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Radiology and Oncology Sep 2023The standard first-line systemic treatment for patients with non-oncogene addicted advanced nonsquamous non-small cell lung cancer (NSCLC) is immunotherapy with immune...
Efficacy and safety of nintedanib and docetaxel in patients with previously treated lung non-squamous non-small cell lung cancer: a multicenter retrospective real-world analysis.
BACKGROUND
The standard first-line systemic treatment for patients with non-oncogene addicted advanced nonsquamous non-small cell lung cancer (NSCLC) is immunotherapy with immune checkpoint inhibitors (ICI) and/or chemotherapy (ChT). Therapy after failing ICI +/- ChT remains an open question, and docetaxel plus nintedanib represent a valid second line option.
PATIENTS AND METHODS
A multicenter retrospective trial of real-life treatment patterns and outcomes of patients with advanced lung adenocarcinoma treated with docetaxel plus nintedanib after the failure of ICI and/or ChT was performed. Patients from 2 Slovenian and 1 Croatian oncological center treated between June 2014 and August 2022 were enrolled. We assessed objective response (ORR), disease control rate (DCR), median progression free survival (PFS), median overall survival (OS), and safety profile of treatment.
RESULTS
There were 96 patients included in the analysis, with ORR of 18.8%, DCR of 57.3%, median PFS of 3.0 months (95% CI: 3.0-5.0 months), and a median OS of 8.0 months (95% CI: 7.0-10.0 months). The majority of patients (n = 47,49%) received docetaxel plus nintedanib as third-line therapy. The ORR for this subset of patients was 19.1%, with a DCR of 57.4%. The highest response rate was observed in patients who received second-line docetaxel plus nintedanib after first-line combination of ChT-ICI therapy (n = 24), with an ORR of 29.2% and DCR of 66.7% and median PFS of 4.0 months (95% CI: 3.0-8.0 months). Fifty-three patients (55.2%) experienced adverse events (AEs), most frequently gastrointestinal; diarrhea (n = 29, 30.2%), and increased liver enzyme levels (n = 17, 17.7%).
CONCLUSIONS
The combination of docetaxel and nintedanib can be considered an effective therapy option with an acceptable toxicity profile for patients with advanced NSCLC after the failure of ICI +/- ChT.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Docetaxel; Retrospective Studies; Lung Neoplasms; Lung
PubMed: 37665737
DOI: 10.2478/raon-2023-0040 -
The Israel Medical Association Journal... Jan 2023
Topics: Humans; Docetaxel; Myositis; Acute Disease
PubMed: 36718745
DOI: No ID Found -
Molecules (Basel, Switzerland) Oct 2020Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one... (Review)
Review
Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and middle-income countries. According to the World Health Organization (WHO), cancer treatment services are not available in more then 70% of low-income countries (90% of high-income countries have them available), and also approximately 70% of cancer deaths are reported in low-income countries. Various approaches on how to combat cancer diseases have since been described, targeting cell division being among them. The so-called mitotic poisons are one of the cornerstones in cancer therapies. The idea that cancer cells usually divide almost uncontrolled and far more rapidly than normal cells have led us to think about such compounds that would take advantage of this difference and target the division of such cells. Many groups of such compounds with different modes of action have been reported so far. In this review article, the main approaches on how to target cancer cell mitosis are described, involving microtubule inhibition, targeting aurora and polo-like kinases and kinesins inhibition. The main representatives of all groups of compounds are discussed and attention has also been paid to the presence and future of the clinical use of these compounds as well as their novel derivatives, reviewing the finished and ongoing clinical trials.
Topics: Animals; Antineoplastic Agents; Colchicine; Docetaxel; Humans; Mitosis; Paclitaxel
PubMed: 33053667
DOI: 10.3390/molecules25204632 -
Pharmaceutical Nanotechnology 2017Cancer chemotherapy is accompanied with administration of highly potent cytotoxic agents in doses that can result in non-specific drug toxicity and side effects.... (Review)
Review
BACKGROUND
Cancer chemotherapy is accompanied with administration of highly potent cytotoxic agents in doses that can result in non-specific drug toxicity and side effects. Chemotherapeutic agents possess limitations such as lack of water solubility, high volume of distribution, poor bioavailability, narrow therapeutic indices, multi-drug resistance, etc. that raise serious matters of concern regarding drug's pharmaceutical and clinical aspects. However, application of nanoparticles in delivery of anti-cancer agents has been a popular approach to address these concerns. Poly (lactide-co-glycolide) (PLGA), a biocompatible/biodegradable FDA-approved polymer has been widely used as drug carrier to enhance pharmaceutical/therapeutic properties of anticancer agents, prolonging their circulation time, targeting cancer tissues or protecting the drug from rapid elimination/premature degradation. This favourably modifies drug's pharmacokinetics and pharmacodynamics.
