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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 -
Journal of Experimental & Clinical... Nov 2023Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast cancer (BC). Novel approaches to increase the response rate combine this treatment with immunotherapies such as PD-1 inhibition. However, the expected stimulatory effect on lymphocytes may depend on the chemotherapy backbone. Therefore, we separately compared the immunomodulatory effects of EC and D in the setting of a randomized clinical trial.
METHODS
Tumor and blood samples of 154 patients from the ABCSG-34 trial were available (76 patients received four cycles of EC followed by four cycles of D; 78 patients get the reverse treatment sequence). Tumor-infiltrating lymphocytes, circulating lymphocytes and 14 soluble immune mediators were determined at baseline and at drug change. Furthermore, six BC cell lines were treated with E, C or D and co-cultured with immune cells.
RESULTS
Initial treatment with four cycles of EC reduced circulating B and T cells by 94% and 45%, respectively. In contrast, no comparable effects on lymphocytes were observed in patients treated with initial four cycles of D. Most immune mediators decreased under EC whereas D-treatment resulted in elevated levels of CXCL10, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR). Accordingly, only the exposure of BC cell lines to D induced similar increases as compared to E. While treatment of BC cells with E was associated with cell shrinkage and apoptosis, D induced cell swelling and accumulation of cells in G2 phase.
CONCLUSION
The deleterious effect of EC on lymphocytes indicates strong immunosuppressive properties of this combination therapy. D, in contrast, has no effect on lymphocytes, but triggers the secretion of stimulatory proteins in vivo and in vitro, indicating a supportive effect on the immune system. Underlying differences in the induced cell death might be causal. These divergent immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel should be considered when planning future combinations with immunotherapies in breast cancer.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Docetaxel; Epirubicin; Fluorouracil; Neoadjuvant Therapy; Treatment Outcome
PubMed: 37957750
DOI: 10.1186/s13046-023-02876-x -
Chinese Clinical Oncology Jun 2023In the last two decades, the incidence of gastroesophageal junction (GEJ) adenocarcinomas (AC) has increased, in part due to the increasing prevalence of obesity and... (Review)
Review
In the last two decades, the incidence of gastroesophageal junction (GEJ) adenocarcinomas (AC) has increased, in part due to the increasing prevalence of obesity and untreated gastroesophageal reflux disease (GERD). Esophageal and GEJ cancers have become one of the leading causes of cancer deaths worldwide due to its aggressive nature. While the mainstay of treatment for locally advanced gastroesophageal cancers (GECs) remains surgery, several studies have now shown that multimodality approach yields better outcomes. GEJ cancers have historically been included both in esophageal cancer as well as gastric cancer trials. Therefore, both approaches, neoadjuvant chemoradiation (CRT) or perioperative chemotherapy are considered standard treatment options. thereon the same token, there yet remains a debate for the 'gold standard' treatment of locally advanced GEJ cancers. The landmark trials, fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT) and ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), have shown similar improvements in overall survival (OS) and disease-free survival (DFS) for patients with resectable locoregional GEJ cancers. In this review, the authors attempt to highlight the historical evolution of current standard treatments and provide a sneak peek into the future of treatment of GEJ cancers. Several factors must be borne in mind when making the optimal choice for a patient. Some of these include surgical candidacy, tolerance to chemotherapy, eligibility for radiation (RT) as well as institutional preferences.
Topics: Humans; Stomach Neoplasms; Docetaxel; Oxaliplatin; Leucovorin; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Esophageal Neoplasms; Esophagogastric Junction; Neoadjuvant Therapy
PubMed: 37303220
DOI: 10.21037/cco-23-5 -
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 -
British Journal of Clinical Pharmacology Feb 2021The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs.... (Review)
Review
The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3-weekly) or optimal average dose (cabazitaxel, nab-paclitaxel) has not been fully resolved, as it may differ according to tumour entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has been partly explored for 3-weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab-paclitaxel at present.
Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Docetaxel; Female; Humans; Paclitaxel; Taxoids
PubMed: 33247980
DOI: 10.1111/bcp.14678 -
Gastric Cancer : Official Journal of... Nov 2023A phase III trial comparing S-1 and docetaxel with S-1 alone as postoperative chemotherapy for pathologically Stage III gastric cancer was conducted and clarified the... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
A phase III trial comparing S-1 and docetaxel with S-1 alone as postoperative chemotherapy for pathologically Stage III gastric cancer was conducted and clarified the superiority of the doublet in terms of 3-year relapse-free survival as the primary endpoint (67.7% versus 57.4%, hazard ratio [HR] 0.715, 95% confidence interval [CI] 0.587-0.871; p = 0.0008). This final report analyzed 5-year survival outcomes along with the incidence and pattern of late recurrences.
PATIENTS AND METHODS
Patients with histologically confirmed Stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. The same 912 patients who were evaluated for 3-year survival outcomes in the previous report were analyzed.
RESULTS
Five-year overall survival rate of the S-1 plus docetaxel group (67.91%) was significantly superior to that in the S-1 group (60.27%; HR 0.752, 95% CI 0.613-0.922; p = 0.0059). The incidence of late recurrence at > 3 years after randomization was similar in both groups (7.3% versus 7.2%). Peritoneal dissemination was the most common pattern of late recurrence. Addition of docetaxel significantly suppressed relapse through the lymphatic (6.8% [95% CI 4.52-9.17] versus 15% [95% CI 11.76-18.30]; p < 0.0001) and hematogenous (10.2% [95% CI 7.37-12.94] versus 15.7% [95% CI 12.36-19.01]; p < 0.0137) pathways throughout the 5 years of follow-up.
CONCLUSION
The survival benefit of postoperative chemotherapy with S-1 and docetaxel in terms of 5-year overall survival rate was confirmed for patients with pathologically Stage III gastric cancer, although late recurrences were not prevented.
Topics: Humans; Stomach Neoplasms; Docetaxel; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Proportional Hazards Models; Neoplasm Staging; Gastrectomy
PubMed: 37548812
DOI: 10.1007/s10120-023-01419-9 -
The Oncologist Mar 2024In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5%...
BACKGROUND
In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS.
PATIENTS AND METHODS
Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety.
RESULTS
In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%).
CONCLUSION
In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.
Topics: Humans; Male; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Randomized Controlled Trials as Topic
PubMed: 37812679
DOI: 10.1093/oncolo/oyad254 -
Journal of Clinical Oncology : Official... May 2023We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC)...
PURPOSE
We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model.
METHODS
Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high).
RESULTS
The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; < .0001) and 1.9 (95% CI, 1.7 to 2.1; < .0001).
CONCLUSION
This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.
Topics: Male; Humans; Prognosis; Docetaxel; Prostatic Neoplasms, Castration-Resistant; Proportional Hazards Models; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 37040594
DOI: 10.1200/JCO.22.02661 -
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