-
Breast Cancer Research and Treatment Nov 2018PARP-3 is member of the PARP family of poly (ADP-ribose) polymerases involved in ADPribosylation. PARPs are involved in the basic mechanisms of DNA repair. PARP3, a...
PURPOSE
PARP-3 is member of the PARP family of poly (ADP-ribose) polymerases involved in ADPribosylation. PARPs are involved in the basic mechanisms of DNA repair. PARP3, a critical player for efficient mitotic progression, is required for the stabilization of the mitotic spindle by regulation of the mitotic components, NuMA and Tankyrase 1.
METHODS
The sensitization effect of vinorelbine on PARP3 inhibition-induced cytotoxicity was assessed by the SRB assay. The contribution of programed cell death and cell cycle arrest to the sensitization effect were determined by assessing changes in Annexin V, a marker of apoptosis. Alterations in cell cycle progression were assessed by cell cycle analysis. We used immunofluorescence to assess the effect of vinorelbine and/or PARP3 inhibitors on tubulin and microtubule depolarization. The PARP3 chemiluminescent assay kit was used for PARP3 activity.
RESULTS
PARP3 inhibitors sensitize breast cancer cells to vinorelbine, a vinca alkaloid used in the treatment of metastatic breast cancer. Olaparib which was originally described as a PARP1 and 2 inhibitor has recently been shown to be a potent PARP3 inhibitor while ME0328 is a more selective PARP3 inhibitor. The combination of vinorelbine with nontoxic concentrations of ME0328 or olaparib reduces vinorelbine resistance by 10 and 17 fold, respectively, potentiating vinorelbine-induced arrest at the G2/M boundary. In addition, PARP3 inhibition potentiates vinorelbine interaction with tubulin. Furthermore, olaparib or ME0328 potentiates vinorelbine-induced PARP3 inhibition, mitotic arrest, and apoptosis.
CONCLUSION
Our results indicated this approach with PARP3 inhibitors and vinorelbine is unique and promising for breast cancer patients with metastases. This combination could significantly increase the survival of breast cancer patients with metastases.
Topics: Antigens, Nuclear; Apoptosis; Breast Neoplasms; Cell Cycle Proteins; DNA Repair; Drug Resistance, Neoplasm; Female; Humans; MCF-7 Cells; Nuclear Matrix-Associated Proteins; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerases; Quinazolinones; Spindle Apparatus; Tankyrases; Vinorelbine
PubMed: 30039287
DOI: 10.1007/s10549-018-4888-6 -
Medicine May 2023The extensive and intricate relationships between circadian rhythm and cancer have been reported in numerous studies. However, in breast cancer (BC), the potential role...
The extensive and intricate relationships between circadian rhythm and cancer have been reported in numerous studies. However, in breast cancer (BC), the potential role of circadian clock-related genes (CCRGs) in prognosis prediction has not been fully clarified. The transcriptome data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. A CCRGs-based risk signature was established by differential expression analysis, univariate, Lasso and multivariate Cox regression analyses. we conducted a gene set enrichment analysis (GSEA) between groups. A nomogram integrating independent clinical factors and risk score was generated and evaluated by calibration curves and decision curve analysis (DCA). Differentially expression analysis revealed 80 differentially expressed CCRGs, and 27 of them were significantly associated with the overall survival (OS) of BC. BC can be classified into 4 molecular subtypes with significant differences in prognosis based on the 27 CCRGs. Three prognostic CCRGs, including desmocollin 1 (DSC1), LEF1, and protocadherin 9 (PCDH9), were identified to be independent risk factors of BC prognosis and were used to construct a risk score model. BC patients were divided into high- and low-risk groups, and there were significant differences in prognosis between the 2 groups both in the training and validation cohorts. It was found that patients in different groups of race, status, or T stage had significant levels of risk score. Furthermore, patients of different risk levels exhibit varying degrees of sensitivity to vinorelbine, lapatinib, metformin, and vinblastine. GSEA showed that in the high-risk group, immune response-related activities were dramatically repressed whereas cilium-related processes were significantly stimulated. Cox regression analysis demonstrated that age, N stage, radiotherapy and the risk score were independent prognostic risk factors of BC, and a nomogram was established based on these variables. The nomogram exerted a favorable concordance index (0.798) as well as calibration performance, which strongly supports the clinical application of the nomogram. Our study indicated the disruption of the expression of CCRGs in BC and built a favorable prognostic risk model based on 3 independent prognostic CCRGs. These genes may be applied as candidate molecular targets for the diagnosis and therapy of BC.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Nomograms; Vinblastine; Vinorelbine
PubMed: 37144994
DOI: 10.1097/MD.0000000000033718 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Jul 2021To develop a pirarubicin (THP) and vinorelbine (VRL) codelivery nano-micellar system (T+V-CS micelles) of pirarubicin (THP) and vinorelbine (VRL) by using chondroitin...
