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Journal of Biomolecular Structure &... Nov 2023Vinorelbine, a vinca alkaloid, is an antimitotic drug that inhibits polymerisation process of tubulins to microtubules, and is widely used in cancer chemotherapy. Due to...
Vinorelbine, a vinca alkaloid, is an antimitotic drug that inhibits polymerisation process of tubulins to microtubules, and is widely used in cancer chemotherapy. Due to the importance of the structure-activity relationship, in this work the conformational preferences of the vinorelbine molecule were surched by PM3 method. The obtained lowest energy conformer was then optimized at DFT/B3LYP/6-31G(d,p) level of theory and the structural characteristics were determined. Frontier orbital (HOMO, LUMO) and molecular electrostatic potential (MEP) analyses were performed for the optimized structure. The experimental FT-IR, Raman and UV-VIS spectral data of vinorelbine along with the theoretical DFT/B3LYP/6-31G(d,p) calculations were investigated in detail. The vibrational wavenumbers were assigned based on the calculated potential energy distribution (PED) of the vibrational modes. To shed light into the anticancer property of vinorelbine as microtubule destabilizer, the most favourable binding mode and the interaction details between vinorelbine and tubulin were revealed by molecular docking studies of vinorelbine into the α,β-tubulin (PDB IDs: 4O2B; 1SA0; 7CNN) and binding free energies were calculated by the combination of Molecular Mechanics/Generalized Born Surface Area (MMGBSA) and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methods {MM/PB(GB)SA}. The calculated vinorelbine-7CNN binding free energy, using by MM/PB(GB)SA approach, was found to be the best (-50.39 kcal/mol), and followed by vinorelbine-4O2B (-28.5 kcal/mol) and vinorelbine-1SA0 (-17.59 kcal/mol) systems. Moreover, the interaction of vinorelbine with the cytochrome P450 enzymes (CYP), which are known to help in the metabolism of many drugs in the body, was investigated by docking studies against CYP2D6 and CYP3A4 targets.Communicated by Ramaswamy H. Sarma.
Topics: Molecular Docking Simulation; Vinorelbine; Vinca; Spectroscopy, Fourier Transform Infrared; Molecular Conformation; Vibration; Spectrum Analysis, Raman; Quantum Theory; Spectrophotometry, Ultraviolet; Thermodynamics
PubMed: 36369834
DOI: 10.1080/07391102.2022.2145369 -
Journal of Oncology Pharmacy Practice :... Jul 2023Vinorelbine, a semi-synthetic vinca alkaloid with anticancer activity by binding to tubulin, has shown to be successful in the treatment of cancer types including...
INTRODUCTION
Vinorelbine, a semi-synthetic vinca alkaloid with anticancer activity by binding to tubulin, has shown to be successful in the treatment of cancer types including advanced non-small cell lung cancer, uterine cancer, and metastatic breast cancer. Myelosuppression, hematological effects, nausea, vomiting, exhaustion, and neuropathy are some of the most typical side effects of vinorelbine. We discuss the unusual presentation of vinorelbine-induced tetraplegia in a breast cancer patient.
CASE REPORT
A 66-year-old patient with breast cancer, who was followed up with adjuvant aromatase inhibitor therapy after mastectomy, presented with lung and bone metastases. She progressed in the follow-ups after receiving platinum and taxane chemotherapy, vinorelbine treatment was then started. The patient complained of weakness, weariness, and trouble walking after receiving a total dose of 180 mg. Tetraplegia was found after a neurological assessment.
MANAGEMENT AND OUTCOME
It was thought that vinorelbine was responsible for the recent acute weakness. The patient's vinorelbine treatment was stopped. During follow-up, upper extremity paresis regressed, while lower extremities muscle strength remained unchanged.
DISCUSSION
Vinorelbine, frequently used in oncology practice, causes some side effects. Although very rare in the literature, in this case severe peripheral neuropathy has been reported in the follow-up of post-vinorelbine quadriparesis.
