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Cell Division Jan 2021Cancer cell aggregation is a key process involved in the formation of tumor cell clusters. It has recently been shown that clusters of circulating tumor cells (CTCs)...
BACKGROUND
Cancer cell aggregation is a key process involved in the formation of tumor cell clusters. It has recently been shown that clusters of circulating tumor cells (CTCs) have an increased metastatic potential compared to isolated circulating tumor cells. Several widely used chemotherapeutic agents that target the cytoskeleton microtubules and cause cell cycle arrest at mitosis have been reported to modulate CTC number or the size of CTC clusters.
RESULTS
In this study, we investigated in vitro the impact of mitotic arrest on the ability of breast tumor cells to form clusters. By using live imaging and quantitative image analysis, we found that MCF-7 cancer cell aggregation is compromised upon incubation with paclitaxel or vinorelbine, two chemotherapeutic drugs that target microtubules. In line with these results, we observed that MCF-7 breast cancer cells experimentally synchronized and blocked in metaphase aggregated poorly and formed loose clusters. To monitor clustering at the single-cell scale, we next developed and validated an in vitro assay based on live video-microscopy and custom-designed micro-devices. The study of cluster formation from MCF-7 cells that express the fluorescent marker LifeAct-mCherry using this new assay allowed showing that substrate anchorage-independent clustering of MCF-7 cells was associated with the formation of actin-dependent highly dynamic cell protrusions. Metaphase-synchronized and blocked cells did not display such protrusions, and formed very loose clusters that failed to compact.
CONCLUSIONS
Altogether, our results suggest that mitotic arrest induced by microtubule-targeting anticancer drugs prevents cancer cell clustering and therefore, could reduce the metastatic potential of circulating tumor cells.
PubMed: 33514388
DOI: 10.1186/s13008-021-00070-z -
Future Science OA Dec 2021A retrospective analysis of 70 patients with triple-negative or hormone-resistant advanced breast carcinoma who had not previously received chemotherapy was carried out....
A retrospective analysis of 70 patients with triple-negative or hormone-resistant advanced breast carcinoma who had not previously received chemotherapy was carried out. Patients received oral vinorelbine 60 mg/m on day 1 and 8, plus capecitabine 1000 mg/m bid for 14 consecutive days every 3 weeks. Overall response rate was 53% with a 9% complete response rate. Stable disease was recorded in 27% of the cases. Median progression-free survival was 7.9 months and median overall survival was 29.2 months. Toxicity was generally mild and easily manageable. These data demonstrate that this combination is feasible, safe and active as first-line treatment of triple-negative fully hormone-resistant advanced breast carcinoma patients.
PubMed: 34840807
DOI: 10.2144/fsoa-2020-0095 -
Breast Cancer Research : BCR Feb 2022Clinical cancer imaging focuses on tumor growth rather than metastatic phenotypes. The microtubule-depolymerizing drug, Vinorelbine, reduced the metastatic phenotypes of...
Clinical cancer imaging focuses on tumor growth rather than metastatic phenotypes. The microtubule-depolymerizing drug, Vinorelbine, reduced the metastatic phenotypes of microtentacles, reattachment and tumor cell clustering more than tumor cell viability. Treating mice with Vinorelbine for only 24 h had no significant effect on primary tumor survival, but median metastatic tumor survival was extended from 8 to 30 weeks. Microtentacle inhibition by Vinorelbine was also detectable within 1 h, using tumor cells isolated from blood samples. As few as 11 tumor cells were sufficient to yield 90% power to detect this 1 h Vinorelbine drug response, demonstrating feasibility with the small number of tumor cells available from patient biopsies. This study establishes a proof-of-concept that targeted microtubule disruption can selectively inhibit metastasis and reveals that existing FDA-approved therapies could have anti-metastatic actions that are currently overlooked when focusing exclusively on tumor growth.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Mice; Microtubules; Neoplasm Metastasis; Vinorelbine
PubMed: 35164808
DOI: 10.1186/s13058-022-01506-2 -
Oncology Research May 2020The use of vinorelbine as a single agent or in combination regimens in non-small cell lung cancer (NSCLC) is associated with satisfactory clinical activity. However, the...