OBJECTIVE
To develop a pirarubicin (THP) and vinorelbine (VRL) codelivery nano-micellar system (T+V-CS micelles) of pirarubicin (THP) and vinorelbine (VRL) by using chondroitin sulfate-cholesterol polymers (CS-Chol) and DSPE-mPEG and to evaluate the therapeutic efficacy of the codelivery nano-micelles in breast cancer treatment.
METHODS
T+V-CS micelles were prepared by ultrasonic-dialysis method, and the physicochemical characterization were evaluated using multiple technological means. The anti-tumor efficacy of T+V-CS micelles was evaluated by MTT assay and cell cycle arrest analysis. Evaluation of the therapeutic effect of T+V-CS micelles was carried out on xenograft 4T1 murine breast cancer bearing BALB/c mice model.
RESULTS
T+V-CS micelles displayed a nearly spherical shape when observed through transmission electron microscope. The particle size and polydispersity indexes (PDI) of T+V-CS micelles was (155.5±4.5) nm and 0.170±0.003 respectively, while the Zeta potential was (-23.0±0.9) mV. Meanwhile, T+V-CS micelles demonstrated high encapsulation efficiency of (81.87±2.56)% for THP and (87.54±2.82)% for VRL and a high overall drug loading efficiency of (10.20±1.20)%. and studies of the therapeutic efficacy of breast cancer showed that T+V-CS micelles had synergistic anti-tumor effect and induced increased G /M cell cycle arrest in 4T1 cells, which could significantly inhibit tumor growth and prolong survival compared with the therapeutic efficacy of micelles loaded with a single kind of drug or free drug solutions.
CONCLUSION
The study showed that T+V-CS micelles had excellent anti-tumor effect, offering a reference to the clinical treatment of breast cancer.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Carriers; Female; Humans; Mice; Mice, Inbred BALB C; Micelles; Polyethylene Glycols; Vinorelbine
PubMed: 34323039
DOI: 10.12182/20210760105 -
Cancer Chemotherapy and Pharmacology Aug 2014We investigated E-selectin expression in mice and rabbits with vinorelbine-induced phlebitis and the effect of cimetidine. To find the relationship between E-selectin...
PURPOSE
We investigated E-selectin expression in mice and rabbits with vinorelbine-induced phlebitis and the effect of cimetidine. To find the relationship between E-selectin expression and vinorelbine-induced phlebitis.
METHODS
Mouse and rabbit model of vinorelbine-induced phlebitis was established by intravenous infusion of vinorelbine. Pathological observation, molecular-biological determination of E-selectin and protein function of it was evaluated.
RESULTS
Grossly, we observed swelling, edema and cord-like vessel changes in mice receiving vinorelbine but only mild edema in mice pretreated with cimetidine. Pathological scoring yielded a total score of 37 for vinorelbine-treated mice and 17 for mice pretreated with cimetidine (P < 0.05). ELISA revealed that rabbits treated with vinorelbine had markedly higher serum contents of E-selectin than normal saline (NS) controls (vinorelbine 1.534 ± 0.449 vs. NS 0.746 ± 0.170 ng/mL, P < 0.05), which was markedly attenuated by cimetidine (cimetidine 0.717 ± 0.468 vs. vinorelbine 1.534 ± 0.449 ng/mL, P < 0.05). Rose Bengal staining assays showed that vinorelbine markedly increased the adhesion rate of neutrophils for endothelial cells (vinorelbine 38.70 ± 8.34% vs. controls 8.93 ± 4.85%, P < 0.01), which, however, was significantly suppressed by cimetidine (9.93 ± 5.91%, P < 0.01 vs. vinorelbine). In E-selectin knockout mice, we found no apparent difference in tail swelling in mice receiving vinorelbine or cimetidine and vinorelbine.
CONCLUSIONS
In conclusion, cimetidine attenuates vinorelbine-induced phlebitis in mice probably by suppressing increased expression of E-selectin.