PubMed: 37499222
DOI: 10.1177/10781552231191469 -
Aging Jul 2023In this study, we compared the prognosis, tumor immune microenvironment (TIM), and drug treatment response between left-sided (LCC) and right-sided (RCC) colon cancer to...
Comparative analyses of the prognosis, tumor immune microenvironment, and drug treatment response between left-sided and right-sided colon cancer by integrating scRNA-seq and bulk RNA-seq data.
BACKGROUND
In this study, we compared the prognosis, tumor immune microenvironment (TIM), and drug treatment response between left-sided (LCC) and right-sided (RCC) colon cancer to predict outcomes in patients with LCC and RCC.
METHODS
Based on identified differentially expressed genes and using single-cell RNA sequencing data, we constructed and validated a prognostic model for LCC and RCC patients in the TCGA-COAD cohort and GSE103479 cohort. Moreover, we compared the differences of TIM characteristics and drug treatment response between LCC and RCC patients.
RESULTS
We constructed and validated a five-gene prognostic model for LCC patients and a four-gene prognostic model for RCC patients, and both showed excellent performance. The RCC patients with higher risk scores were significantly associated with greater metastasis ( = 2.6×10), N stage ( = 0.012), advanced pathological stage ( = 1.4×10), and more stable microsatellite status ( = 0.007) but not T stage ( = 0.200). For LCC patients, the risk scores were not significantly associated with tumor stage and microsatellite status ( > 0.05). Additionally, immune infiltration by CD8 and regulatory T cells and M0, M1, and M2 macrophages differed significantly between LCC and RCC patients ( < 0.05). and mutations were significantly more common in LCC patients ( < 0.05). In contrast, , , and mutations were significantly more common in RCC patients ( < 0.05). In addition, tumor mutation burden values were significantly higher in RCC patients than in LCC patients ( = 5.9×10). Moreover, the expression of immune checkpoint targets was significantly higher in RCC patients than in LCC patients ( < 0.05), indicating that RCC patients maybe more sensitive to immunotherapy. However, LCC and RCC patients did not differ significantly in their sensitivity to eight selected chemicals or target drugs ( > 0.05). The average half-maximal inhibitory concentrations for camptothecin, teniposide, vinorelbine, and mitoxantrone were significantly lower in low-risk than in high-risk RCC patients ( < 0.05), indicating that the lower risk score of RCC patients, the more sensitive they were to these four drugs.
CONCLUSIONS
We investigated the differences in prognosis, TIM, and drug treatment response between LCC and RCC patients, which may contribute to accurate colon cancer prognosis and treatment of colon cancer.
Topics: Humans; Carcinoma, Renal Cell; RNA-Seq; Single-Cell Gene Expression Analysis; Prognosis; Colonic Neoplasms; Kidney Neoplasms; Tumor Microenvironment
PubMed: 37480572
DOI: 10.18632/aging.204894 -
Cancer Biotherapy & Radiopharmaceuticals Oct 2023This study investigated the loadability and releasing profiles of vinorelbine and raltitrexed from CalliSpheres Beads (CB) , and further explored the pharmacokinetic...
This study investigated the loadability and releasing profiles of vinorelbine and raltitrexed from CalliSpheres Beads (CB) , and further explored the pharmacokinetic features of vinorelbine and raltitrexed eluting CB Ten milligrams vinorelbine and 0.2 mg raltitrexed were mixed with 0.15 g CB at two sizes (100-300 and 300-500 μm) for 24 h, respectively, to measure the loadability. Then vinorelbine/raltitrexed loading CBs were placed in 20% phosphate-buffered saline for 24 h to measure the release profiles. Transcatheter arterial chemoembolization (TACE) with 1 mg vinorelbine eluting CBs (two sizes respectively) and transcatheter arterial hepatic infusion (TAI) with 1 mg vinorelbine were performed in 9 rabbits (3 rabbits in each group). The above experiments were repeated with 0.2 mg raltitrexed. Vinorelbine loading efficiency quickly reached 90% within 10 min with maximum loadability >90% by CB with both two sizes, and vinorelbine release rate gradually increased to ∼100% within 1 h. Raltitrexed loading efficiency gradually increased to >40% within 15 min, then slowly increased to >60% within 24 h, with maximum loadability <70% by CB with both sizes, and raltitrexed release rate gradually increased to >90% within 1 h. Besides, vinorelbine/raltitrexed eluting CB showed greatly decreased maximum serum concentration (Cmax) of the drug compared with TAI in rabbits with similar area under the curve (0-t), mean residence time (0-t), and half-time (T1/2). CB exhibits good loadability and an acceptable releasing profile for eluting vinorelbine and raltitrexed, and shows lower Cmax and numerically stable concentration than TAI.