OBJECTIVE
This paper provides a general perspective on how association of docetaxel to PLGA nanoparticles potentially modifies pharmacokinetics and biodistribution profile of the anticancer agent.
METHOD
A comprehensive literature search has been conducted and dedicated to compile most relevant and up-to-date material about pharmacokinetic consequences of PLGA nanoparticles in docetaxel drug delivery.
RESULTS
A set of determinants are considered to be influential on biodistribution and fate of docetaxel and PLGA nanoparticles. These are attributed to physicochemical properties of PLGA polymer, docetaxel, nanoparticle, and the set of events imposed to the nanoparticles by the host body.
CONCLUSION
Association of PLGA nanoparticles and docetaxel has demonstrated to modify the drug's pharmacokinetic and biodistribution profile.
Topics: Animals; Antineoplastic Agents; Biological Availability; Docetaxel; Drug Carriers; Drug Liberation; Humans; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Solubility; Surface Properties
PubMed: 28948907
DOI: 10.2174/2211738505666161230110108 -
JCI Insight Dec 2022Docetaxel (DTX) combined with cisplatin and 5-fluorouracil has been used as induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). However, the...
Docetaxel (DTX) combined with cisplatin and 5-fluorouracil has been used as induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). However, the development of acquired resistance remains a major obstacle to treatment response. Tumor-associated macrophages are associated with chemotherapeutic resistance. In the present study, increased infiltration of macrophages into the tumor microenvironment (TME) was significantly associated with shorter overall survival and increased resistance to chemotherapeutic drugs, particularly DTX, in patients with HNSCC. Macrophage coculture induced expression of intercellular adhesion molecule 1 (ICAM1), which promotes stemness and the formation of polyploid giant cancer cells, thereby reducing the efficacy of DTX. Both genetic silencing and pharmacological inhibition of ICAM1 sensitized HNSCC to DTX. Macrophage secretion of IL-1β was found to induce tumor expression of ICAM1. IL-1β neutralization and IL-1 receptor blockade reversed DTX resistance induced by macrophage coculture. IL-1β activated superoxide dismutase 2 and inhibited catalase, thereby modulating intracellular levels of ROS and inducing ICAM1 expression. Arsenic trioxide (ATO) reduced macrophage infiltration into the TME and impaired IL-1β secretion by macrophages. The combinatorial use of ATO enhanced the in vivo efficacy of DTX in a mouse model, which may provide a revolutionary approach to overcoming acquired therapeutic resistance in HNSCC.
Topics: Animals; Mice; Docetaxel; Head and Neck Neoplasms; Intercellular Adhesion Molecule-1; Macrophages; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Humans; Interleukin-1beta; Signal Transduction
PubMed: 36264639
DOI: 10.1172/jci.insight.157285 -
International Journal of Biological... 2023Triple-negative breast cancer (TNBC) is difficult to treat; therefore, the development of drugs directed against its oncogenic vulnerabilities is a desirable goal....
Triple-negative breast cancer (TNBC) is difficult to treat; therefore, the development of drugs directed against its oncogenic vulnerabilities is a desirable goal. Herein, we report the antitumor effects of CM728, a novel quinone-fused oxazepine, against this malignancy. CM728 potently inhibited TNBC cell viability and decreased the growth of MDA-MB-231-induced orthotopic tumors. Furthermore, CM728 exerted a strong synergistic antiproliferative effect with docetaxel and this combination was more effective than the individual treatments . Chemical proteomic approaches revealed that CM728 bound to peroxiredoxin-1 (Prdx1), thereby inducing its oxidation. Molecular docking corroborated these findings. CM728 induced oxidative stress and a multi-signal response, including JNK/p38 MAPK activation and STAT3 inhibition. Interestingly, Prdx1 downregulation mimicked these effects. Finally, CM728 led to DNA damage, cell cycle blockage at the S and G/M phases, and the activation of caspase-dependent apoptosis. Taken together, our results identify a novel compound with antitumoral properties against TNBC. In addition, we describe the mechanism of action of this drug and provide a rationale for the use of Prdx1 inhibitors, such as CM728, alone or in combination with other drugs, for the treatment of TNBC.