Topics: Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Cell Proliferation; Cells, Cultured; Cimetidine; E-Selectin; Endothelium, Vascular; Flow Cytometry; Histamine H2 Antagonists; Humans; Infusions, Intravenous; Mice; Mice, Inbred C57BL; Mice, Knockout; Phlebitis; RNA, Messenger; Rabbits; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Vinblastine; Vinorelbine
PubMed: 24879290
DOI: 10.1007/s00280-014-2487-8 -
International Journal of Molecular... Aug 2019Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine,...
Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the differentiation of breast preadipocytes, by increasing C/EBPα and PPARγ expression and by downregulating tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and IL-11 expression. Radiation inhibits both proliferation and differentiation through the downregulation of C/EBPα and PPARγ and by stimulating TNFα expression. In addition, docetaxel and radiation decrease aromatase activity and expression by decreasing aromatase promoter II and cyclooxygenases 1 and 2 (COX-1 and COX-2) expression. Melatonin potentiates the stimulatory effect of docetaxel and vinorelbine on differentiation and their inhibitory effects on aromatase activity and expression, by increasing the stimulatory effect on C/EBPα and PPARγ expression and the downregulation of antiadipogenic cytokines and COX expression. Melatonin also counteracts the inhibitory effect of radiation on differentiation of preadipocytes, by increasing C/EBPα and PPARγ expression and by decreasing TNFα expression. Melatonin also potentiates the inhibitory effect exerted by radiation on aromatase activity and expression by increasing the downregulation of promoter II, and COX-1 and COX-2 expression. Our findings suggest that melatonin modulates regulatory effects induced by chemotherapeutic drugs or radiation on preadipocytes, which makes it a promising adjuvant for chemotherapy and radiotherapy sensibilization.
Topics: Adipocytes; Antineoplastic Agents; Aromatase; Breast Neoplasms; CCAAT-Enhancer-Binding Protein-alpha; Cancer-Associated Fibroblasts; Cell Differentiation; Docetaxel; Enzyme Activation; Female; Gene Expression Regulation; Humans; Mammary Glands, Human; Melatonin; PPAR gamma; Prostaglandin-Endoperoxide Synthases; Radiation, Ionizing; Vinorelbine
PubMed: 31412584
DOI: 10.3390/ijms20163935 -
AAPS PharmSciTech Jun 2022In recent years, the oral administration of vinorelbine has gradually replaced intravenous administration in the treatment of several types of tumors. Even though the...
In recent years, the oral administration of vinorelbine has gradually replaced intravenous administration in the treatment of several types of tumors. Even though the risk of phlebitis is avoided with oral administration, oral vinorelbine is still not a highly patient-compliant route due to the severe gastrointestinal toxicity. Vinorelbine-loaded liposomes with high encapsulation efficiency and suitable particle size were prepared using the ammonium sulfate gradient method. Chitosan-coated liposomes showed the slowest in vitro release compared to uncoated liposomes and vinorelbine solution. No damage was observed in the intestinal epithelial cells of mice orally administered with coated vinorelbine liposomes due to the low presence of the free drug in the gastrointestinal tract and the LD was increased from 129.83 to 182.25 mg/kg compared to oral vinorelbine solution. In addition, the positive surface potential of chitosan-coating endowed liposomes with mucosal adhesive function, delaying the time to reach the peak plasma concentration of vinorelbine from 1 to 4 h after administration. And bioavailability was increased to 2.1-fold compared to vinorelbine solution. In short, a new strategy to address the severe gastrointestinal side effects of oral vinorelbine has been developed.
Topics: Administration, Oral; Animals; Biological Availability; Chitosan; Liposomes; Mice; Vinorelbine
PubMed: 35680728
DOI: 10.1208/s12249-022-02308-7 -
In Vivo (Athens, Greece) 2020The MILES and ELVIS studies showed that vinorelbine is one of the best options for elderly patients with advanced non-small-cell-lung cancer (NSCLC). Oral vinorelbine at...