The use of vinorelbine as a single agent or in combination regimens in non-small cell lung cancer (NSCLC) is associated with satisfactory clinical activity. However, the role of vinorelbine-based chemotherapy in chemonaive locally advanced unresectable or metastatic NSCLC patients, according to real-world treatment patterns, has still not been widely explored. Eighty-one patients treated at a single institution were retrospectively analyzed. Thirty-seven received standard first-line single-agent vinorelbine, and 44 received vinorelbine plus platinum drugs, based on physician's choice; 61.7% were older than 70 years, and 60.5% were affected by ≥2 comorbidities. Sixty-three patients were evaluable for objective response: 22% achieved partial response and 41% stable disease. Median progression-free survival (PFS) was 5.4 months. A benefit in PFS was observed in patients treated with combinations vs. single-agent vinorelbine (6.7 vs. 3.5 months, = 0.043). Median overall survival (OS) was 10.4 months without a statistically significant difference between treatments (12.4 vs. 7.5 months). In 55 stage IV patients, OS was positively correlated with combination regimens, M1a stage, or ≤2 metastatic lesions. Grade 3-4 toxicity occurred in 33% of patients, and dose reduction in 11%. A statistically significant higher incidence of toxicity was observed in patients receiving combinations, in women, in patients younger than 75 years, or patients with metastases. In this real-word analysis, we confirmed the efficacy and tolerability of vinorelbine as a single agent or combined with platinums in patients usually underrepresented in controlled clinical trials. Single-agent vinorelbine may represent a suitable option in elderly or unfit NSCLC patients and warrants investigation as a potential drug candidate for immunochemotherapy combination regimens.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Treatment Outcome; Vinorelbine
PubMed: 31806078
DOI: 10.3727/096504019X15755437099308 -
Breast Cancer (Dove Medical Press) 2021Eribulin mesylate, a synthetic derivative of the anti-mitotic agent halichondrin B, has a unique tubulin-based mechanism of action that is distinct from other... (Review)
Review
Eribulin mesylate, a synthetic derivative of the anti-mitotic agent halichondrin B, has a unique tubulin-based mechanism of action that is distinct from other anti-microtubule agents including taxanes and vinca alkaloids. Consistent with this unique activity, eribulin has shown clinical efficacy in patients with metastatic breast cancer (MBC) that progressed following prior taxane and anthracycline therapy. The evidence presented in this review indicates that eribulin represents a treatment option for patients with HER2-negative metastatic breast cancer. Improved survival outcomes and better tolerability compared with vinorelbine supported the first approval of eribulin in China in 2019; eribulin was approved for women with locally advanced/metastatic HER2-negative breast cancer after treatment failure with at least two chemotherapy regimens, including an anthracycline and a taxane. Eribulin has also shown promising efficacy in patients with HER2-positive advanced breast cancer when used in combination with trastuzumab or pertuzumab, and subgroup analyses from the Phase III clinical trials support the continued evaluation of eribulin in patients with triple-negative disease. The unique non-mitotic effects of eribulin, including vascular remodeling, coupled with its clinical efficacy and safety profile, may permit the broader use of this agent in patients with MBC.
PubMed: 33658845
DOI: 10.2147/BCTT.S231298 -
Therapeutic Advances in Medical Oncology 2021The study investigated the efficacy and safety of oral vinorelbine-cisplatin (OV-CDDP) and gemcitabine-cisplatin (GEM-CDDP) in patients with squamous non-small cell lung...
OBJECTIVE
The study investigated the efficacy and safety of oral vinorelbine-cisplatin (OV-CDDP) and gemcitabine-cisplatin (GEM-CDDP) in patients with squamous non-small cell lung cancer (sq-NSCLC).
PATIENTS AND METHODS
This was an open-label, prospective, multicenter, international phase II study that enrolled untreated patients with advanced sq-NSCLC. Patients were randomized to receive 3-week cycles of either 60-80 mg/m OV days 1 and 8 in combination with 80 mg/m CDDP day 1 (arm A) or 1250 mg/m GEM days 1 and 8 in combination with 75 mg/m CDDP day 1 (arm B). After four cycles, patients without disease progression continued maintenance dose of OV or GEM until progression or unacceptable toxicity. The primary objective was disease control rate (DCR). Secondary objectives included progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), safety, and quality of life (QoL).
RESULTS
A total of 114 patients with sq-NSCLC were randomized, and 113 were treated (57 in arm A and 56 in arm B). DCR was high in both arms: 73.7% (95%CI: 62.4-100.0) in arm A and 75.0% (95%CI: 63.7-100.0) in arm B. Median PFS and TTF were similar in arm A and B 4.2 and 2.8 months, and 4.3 and 3.1 months, respectively. Even though the difference was not significant, the OS was 10.2 for arm A and 8.4 months for arm B. The safety profiles were consistent with the current knowledge of adverse events. QoL results revealed an improvement in patients under OV treatment.