Topics: Humans; Apoptosis; Cell Line, Tumor; Cell Proliferation; Docetaxel; Molecular Docking Simulation; Proteomics; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays
PubMed: 37063429
DOI: 10.7150/ijbs.78554 -
Cancer Treatment Reviews Nov 2022The current standard of care for the systemic treatment of metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) with either... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The current standard of care for the systemic treatment of metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) with either docetaxel or advanced androgen blockage (AAB). Recently, two studies have tested the combination of ADT, docetaxel and AAB (triplet therapy) relative to docetaxel and ADT in this setting. Herein, we aimed to compare the effect on survival outcomes of available systemic treatments for mHSPC.
METHODS
A comprehensive search for all published phase III randomized control trials on first line mHSPC that evaluated AAB (TITAN, ARCHES, STAMPEDE, LATITUDE, ENZAMET) or docetaxel (GETUG-AFU15, CHAARTED, STAMPEDE) or their combination (ARASENS, PEACE-1) was conducted PubMed, EMBASE, Web of Science, and Scopus databases up to 15/04/2022. We reconstructed survival data from published Kaplan-Meier curves on overall survival (OS) and progression free survival (PFS) and meta-analyzed docetaxel versus AAB versus triplet therapy (grouping together abiraterone/darolutamide and docetaxel). The outcomes of interest were assessed using differences in restricted mean survival time (ΔRMST) at different time points and Cox regression.
RESULTS
Ten trials were included involving 5,544 patients for assessing OS and 5,725 for PFS. Triplet therapy was associated with longer OS when compared to docetaxel (48-month ΔRMST: 2.6; 95 %CI: 1.8,3.4; p < 0.001) but yielded similar OS when compared to AAB (48-month ΔRMST: -0.8; 95 % CI: -1.8, 0.2; p = 0.1). Similarly, triplet therapy was associated with longer PFS when compared to docetaxel (48-month ΔRMST: 10.3; 95 %CI: 9.0,11.6; p < 0.001) but yielded similar PFS when compared to AAB (48-month ΔRMST: 1.1; 95 %CI: -0.2,2.3; p = 0.1).
CONCLUSIONS
Overall, we found no OS nor PFS benefit for patients with mHSPC treated with triplet therapy compared to AAB alone, while an advantage emerged for both AAB or triplet therapy relative to docetaxel.
Topics: Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms
PubMed: 35939976
DOI: 10.1016/j.ctrv.2022.102441 -
Cancer Science Feb 2024Docetaxel is the preferred chemotherapeutic agent in patients with castrate-resistant prostate cancer (CRPC). However, patients eventually develop docetaxel resistance...
Docetaxel is the preferred chemotherapeutic agent in patients with castrate-resistant prostate cancer (CRPC). However, patients eventually develop docetaxel resistance and in the absence of effective treatment options. Consequently, it is essential to investigate the mechanisms generating docetaxel resistance and develop novel alternative therapeutic targets. RNA sequencing was undertaken on docetaxel-sensitive and docetaxel-resistant prostate cancer (PCa) cells. Subsequently, chemoresistance, cancer stemness, and lipid metabolism were investigated. To obtain insight into the precise activities and action mechanisms of NOTCH3 in docetaxel-resistant PCa, immunoprecipitation, mass spectrometry, ChIP, luciferase reporter assay, cell metabolism, and animal experiments were performed. Through RNA sequencing analysis, we found that NOTCH3 expression was markedly higher in docetaxel-resistant cells relative to parental cells, and that this trend was continued in docetaxel-resistant PCa tissues. Experiments in vitro and in vivo revealed that NOTCH3 enhanced stemness, lipid metabolism, and docetaxel resistance in PCa. Mechanistically, NOTCH3 is bound to TUBB3 and activates the MAPK signaling pathway. Moreover, NOTCH3 was directly regulated by MEF2A in docetaxel-resistant cells. Notably, targeting NOTCH3 and the MEF2A/TUBB3 signaling axis was related to docetaxel chemoresistance in PCa. Overall, these results demonstrated that NOTCH3 fostered stemness, lipid metabolism, and docetaxel resistance in PCa via the TUBB3 and MAPK signaling pathways. Therefore, NOTCH3 may be employed as a prognostic biomarker in PCa patients. NOTCH3 could be a therapeutic target for PCa patients, particularly those who have developed docetaxel resistance.
