s00280-019-03872-9 -
Computers in Biology and Medicine Oct 2022Whether pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes exist in gastric cancer (GC) remains unclear.
Pyroptosis, apoptosis, and necroptosis molecular subtype derived prognostic signature universal applicable for gastric cancer-A large sample and multicenter retrospective analysis.
BACKGROUND
Whether pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes exist in gastric cancer (GC) remains unclear.
METHODS
Seven independent cohorts including a total of 1901 GC patients were enrolled in our research. TCGA (n = 371) and GSE84437 (n = 433) were combined into one cohort (n = 804) to screen for prognosis-related PAN genes using a univariate Cox regression analysis. The R package "ConsensusClusterPlus" was applied to conduct a clustering analysis of the combination set based on prognosis-related PAN genes. The R package "limma" was used for the identification of differentially expressed genes (DEGs) between different PAN clusters (FDR <0.05 and |logFC|>1). The combined cohort was randomly divided into a training group (n = 484) and a test group (n = 320) at a ratio of 6:4 to establish and verify the prognostic model. A univariate Cox regression analysis, least absolute shrinkage and selection operator method (LASSO) regression analysis, and multivariate Cox regression analysis were used for the identification of prognostic genes and the construction of risk scores. Another five independent cohorts (GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 109; GSE26253, n = 432; and GSE13861, n = 65) were used for external validation to verify the accuracy and stability of the prognostic signature.
RESULTS
The internal and external validation demonstrated that the 5-gene risk score (LOXL4, SLCO2A1, CST2, PDK4, and MMP11) was an effective instrument for the prognostic risk classification of GC patients. The overall survival (OS) and relapse-free survival (RFS) in the high-risk group were significantly lower than those in the low-risk group and were accompanied by a larger proportion of macrophage and regulatory T cell infiltration. The low-risk group had a good prognosis, with a high tumor mutation burden (TMB), strong cytolytic activity, and a higher proportion of activated CD4 T cell infiltration. In addition, compared with the low-risk group, the cancer-related pathways in the high-risk group were overactivated, and the function of DNA damage repair (DDR) was significantly weakened. Regarding drug sensitivity, the high-risk group was more suitable for targeted drugs, such as axitinib, lapatinib, and nilotinib. The low-risk group was more sensitive to chemotherapy, such as cisplatin, gemcitabine, and vinorelbine.
CONCLUSION
A universally applicable prognostic signature of GC is proposed in this research based on pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes.
Topics: Apoptosis; Axitinib; Cisplatin; Gene Expression Profiling; Humans; Lapatinib; Matrix Metalloproteinase 11; Necroptosis; Organic Anion Transporters; Prognosis; Protein-Lysine 6-Oxidase; Pyroptosis; Stomach Neoplasms; Vinorelbine
PubMed: 36044785
DOI: 10.1016/j.compbiomed.2022.106037 -
Cells Jul 2023Metastasis, rather than the growth of the primary tumor, accounts for approximately 90% of breast cancer patient deaths. Microtentacles (McTNs) formation represents an...
Metastasis, rather than the growth of the primary tumor, accounts for approximately 90% of breast cancer patient deaths. Microtentacles (McTNs) formation represents an important mechanism of metastasis. Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited targeted therapies. The present study aimed to isolate viable circulating tumor cells (CTCs) and functionally analyze them in response to drug treatment. CTCs from 20 TNBC patients were isolated and maintained in culture for 5 days. Biomarker expression was identified by immunofluorescence staining and VyCap analysis. Vinorelbine-induced apoptosis was evaluated based on the detection of M30-positive cells. Our findings revealed that the CTC absolute number significantly increased using TetherChips analysis compared to the number of CTCs in patients' cytospins ( = 0.006) providing enough tumor cells for drug evaluation. Vinorelbine treatment (1 h) on live CTCs led to a significant induction of apoptosis ( = 0.010). It also caused a significant reduction in Detyrosinated α-tubulin (GLU), programmed death ligand (PD-L1)-expressing CTCs ( < 0.001), and disruption of McTNs. In conclusion, this pilot study offers a useful protocol using TetherChip technology for functional analysis and evaluation of drug efficacy in live CTCs, providing important information for targeting metastatic dissemination at a patient-individualized level.
Topics: Humans; Neoplastic Cells, Circulating; Triple Negative Breast Neoplasms; Vinorelbine; Pilot Projects; Cell Line, Tumor; Biomarkers, Tumor
PubMed: 37566019
DOI: 10.3390/cells12151940 -
Scientific Reports Mar 2020Chemotherapeutics are sometimes administered with drugs, like antiangiogenic compounds, to increase their effectiveness. Melatonin exerts antitumoral actions through...
Chemotherapeutics are sometimes administered with drugs, like antiangiogenic compounds, to increase their effectiveness. Melatonin exerts antitumoral actions through antiangiogenic actions. We studied if melatonin regulates the response of HUVECs to chemotherapeutics (docetaxel and vinorelbine). The inhibition that these agents exert on some of the processes involved in angiogenesis, such as, cell proliferation, migratory capacity or vessel formation, was enhanced by melatonin. Regarding to estrogen biosynthesis, melatonin impeded the negative effect of vinorelbine, by decreasing the activity and expression of aromatase and sulfatase. Docetaxel and vinorelbine increased the expression of VEGF-A, VEGF-B, VEGF-C, VEGFR-1, VEGFR-3, ANG1 and/or ANG-2 and melatonin inhibited these actions. Besides, melatonin prevented the positive actions that docetaxel exerts on the expression of other factors related to angiogenesis like JAG1, ANPEP, IGF-1, CXCL6, AKT1, ERK1, ERK2, MMP14 and NOS3 and neutralized the stimulating actions of vinorelbine on the expression of FIGF, FGFR3, CXCL6, CCL2, ERK1, ERK2, AKT1, NOS3 and MMP14. In CAM assay melatonin inhibited new vascularization in combination with chemotherapeutics. Melatonin further enhanced the chemotherapeutics-induced inhibition of p-AKT and p-ERK and neutralized the chemotherapeutics-caused stimulatory effect on HUVECs permeability by modifying the distribution of VE cadherin. Our results confirm that melatonin blocks proangiogenic and potentiates antiangiogenic effects induced by docetaxel and vinorelbine enhancing their antitumor effectiveness.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Docetaxel; Drug Synergism; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Insulin-Like Growth Factor I; Jagged-1 Protein; Melatonin; Neoplasms; Neovascularization, Pathologic; Receptor, Fibroblast Growth Factor, Type 3; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor D; Vinorelbine
PubMed: 32179814
DOI: 10.1038/s41598-020-61622-x -
Cancer Medicine May 2023Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.
AIMS
The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.
MATERIALS & METHODS
Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies.
RESULTS
One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02).
DISCUSSION
Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS.
CONCLUSION
These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.
Topics: Humans; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Vinorelbine; Neoplasm Recurrence, Local; Rhabdomyosarcoma; Cyclophosphamide; Chronic Disease
PubMed: 37016270
DOI: 10.1002/cam4.5749