CONCLUSION
The OV-CDDP combination showed comparable efficacy to GEM-CDDP with acceptable safety profile and enhanced patients' QoL.
TRIAL REGISTRATION
The study was registered under EudraCT number 2012-003531-40.
PubMed: 34349841
DOI: 10.1177/17588359211022905 -
Theranostics 2019: Tumor angiogenesis promotes tumor development, progression, growth, and metastasis. Metronomic chemotherapy involves the frequent administration of low-dose...
: Tumor angiogenesis promotes tumor development, progression, growth, and metastasis. Metronomic chemotherapy involves the frequent administration of low-dose chemotherapeutic agents to block angiogenic activity and reduce side effects. : MDA-MB-231 cells were treated with various concentrations of artemisinin (ART) and vinorelbine (NVB) and the cytotoxic effects of ART/NVB were determined using the CCK-8 assay. Mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) and mass were assessed using MitoSOX, TMRE and MitoTracker green staining. Western blot analysis was used to quantify the expression of autophagy-related proteins. Herein, by using bioinformatics analysis and experimental verification, we identified CREB as a master in MDA-MB-231 cells. : We found that artemisinin (ART), which exhibits anti-angiogenic and anti-cancer effects via mitochondrial regulation, synergized with vinorelbine (NVB) to inhibit MDA-MB-231 cell proliferation. ART and NVB cooperated to regulate mitochondrial biogenesis. CREB acted as a crucial regulator of PGC1α and VEGF, which played critical roles in NVB-dependent growth factor depletion. Moreover, CREB suppression significantly reversed mitochondrial dysfunction following ART/NVB co-treatment. In addition, combination treatment with ART and NVB significantly suppressed tumor growth in a nude mouse xenograft model, with downregulated CREB and PGC1α expression levels observed in tumor biopsies, in agreement with our and data. : These findings support the hypothesis that ART affects cancer and endothelial cells by targeting the auto-paracrine effects of VEGF to suppress mitochondrial biogenesis, angiogenesis, and migration between cancer cells and endothelial cells.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Artemisinins; Breast Neoplasms; Cell Line, Tumor; Culture Media, Conditioned; Cyclic AMP Response Element-Binding Protein; Drug Synergism; Endothelium, Vascular; Female; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice, Inbred BALB C; Mitochondria; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Vinorelbine; Xenograft Model Antitumor Assays
PubMed: 31588240
DOI: 10.7150/thno.33353 -
Frontiers in Oncology 2021Pyrotinib plus capecitabine has been approved in China for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Meanwhile,...
INTRODUCTION
Pyrotinib plus capecitabine has been approved in China for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Meanwhile, vinorelbine is another important chemotherapy option for MBC available in oral and intravenous forms. Thus, pyrotinib plus vinorelbine may represent a new treatment option, particularly for patients with failed capecitabine treatment. This study reported the first real-world data for pyrotinib plus vinorelbine therapy in HER2+ MBC.
METHODS
HER2+ MBC patients (n = 97) treated with pyrotinib plus vinorelbine in six institutions across China from May 2018 to June 2020 were enrolled. Progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and toxicity profiles were determined.
RESULTS
Sixty-seven percent of patients received more than two lines of systematic therapy. Nearly all patients (97.9%) had received trastuzumab and 50.5% were administered lapatinib. When combined with pyrotinib, 74.2% received oral and 25.8% received intravenous vinorelbine. Median PFS (mPFS) was 7.8 (range, 4.7-10.8) months for all patients. The mPFS in patients administered pyrotinib as second-line therapy and third-or-higher-line therapy were 12.0 and 6.4 months, respectively. Patients who received pyrotinib plus oral or intravenous vinorelbine had similar mPFS (7.8 vs. 6.4 months, p = 0.871). The 23 patients with brain metastases had mPFS of 6.3 (range, 3.4-9.2) months. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (10.8 months vs. 5.6 months, p = 0.020). Median OS was not achieved. The ORR for 96 patients was 34.3%. Common grade 3 and 4 adverse events were diarrhea (22.7%), neutropenia (7.2%), and leukopenia (4.1%).