Topics: Male; Animals; Humans; Docetaxel; Drug Resistance, Neoplasm; Cell Line, Tumor; Prostatic Neoplasms; Signal Transduction; Tubulin; Receptor, Notch3
PubMed: 38115797
DOI: 10.1111/cas.16040 -
Chemistry & Biodiversity Feb 2020A mixture of taxols was prepared from 10-deacetyl-7-xylosyltaxanes by three-step reactions: redox, acetylation, and deacetylation. The mixture was separated by column...
A mixture of taxols was prepared from 10-deacetyl-7-xylosyltaxanes by three-step reactions: redox, acetylation, and deacetylation. The mixture was separated by column chromatography on silica gel to afford Taxol, Taxol B (Cephalomannine) and Taxol C. The mixture of Taxol B and Taxol C was converted to Docetaxel by Schwartz's reagent. The structures of Taxol and Docetaxel were characterized by HPLC, H-NMR, C-NMR and MS. This synthetic process has expanded the source of biomass for the chemical semi-synthesis of Taxol and Docetaxel, reduced the production costs, and increased the biomass resource of taxanes.
Topics: Acetylation; Chromatography, High Pressure Liquid; Docetaxel; Magnetic Resonance Spectroscopy; Oxidation-Reduction; Paclitaxel; Taxoids
PubMed: 31967396
DOI: 10.1002/cbdv.201900631 -
The Journal of Infectious Diseases Nov 2023Cryptosporidiosis is a significant diarrheal disease in humans and animals. Immunodeficient mice are the primary small animal models, but their high costs and...
BACKGROUND
Cryptosporidiosis is a significant diarrheal disease in humans and animals. Immunodeficient mice are the primary small animal models, but their high costs and specialized breeding/housing requirements limit in vivo drug testing. Numerous anticryptosporidial lead compounds identified in vitro remain untested in vivo.
METHODS
Cryptosporidium tyzzeri, a natural mouse parasite closely related to Cryptosporidium parvum and Cryptosporidium hominis, was isolated to establish an infection model in immunocompetent mice. The model was validated using classic anticryptosporidial drugs (paromomycin and nitazoxanide) and then employed to assess the efficacy of 3 new leads (vorinostat, docetaxel, and baicalein). An in vitro culture of C. tyzzeri was also developed to complement the animal model.
RESULTS
Chronic C. tyzzeri infection was established in chemically immunosuppressed wild-type mice. Paromomycin (1000 mg/kg/d) and nitazoxanide (100 mg/kg/d) demonstrated efficacy against C. tyzzeri. Vorinostat (30 mg/kg/d), docetaxel (25 mg/kg/d), and baicalein (50 mg/kg/d) were highly effective against C. tyzzeri infection. In vitro, nitazoxanide, vorinostat, docetaxel, and baicalein exhibited low to submicromolar efficacy against C. tyzzeri.
CONCLUSIONS
Novel in vivo and in vitro models have been developed for cost-effective anticryptosporidial drug testing. Vorinostat, docetaxel, and baicalein show potential for repurposing and/or optimization for developing new anticryptosporidial drugs.
Topics: Animals; Mice; Humans; Paromomycin; Cryptosporidiosis; Vorinostat; Antiprotozoal Agents; Docetaxel; Cryptosporidium; Cost-Benefit Analysis; Plant Breeding; Cryptosporidium parvum
PubMed: 37418629
DOI: 10.1093/infdis/jiad243