Topics: Animals; Rabbits; Vinorelbine; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic
PubMed: 32614660
DOI: 10.1089/cbr.2019.3360 -
Tumori Oct 2023Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic...
BACKGROUND
Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic advanced or progressive forms is recommended. Following promising results in adult patients, oral vinorelbine is investigated in young patients.
METHODS
A retrospective review of young patients (<25 years old) with advanced or progressive desmoid type fibromatosis treated with oral vinorelbine in eight large centers of the Société Française des Cancers de l'Enfant was performed. In addition to tumor assessment according to RECIST 1.1, pre-treatment and during-treatment imagery were reviewed centrally to assess tumor volume and estimate fibrosis score through the change in percentage in hypoT2 signal intensity.
RESULTS
From 2005 to 2020, 24 patients (median age 13.9 years [range, 1.0-23.0]) received oral vinorelbine. Median number of prior systemic lines of treatment was 1 (range, 0-2), mainly based on intravenous low dose methotrexate and vinblastine. Before vinorelbine initiation, all patients had a progressive disease: radiological for 19, radiological and clinical (pain) for three and only clinical for two. Oral vinorelbine was delivered for a median duration of 12 months (range, 1-42). The toxicity profile was favorable, with no grade 3-4 event. Overall response estimated on 23 evaluable patients according to RECIST 1.1 criteria was three partial responses (13%), 18 stabilization (78%) and two progressive disease (9%). Overall progression-free survival was 89.3% (95% confidential intervals 75.2-100) at 24 months. Four stable tumors according to standard RECIST criteria displayed a partial response with > 65% tumor volume reduction. Among 21 informative patients, the estimated fibrosis score decreased for 15 patients, was stable for four patients and increased for two patients.
CONCLUSION
Oral vinorelbine seems to be effective to control advanced or progressive desmoid type fibromatosis in young patients, with a well-tolerated profile. These results support testing this drug as first-line alone or in combination to improve response rate while preserving quality of life.
Topics: Adult; Child; Adolescent; Humans; Vinorelbine; Fibromatosis, Aggressive; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Vinblastine; Fibrosis; Treatment Outcome
PubMed: 37114926
DOI: 10.1177/03008916231169806 -
Frontiers in Pharmacology 2023Despite the low incidence of soft tissue sarcomas (STSs), hundreds of thousands of new STS cases are diagnosed annually worldwide, and approximately half of them... (Review)
Review
Despite the low incidence of soft tissue sarcomas (STSs), hundreds of thousands of new STS cases are diagnosed annually worldwide, and approximately half of them eventually progress to advanced stages. Currently, chemotherapy is the first-line treatment for advanced STSs. There are difficulties in selecting appropriate drugs for multiline chemotherapy, or for combination treatment of different STS histological subtypes. In this study, we first comprehensively reviewed the efficacy of various chemotherapeutic drugs in the treatment of STSs, and then described the current status of sensitive drugs for different STS subtypes. anthracyclines are the most important systemic treatment for advanced STSs. Ifosfamide, trabectedin, gemcitabine, taxanes, dacarbazine, and eribulin exhibit certain activities in STSs. Vinca alkaloid agents (vindesine, vinblastine, vinorelbine, vincristine) have important therapeutic effects in specific STS subtypes, such as rhabdomyosarcoma and Ewing sarcoma family tumors, whereas their activity in other subtypes is weak. Other chemotherapeutic drugs (methotrexate, cisplatin, etoposide, pemetrexed) have weak efficacy in STSs and are rarely used. It is necessary to select specific second- or above-line chemotherapeutic drugs depending on the histological subtype. This review aims to provide a reference for the selection of chemotherapeutic drugs for multi-line therapy for patients with advanced STSs who have an increasingly long survival.