BACKGROUND
The MILES and ELVIS studies showed that vinorelbine is one of the best options for elderly patients with advanced non-small-cell-lung cancer (NSCLC). Oral vinorelbine at standard schedule (60-80 mg/m/weekly) has good activity in terms of response rates and progression-free survival. In recent years, a metronomic schedule of oral vinorelbine (40-50 mg/m three times a week, continuously) has been studied in phase II trials, especially in unfit and elderly patients. In the MOVE trial metronomic oral vinorelbine had a clinical benefit [partial response (PR)+stable disease (SD) >12 weeks] in 58.1% of patients with mild toxicity. On this basis, in 2017 we started a phase II study with metronomic oral vinorelbine in elderly (over 70 years) or unfit [Eastern Cooperative Oncology Group performance score (ECOG-PS) of 2] patients with locally/advanced and metastatic NSCLC. Primary aims were clinical benefit (PR+SD ≥6 months) and toxicity; secondary aims were progression-free survival and overall survival.
PATIENTS AND METHODS
A total of 25 patients entered the study: 11 with local/advanced and 14 with metastatic NSCLC (five squamous and 20 adenocarcinoma). None of the patients had epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocation, or programmed death ligand 1 (PDL1) expression; those with squamous carcinoma did not have PDL1 expression. The median age was 79 (range=44-90) years. The PS was 0 in 12 patients (48%), 1 in four patients (16%) and 2 in nine patients (36%). Oral vinorelbine was administered at 40 mg three times a week continuously.
RESULTS
Clinical benefit was achieved in eight patients (32%). Objective responses were partial response in two patients (8%), stable disease in seven (28%), progressive disease in nine (36%); seven patients were not evaluable for response (28%). Median progression-free survival was 2 months; median overall survival was 4 months but four out of eight patients with clinical benefit were still alive at 18 months. Overall survival at 1 year was 32%. Toxicity was mild: only one patient experienced grade 4 neutropenia, one grade 3 peripheral neuropathy, four grade 2 asthenia, one grade 2 mucositis, and one grade 2 diarrhoea. The dose needed to be reduced to 30 mg/m/three times a week in three patients.
CONCLUSION
Our study confirmed the activity and safety of metronomic oral vinorelbine in patients with wild-type local/advanced and metastatic NSCLC unsuitable for treatment with standard i.v. chemotherapy, allowing patients a comfortable home-based therapy, thereby avoiding frequent hospital visits.
Topics: Administration, Metronomic; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Treatment Outcome; Vinblastine; Vinorelbine
PubMed: 32871800
DOI: 10.21873/invivo.12088 -
Journal of Oncology Pharmacy Practice :... Jan 2019Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early non-small cell lung cancer. However, few...
BACKGROUND
Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early non-small cell lung cancer. However, few validated alternatives exist when cisplatin is not indicated or tolerated. Carboplatin is frequently used in this setting. We evaluated the 5-year overall survival, progression-free survival and toxicity in patients treated for stage IB to IIIB resected non-small cell lung cancer receiving adjuvant carboplatin-based chemotherapy compared to cisplatin in association with vinorelbine.
METHODS
Single-center retrospective study of patients having received adjuvant chemotherapy between January 2004 and December 2013 at the oncology clinic at Institut Universitaire de Cardiologie et de Pneumologie de Québec (Canada). Three sub-groups, cisplatin/vinorelbine, carboplatin/vinorelbine and the substitution of cisplatin/vinorelbine for carboplatin/vinorelbine (cisplatin/vinorelbine/carboplatin/vinorelbine), were studied during treatment.
RESULTS
One hundred twenty-seven patients were included in this study. The median PFS was not significantly different, with 50.4 months for cisplatin/vinorelbine, 57.3 months for cisplatin/vinorelbine/carboplatin/vinorelbine and not yet achieved for the carboplatin/vinorelbine group ( p = 0.80). Overall survival also did not differ significantly between the three groups. The 5-year overall survival rates were 66% in cisplatin/vinorelbine group, 55% in carboplatin/vinorelbine group and 70% in cisplatin/vinorelbine/carboplatin/vinorelbine group ( p = 0, 95). No differences were noted between groups concerning high-grade hematologic toxicity.
CONCLUSIONS
Although the effectiveness and hematologic toxicity are comparable between cisplat in and carboplatin in the adjuvant treatment of resected non-small cell lung cancer, the results obtained corroborate the practice used at our oncology clinic. Nevertheless, more prospective studies would be needed to confirm these results.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Canada; Carboplatin; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cisplatin; Female; Hematologic Diseases; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Rate; Treatment Outcome; Vinorelbine
PubMed: 28825377
DOI: 10.1177/1078155217724595 -
Tumori Jun 2023The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016,...
