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NPJ Breast Cancer Sep 2022While therapies such as chemotherapy combined with immunotherapy, sacituzumab govitecan, and PARP inhibitors are available for metastatic TNBC, on disease progression...
While therapies such as chemotherapy combined with immunotherapy, sacituzumab govitecan, and PARP inhibitors are available for metastatic TNBC, on disease progression after these therapies, the mainstay of therapy is chemotherapy. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for TNBC. We aimed to evaluate the safety and efficacy of adding apatinib to chemotherapy in patients with advanced TNBC with failed first/second-line treatment. A total of 66 patients were randomly assigned, in a 1:1 ratio, to receive vinorelbine or vinorelbine with apatinib in 28-day cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. 33 received apatinib plus vinorelbine and 32 received vinorelbine (1 was withdrawal). Median PFS was significantly longer in the apatinib plus vinorelbine group than in the vinorelbine group (3.9 months vs. 2.0 months; hazard ratio, 1.82; 95% confidence interval [CI], 1.06 to 3.11; P = 0.026). Median OS was 11.5 months with apatinib plus vinorelbine and 9.9 months with vinorelbine (HR,1.01; 95% CI, 0.51 to 1.97; P = 0.985). The ORR was 9.1% in the apatinib plus vinorelbine group and 6.3% in the vinorelbine group (P = 0.667). The most common treatment-related hematologic grade 3-4 adverse events in apatinib plus vinorelbine group, were leukopenia, granulocytopenia, anemia, and thrombocytopenia. no treatment-related nonhematologic grade 4 adverse events or treatment-related deaths were observed. Collectively, adding apatinib to vinorelbine shows a promising benefit in PFS compared to vinorelbine monotherapy, with an excellent toxicity profile, warranting further exploration.
PubMed: 36127351
DOI: 10.1038/s41523-022-00462-6 -
Molecules (Basel, Switzerland) Apr 2022The problems with anticancer therapy are resistance and toxicity. From 3000 Cisplatin derivatives tested as antitumor agents, most of them have been rejected, due to... (Review)
Review
The problems with anticancer therapy are resistance and toxicity. From 3000 Cisplatin derivatives tested as antitumor agents, most of them have been rejected, due to toxicity. The aim of current study is the comparison of therapeutic combinations of the currently applied in clinical practice: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, and Satraplatin. The literature data show that the strategies for the development of platinum anticancer agents and bypassing of resistance to Cisplatin derivatives and their toxicity are: combination therapy, Pt IV prodrugs, the targeted nanocarriers. The very important strategy for the improvement of the antitumor effect against different cancers is synergistic combination of Cisplatin derivatives with: (1) anticancer agents-Fluorouracil, Gemcitabine, Cytarabine, Fludarabine, Pemetrexed, Ifosfamide, Irinotecan, Topotecan, Etoposide, Amrubicin, Doxorubicin, Epirubicin, Vinorelbine, Docetaxel, Paclitaxel, Nab-Paclitaxel; (2) modulators of resistant mechanisms; (3) signaling protein inhibitors-Erlotinib; Bortezomib; Everolimus; (4) and immunotherapeutic drugs-Atezolizumab, Avelumab, Bevacizumab, Cemiplimab, Cetuximab, Durvalumab, Erlotinib, Imatinib, Necitumumab, Nimotuzumab, Nivolumab, Onartuzumab, Panitumumab, Pembrolizumab, Rilotumumab, Trastuzumab, Tremelimumab, and Sintilimab. An important approach for overcoming the drug resistance and reduction of toxicity of Cisplatin derivatives is the application of nanocarriers (polymers and liposomes), which provide improved targeted delivery, increased intracellular penetration, selective accumulation in tumor tissue, and enhanced therapeutic efficacy. The advantages of combination therapy are maximum removal of tumor cells in different phases; prevention of resistance; inhibition of the adaptation of tumor cells and their mutations; and reduction of toxicity.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Erlotinib Hydrochloride; Humans; Neoplasms
PubMed: 35458666
DOI: 10.3390/molecules27082466 -
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 -
European Journal of Medicinal Chemistry Aug 2020Cancer chemotherapy is frequently hampered by drug resistance, so the resistance to anticancer agents represents one of the major obstacles for the effective cancer... (Review)
Review
Cancer chemotherapy is frequently hampered by drug resistance, so the resistance to anticancer agents represents one of the major obstacles for the effective cancer treatment. Indole derivatives have the potential to act on diverse targets in cancer cells and exhibit promising activity against drug-resistant cancers. Moreover, some indole-containing compounds such as Semaxanib, Sunitinib, Vinorelbine, and Vinblastine have already been applied in clinics for various kinds of cancer even drug-resistant cancer therapy. Thus, indole derivatives are one of significant resources for the development of novel anti-drug-resistant cancer agents. This review focuses on the recent development of indole derivatives with potential therapeutic application for drug-resistant cancers, and the mechanisms of action, the critical aspects of design as well as structure-activity relationships, covering articles published from 2010 to 2020.