PubMed: 37637411
DOI: 10.3389/fphar.2023.1199292 -
Child's Nervous System : ChNS :... May 2024Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term...
Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term morbidities, particularly in younger patients. While historically chemotherapy was reserved for cases progressing after radiotherapy, evolving recommendations now advocate for its early use, particularly in younger age groups. The carboplatin and vincristine (CV) combination stands as a standard systemic therapy for PLGG, varying in dosage and administration between North America and Europe. Clinical trials have shown promising response rates, albeit with varying toxicity profiles. Vinblastine has emerged as another effective regimen with minimal toxicity. TPCV, a regimen combining thioguanine, procarbazine, lomustine, and vincristine, was compared to CV in a Children's Oncology Group trial, showing comparable outcomes, but more toxicity. Vinorelbine, temozolomide, and metronomic chemotherapy have also been explored, with varied success rates and toxicity profiles. Around 40-50% of PLGG patients require subsequent chemotherapy lines. Studies have shown varied efficacy in subsequent lines, with NF1 patients generally exhibiting better outcomes. The identification of molecular drivers like BRAF mutations has led to targeted therapies' development, showing promise in specific molecular subgroups. Trials comparing targeted therapy to conventional chemotherapy aim to delineate optimal treatment strategies based on molecular profiles. The landscape of chemotherapy in PLGG is evolving, with a growing focus on molecular subtyping and targeted therapies. Understanding the role of chemotherapy in conjunction with novel treatments is crucial for optimizing outcomes in pediatric patients with low-grade gliomas.
PubMed: 38819670
DOI: 10.1007/s00381-024-06458-w -
Thoracic Cancer Aug 2023This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in...
A phase II study of a doublet metronomic chemotherapy regimen consisting of oral vinorelbine and capecitabine in Chinese women with HER2-negative metastatic breast cancer.
BACKGROUND
This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in women with HER2-negative metastatic breast cancer (MBC) in China.
METHODS
The mNC regimen was administered to the enrolled cases, including oral vinorelbine (VNR) 40 mg three times weekly (on days 1, 3 and 5 every week) and capecitabine (CAP) 500 mg three times a day, until disease progression or intolerable toxicity. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and treatment-related adverse events (TRAEs). Stratified factors included treatment lines and hormone receptor (HR) status.
RESULTS
Between June 2018 and March 2023, 29 patients were enrolled into the study. The median follow-up time was 25.4 months (range, 2.0-53.8). In the entire group, the 1-year PFS rate was 54.1%. ORR, DCR and CBR were 31.0%, 96.6% and 62.1%, respectively. The mPFS was 12.5 months (range, 1.1-28.1). Subgroup analysis revealed that ORRs were 29.4% and 33.3% in first- and ≥second-line chemotherapy, respectively. ORRs were 29.2% (7/24) and 40.0% (2/5) for HR-positive MBC and metastatic triple-negative breast cancer (mTNBC), respectively. Grade 3/4 TRAEs were neutropenia (10.3%) and nausea/vomiting (6.9%).
CONCLUSIONS
The dual oral mNC regimen showed very good safety features and improved compliance without loss of efficacy in both first- and second-line treatments. The regimen also reached an excellent ORR in the mTNBC subgroup.