CONCLUSIONS
Pyrotinib plus vinorelbine therapy demonstrated promising effects in HER2+ MBC with tolerable toxicity, particularly in patients with second-line treatment and without prior lapatinib treatment, as well as in patients with brain metastases. Oral vinorelbine is a useful alternative to the intravenous form when combined with pyrotinib.
CLINICAL TRIAL REGISTRATION
[ClinicalTrials.gov], identifier [NCT04517305].
PubMed: 33996589
DOI: 10.3389/fonc.2021.664429 -
Journal of Oncology 2022To assess the application value of serum thymidine kinase 1 (TK1) and PC cell-derived growth factor (PCDGF), cytokeratin 19 fragment 21-1 (CYFRA21-1), neuron-specific...
OBJECTIVE
To assess the application value of serum thymidine kinase 1 (TK1) and PC cell-derived growth factor (PCDGF), cytokeratin 19 fragment 21-1 (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) plus enhanced CT scan in the diagnosis of nonsmall cell lung cancer (NSCLC) and chemotherapy monitoring.
METHODS
Between April 2019 and April 2021, 30 patients with NSCLC assessed for eligibility treated in our institution were included in the experimental group, and 30 healthy individuals screened out from physical examinations were recruited in the control group. The chemotherapy regimens included gemcitabine plus cisplatin, pemetrexed disodium plus cisplatin, and vinorelbine plus cisplatin. The application value of serum TK1, PCDGF, CYFRA21-1, NSE, CEA, and enhanced CT scan in the diagnosis and chemotherapy monitoring of NSCLC was analyzed.
RESULTS
Before treatment, the eligible patients had significantly higher serum levels of TK1, PCDGF, CYFRA21-1, NSE, and CEA than those of the healthy individuals included ( < 0.05). Clinical efficacy was categorized into good and poor, and the good efficacy included complete response and partial response, with the poor efficacy including stable disease and progressive disease. Patients with good clinical efficacy had lower levels of serum TK1, PCDGF, CYFRA21-1, NSE, and CEA than those with poor efficacy ( < 0.05). Joint detection showed a larger area under the curve (AUC) (0.900; 95%CI, 0.812-0.988), a higher sensitivity, and a superior detection outcome to the stand-alone detection ( < 0.05). Diagnostic results were similar between joint detection and pathological examination ( > 0.05).
CONCLUSION
The application of serum TK1, PCDGF, CYFRA21-1, NSE, and CEA assay plus enhanced CT scan shows high sensitivity and diagnostic accuracy in the diagnosis and chemotherapy monitoring of nonsmall cell lung cancer and thus provides a diagnostic reference basis.
PubMed: 35368891
DOI: 10.1155/2022/8800787 -
PharmacoEconomics - Open May 2023The National Institute for Health and Care Excellence (NICE) provides guidance to improve health and social care in England and Wales. NICE invited Daiichi Sankyo to... (Review)
Review
Trastuzumab Deruxtecan for Treating HER2-Positive Unresectable or Metastatic Breast Cancer After Two or More Anti-HER2 Therapies: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.
The National Institute for Health and Care Excellence (NICE) provides guidance to improve health and social care in England and Wales. NICE invited Daiichi Sankyo to submit evidence for the use of trastuzumab deruxtecan (T-DXd) for treating human epidermal growth factor 2 (HER2)-positive unresectable or metastatic breast cancer (UBC/MBC) after two or more anti-HER2 therapies, in accordance with NICE's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group, part of the University of Liverpool, was commissioned to act as the Evidence Review Group (ERG). This article summarises the ERG's review of the evidence submitted by the company and provides an overview of the NICE Appraisal Committee's (AC's) final decision made in May 2021. Results from the company's base-case fully incremental analysis showed that, compared with T-DXd, eribulin and vinorelbine were dominated and the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained versus capecitabine was £47,230. The ERG scenario analyses generated a range of ICERs, with the highest being a scenario relating to a comparison of T-DXd versus capecitabine (£78,142 per QALY gained). The ERG considered that due to a lack of appropriate clinical effectiveness evidence, the relative effectiveness of T-DXd versus any comparator treatment could not be determined with any degree of certainty. The NICE AC agreed that the modelling of overall survival was highly uncertain and concluded that treatment with T-DXd could not be recommended for routine use within the National Health Service (NHS). T-DXd was, however, recommended for use within the Cancer Drugs Fund, provided Managed Access Agreement conditions were followed.
PubMed: 37084172
DOI: 10.1007/s41669-023-00405-2