INTRODUCTION
The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016, and confirmed in its fifth edition. The biological behavior and dismal prognosis of this tumor resemble diffuse intrinsic pontine gliomas (DIPG). Homogeneously-treated series are rarely reported.
METHODS
From 2016 onwards, we treated patients with DMG with radiotherapy and concomitant/adjuvant nimotuzumab/vinorelbine, plus re-irradiation at relapse, as already done for DIPG.
RESULTS
We treated nine patients, seven females, with a median age at diagnosis of 13 years. Tumor sites were: thalamic in five cases, pontocerebellar in two, pineal in one, and paratrigonal with nodular/leptomeningeal dissemination in one. Three patients were biopsied, and six had partial tumor resections. Central pathological review was always performed. The median time to local progression was 12.7 months, and the median overall survival was 17.8 months. Six patients died of tumor progression, one of cerebral bleeding at progression. Two were alive, one in continuous remission, the other after relapsing, at 38.6 and 46.3 months after diagnosis. Progression-free survival was 33.3% at one year. Overall survival was 88.9%, 33.3% and 22.2% at 1, 2 and 3 years, respectively.
CONCLUSIONS
This is a small series of homogeneously-treated DMG patients. The results obtained are comparable with those of DIPG patients. Given the phenotypically- and molecularly-defined setting of DMG and severe outcome in this orphan population, they should be treated and included in registries and protocols of DIPG.
Topics: Female; Humans; Adolescent; Glioma; Brain Stem Neoplasms; Neoplasm Recurrence, Local; Prognosis; Vinorelbine
PubMed: 35708347
DOI: 10.1177/03008916221099067 -
British Journal of Cancer May 2018Anti-PD-1 and anti-PD-L1 checkpoint inhibitors (CIs) are clinically active in many types of cancer. However, only a minority of patients achieve a complete and/or...
Vinorelbine, cyclophosphamide and 5-FU effects on the circulating and intratumoural landscape of immune cells improve anti-PD-L1 efficacy in preclinical models of breast cancer and lymphoma.
BACKGROUND
Anti-PD-1 and anti-PD-L1 checkpoint inhibitors (CIs) are clinically active in many types of cancer. However, only a minority of patients achieve a complete and/or long-lasting clinical response. We studied the effects of different doses of three widely used, orally active chemotherapeutics (vinorelbine, cyclophosphamide and 5-FU) over local and metastatic tumour growth, and the landscape of circulating and tumour-infiltrating immune cells involved in CI activity.
METHODS
Immunocompetent Balb/c mice were used to generate models of breast cancer (BC) and B-cell lymphoma. Vinorelbine, cyclophosphamide and 5-FU (alone or in combination with CIs), were given at low-dose metronomic, medium, or maximum tolerable dosages.
RESULTS
Cyclophosphamide increased circulating myeloid derived suppressor cells (MDSC). Vinorelbine, cyclophosphamide and 5-FU reduced circulating APCs. Vinorelbine and cyclophosphamide (at medium/high doses) reduced circulating Tregs. Cyclophosphamide (at low doses) and 5-FU (at medium doses) slightly increased circulating Tregs. Cyclophosphamide was the most potent drug in reducing circulating CD3+CD8+ and CD3+CD4+ T cells. Vinorelbine, cyclophosphamide and 5-FU reduced the number of circulating B cells, with cyclophosphamide showing the most potent effect. Vinorelbine reduced circulating NKs, whereas cyclophosphamide and 5-FU, at low doses, increased circulating NKs. In spite of reduced circulating T, B and NK effector cells, preclinical synergy was observed between chemotherapeutics and anti-PD-L1. Most-effective combinatorial regimens where associated with neoplastic lesions enriched in B cells, and, in BC-bearing mice (but not in mice with lymphoma) also in NK cells.
CONCLUSIONS
Vinorelbine, cyclophosphamide and 5-FU have significant preclinical effects on circulating and tumour-infiltrating immune cells and can be used to obtain synergy with anti-PD-L1.
Topics: Animals; B7-H1 Antigen; Breast Neoplasms; Cell Line, Tumor; Cyclophosphamide; Fluorouracil; Humans; Killer Cells, Natural; Lymphocytes, Tumor-Infiltrating; Lymphoma; Mice; Myeloid-Derived Suppressor Cells; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Vinorelbine; Xenograft Model Antitumor Assays
PubMed: 29695766
DOI: 10.1038/s41416-018-0076-z