Topics: Humans; Female; Breast Neoplasms; Capecitabine; Vinorelbine; East Asian People; Prospective Studies; Vinblastine; Antineoplastic Combined Chemotherapy Protocols; Receptor, ErbB-2; Triple Negative Breast Neoplasms; Neoplasm Metastasis; Treatment Outcome
PubMed: 37402471
DOI: 10.1111/1759-7714.15011 -
Brain Sciences Oct 2023To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a...
To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a retrospective case series on three children treated at our institution from 2018 to 2022. All children were candidates to receive systemic therapy with vinorelbine and nimotuzumab. Radiotherapy was administered to a total dose of 54 Gy. At any disease progression, our local tumor board evaluated the possibility of offering a new course of radiotherapy. To determine feasibility and assess toxicity rates, all children underwent clinical and hematological evaluation both during and after the treatment. To assess efficacy, all children performed contrast-enhanced MRI almost quarterly after the end of the treatment. In all children, following any treatment course, neurological improvement (>80%) was associated with a radiological response (41.7-46%). The longest overall survival (24 months) was observed in the child who underwent three courses of radiotherapy, without experiencing significant side effects. Even though it goes beyond the understanding of conventional radiobiology, first and second reirradiation in pediatric patients with progressive DIPG may represent a feasible and safe approach, capable of increasing overall survival and disease-free survival in selected patients and improving their quality of life.
PubMed: 37891817
DOI: 10.3390/brainsci13101449 -
Hereditas Jul 2023Copper-induced cell death (cuproptosis) is a new regulatory cell death mechanism. Long noncoding RNAs (lncRNAs) are related to tumor immunity and metastasis. However,...
BACKGROUND
Copper-induced cell death (cuproptosis) is a new regulatory cell death mechanism. Long noncoding RNAs (lncRNAs) are related to tumor immunity and metastasis. However, the correlation of cuproptosis-related lncRNAs with the immunotherapy response and prognosis of lung adenocarcinoma (LUAD) patients is not clear.
METHODS
We obtained the clinical characteristics and transcriptome data from TCGA-LUAD dataset (containing 539 LUAD and 59 paracancerous tissues). By utilizing LASSO-penalized Cox regression analysis, we identified a prognostic signature composed of cuproptosis-related lncRNAs. This signature was then utilized to segregate patients into two different risk categories based on their respective risk scores. The identification of differentially expressed genes (DEGs) between high- and low-risk groups was carried out using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We evaluated the immunotherapy response by analyzing tumor mutational burden (TMB), immunocyte infiltration and Tumor Immune Dysfunction and Exclusion (TIDE) web application. The "pRRophetic" R package was utilized to conduct further screening of potential therapeutic drugs for their sensitivity.
RESULTS
We ultimately identified a prognostic risk signature that includes six cuproptosis-related lncRNAs (AP003778.1, AC011611.2, CRNDE, AL162632.3, LY86-AS1, and AC090948.1). Compared with clinical characteristics, the signature was significantly correlated with prognosis following the control of confounding variables (HR = 2.287, 95% CI = 1.648-3.174, p ˂ 0.001), and correctly predicted 1-, 2-, and 3-year overall survival (OS) rates (AUC value = 0.725, 0.715, and 0.662, respectively) in LUAD patients. In terms of prognosis, patients categorized as low risk exhibited more positive results in comparison to those in the high-risk group. The enrichment analysis showed that the two groups had different immune signaling pathways. Immunotherapy may offer a more appropriate treatment option for high-risk patients due to their higher TMB and lower TIDE scores. The higher risk score may demonstrate increased sensitivity to bexarotene, cisplatin, epothilone B, and vinorelbine.
CONCLUSIONS
Based on cuproptosis-related lncRNAs, we constructed and validated a novel risk signature that may be used to predict immunotherapy efficacy and prognosis in LUAD patients.
Topics: Humans; Adenocarcinoma; Immunotherapy; Lung; Prognosis; RNA, Long Noncoding; Copper; Apoptosis
PubMed: 37482612
DOI: 10.1186/s41065-023-00293-w