Topics: Antineoplastic Agents; Drug Design; Drug Resistance, Neoplasm; Humans; Indoles; Structure-Activity Relationship
PubMed: 32531682
DOI: 10.1016/j.ejmech.2020.112359 -
Journal of Oncology 2022Pyroptosis is a programmed cell death that may either promote or hinder cancer growth under different circumstances. Pyroptosis-related genes (PRGs) could be a useful...
Pyroptosis is a programmed cell death that may either promote or hinder cancer growth under different circumstances. Pyroptosis-related genes (PRGs) could be a useful target for cancer therapy, and are uncommon in lung adenocarcinoma (LUAD). The expression profiles, mutation data and clinical information of LUAD patients were included in this study. A pyroptosis-related prognostic risk score (PPRS) model was constructed by performing Cox regression, weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO) analysis to score LUAD patients. Somatic mutation and copy number variation (CNV), tumor immunity, and sensitivity to immunotherapy/chemotherapy were compared between different PPRS groups. Clinical parameters of LUAD were combined with PPRS to construct a decision tree and nomogram. Red module was highly positively correlated with pyroptosis. Seven genes (FCRLB, COTL1, GNG10, CASP4, DOK1, CCR2, and AQP8) were screened from the red module to construct a PPRS model. Significantly lower overall survival (OS), higher incidence of somatic mutation and CNV, elevated infiltration level of the immune cell together with increased probability of immune escape were observed in LUAD patients with higher PPRS, and were more sensitive to Cisplatin, Docetaxel, and Vinorelbine. We constructed a new PPRS model for patients with LUAD. The model might have clinical significance in the prediction of the prognosis of patients with LUAD and in the efficacy of chemotherapy and immunotherapy.
PubMed: 35938142
DOI: 10.1155/2022/6905588 -
Frontiers in Pharmacology 2022Microtubule-targeting (MT) drugs taxanes and vinca alkaloids are widely used as chemotherapeutic agents against different tumors for more than 30 years because of their...
Microtubule-targeting (MT) drugs taxanes and vinca alkaloids are widely used as chemotherapeutic agents against different tumors for more than 30 years because of their ability to block mitotic progression by disrupting the mitotic spindle and activating the spindle assembly checkpoint (SAC) for a prolonged period of time. However, responses to mitotic arrest are different-some cells die during mitotic arrest, whereas others undergo mitotic slippage and survive becoming able for proliferation. Using normal fibroblasts and several cancer cell types we determined two critical doses, T1 and T2, of mitotic inhibitors (nocodazole, Taxol, and vinorelbine). T1 is the maximal dose cells can tolerate undergoing normal division, and T2 is the minimal mitostatic dose, wherein > 90% of mitotic cells are arrested in mitosis. In all studied cell lines after treatment with mitotic inhibitors in a dose above T2 cells had entered mitosis either die or undergo mitotic slippage. We show that for all three drugs used cell death during mitotic arrest and after slippage proceeded mitochondria-dependent apoptosis. We determined two types of cancer cells: sensitive to mitotic arrest, that is, undergoing death in mitosis (DiM) frequently, and resistant to mitotic arrest, that is, undergoing mitotic slippage followed by prolonged survival. We then determined that inhibition of Bcl-xL, but not other anti-apoptotic proteins of the Bcl-2 group that regulate MOMP, make resistant cells susceptible to DiM induced by mitotic inhibitors. Combined treatment with MT drugs and highly specific Bcl-xL inhibitors A-1155643 or A-1331852 allows achieving 100% DiM in a time significantly shorter than maximal duration of mitotic arrest in all types of cultured cells tested. We further examined efficacy of sequential treatment of cultured cells using mitotic inhibitors followed by inhibitors of Bcl-xL anti-apoptotic protein and for the first time show that sensitivity to Bcl-xL inhibitors rapidly declines after mitotic slippage. Thus sequential use of mitotic inhibitors and inhibitors of Bcl-xL anti-apoptotic protein will be efficient only if the Bcl-xL inhibitor will be added before mitotic slippage occurs or soon afterward. The combined treatment proposed might be an efficient approach to anti-cancer therapy.
PubMed: 36188556
DOI: 10.3389/fphar.2022.933112 -
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 -
Journal of Oncology 2020Despite the recent advances in the biological understanding of breast cancer (BC), chemotherapy still represents a key component in the armamentarium for this disease.... (Review)
Review
Despite the recent advances in the biological understanding of breast cancer (BC), chemotherapy still represents a key component in the armamentarium for this disease. Different agents are available as mono-chemotherapy options in patients with locally advanced or metastatic BC (MBC) who progress after a first- and second-line treatment with anthracyclines and taxanes. However, no clear indication exists on what the best option is in some populations, such as heavily pretreated, elderly patients, triple-negative BC (TNBC), and those who do not respond to the first-line therapy. In this article, we summarize available literature evidence on different chemotherapy agents used beyond the first-line, in locally advanced or MBC patients, including rechallenge with anthracyclines and taxanes, antimetabolite and antimicrotubule agents, such as vinorelbine, capecitabine, eribulin, ixabepilone, and the newest developed agents, such as vinflunine, irinotecan, and etirinotecan.
PubMed: 33312203
DOI: 10.1155/2020/9645294 -
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