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1.
Anticancer Res ; 41(11): 5767-5773, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732450

RESUMO

BACKGROUND: This study aimed to investigate the response to platinum-based chemotherapy rechallenge in patients with pembrolizumab-refractory urothelial carcinoma. PATIENTS AND METHODS: We retrospectively reviewed 14 patients with pembrolizumab-refractory urothelial carcinoma. Each patient received a regimen that they had not previously received (paclitaxel plus carboplatin in 10, gemcitabine plus docetaxel and carboplatin in four). Tumor response and adverse events were assessed. We evaluated overall survival from the chemotherapy rechallenge start date until death. RESULTS: The median overall survival was 11.2 months. The disease-control rate was 85.7%. Partial responses occurred in the metastases in lymph nodes in three (37.5%) patients, lung in one (25%), peritoneal in three (75%), and liver in three (100%). Neutropenia of grade ≥3 occurred in 13 (92.9%) patients. CONCLUSION: The activity of platinum-based chemotherapy rechallenge after pembrolizumab was maintained. Neutropenia was observed in most patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma/mortalidade , Carcinoma/secundário , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Paclitaxel/uso terapêutico , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
2.
Cells ; 10(10)2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34685704

RESUMO

Patients with prostate cancer (PCa) receiving docetaxel chemotherapy invariably develop chemoresistance. The transcription co-activator lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 and PSIP1, is upregulated in several human cancers, including PCa and promotes resistance to docetaxel and other drugs. The C-terminal region of LEDGF/p75 contains an integrase binding domain (IBD) that tethers nuclear proteins, including the HIV-1 integrase and transcription factors, to active chromatin to promote viral integration and transcription of cellular survival genes. Here, we investigated the contribution of the LEDGF/p75 IBD interactome to PCa chemoresistance. Quantitative immunoblotting revealed that LEDGF/p75 and its IBD-interacting partners are endogenously upregulated in docetaxel-resistant PCa cell lines compared to docetaxel-sensitive parental cells. Using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners JPO2, menin, MLL, IWS1, ASK1, and PogZ, as well as transcription factors c-MYC and HRP2, in docetaxel-resistant cells, and confirmed their nuclear co-localization by confocal microscopy. Depletion of LEDGF/p75 and selected interacting partners robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of docetaxel-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.


Assuntos
Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Esferoides Celulares/patologia , Especificidade de Anticorpos/imunologia , Apoptose/efeitos dos fármacos , Autoanticorpos/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Esferoides Celulares/efeitos dos fármacos
3.
J Healthc Eng ; 2021: 1040374, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659676

RESUMO

The study focused on the dual-source computed tomography (CT) images segmented by the decision tree algorithm, to explore the efficacy of docetaxel combined with fluorouracil therapy on gastric patients undergoing chemotherapy. In this study, 98 patients with gastric cancer who were treated in the hospital were selected as the research subjects. The decision tree algorithm was applied to segment dual-source CT images of gastric cancer patients. The decision tree is established according to the feature ring and the segmentation position. The machine inductively learns from the decision tree to extract the features of the CT image to obtain the optimal segmentation boundary. The observation group was treated with docetaxel combined with fluorouracil, and the control group was treated with docetaxel combined with tegafur gimeracil oteracil potassium capsules. The general data of the two groups of patients were comparable and not statistically significant (P > 0.05). The two groups were compared for clinical efficacy, physical status, KPS score, improvement rate, and adverse drug reactions after treatment. The results showed that the improvement rate of physical fitness in the observation group was 38.78%, and the improvement rate in the control group was 18.37%. The total effective rate in the observation group was 42.85%, and the total effective rate in the control group was 36.73%. Obviously, the curative effect and improvement rate of physical fitness in the observation group were significantly better than those in the control group (P < 0.05). In conclusion, the decision tree algorithm proposed in this study demonstrates superb capabilities in feature extraction of CT images. The machine inductively learns from the decision tree to extract the features of the CT image to obtain the optimal segmentation boundary. The effect of docetaxel combined with fluorouracil is better than that of docetaxel combined with tegafur gimeracil oteracil potassium capsules.


Assuntos
Neoplasias Gástricas , Algoritmos , Docetaxel , Fluoruracila , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/tratamento farmacológico , Tomografia Computadorizada por Raios X
4.
Cell Prolif ; 54(11): e13130, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34599546

RESUMO

OBJECTIVES: It is imperative to develop efficient strategies on the treatment of prostate cancer. Here, we constructed multifunctional nanoparticles, namely AS1411@MPDA-DTX (AMD) for targeted and synergistic chemotherapy/photothermal therapy of prostate cancer. MATERIALS AND METHODS: Mesoporous polydopamine (MPDA) nanoparticles were prepared by a one-pot synthesis method, DTX was loaded through incubation, and AS1411 aptamer was modified onto MPDA by the covalent reaction. The prepared nanoparticles were characterized by ultra-micro spectrophotometer, Fourier transform infrared spectra, transmission electron microscope, and so on. The targeting ability was detected by selective uptake and cell killing. The mechanism of AMD-mediated synergistic therapy was detected by Western blot and immunofluorescence. RESULTS: The prepared nanoparticles can be easily synthesized and possessed excellent water solubility, stability, and controlled drug release ability, preferentially in acidic context. Based on in vitro and in vivo results, the nanoparticles can efficiently target prostate cancer cells, promote DTX internalization, and enhance the antitumor effects of chemo-photothermal therapy strategies under the NIR laser irradiation. CONCLUSIONS: As a multifunctional nanoplatform, AS1411@MPDA-DTX could efficiently target prostate cancer cells, promote DTX internalization, and synergistically enhance the antiprostate cancer efficiency by combining with NIR irradiation.


Assuntos
Docetaxel/farmacologia , Doxorrubicina/farmacologia , Indóis/farmacologia , Polímeros/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Nanopartículas/uso terapêutico , Terapia Fototérmica/métodos , Porosidade/efeitos dos fármacos
5.
Exp Cell Res ; 408(1): 112853, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34597679

RESUMO

Docetaxel could inhibit the proliferation of tumor cells by targeting microtubules. The extension of cellular microtubules plays an important role in the invasion and metastasis of tumor cells. This paper aims to study the distribution and mechanical properties of cytoskeletal proteins with low concentration of docetaxel. MTT assay was used to detect the minimum drug activity concentration of docetaxel on SKOV-3 cells, fluorescence staining was used to analyze the distribution of cytoskeleton proteins, scanning electron microscopy(SEM) was used to observe the morphology of single cells, and atomic force microscopy(AFM) was used to determine the microstructure and mechanical properties of cells. The results showed that the IC10 of docetaxel was 1 ng/ml. Docetaxel can effectively inhibit the formation of cell pseudopodia, hinder the indirectness between cells, reduce the cell extension area, and make the cells malformed. In addition, when AFM analyzes the effects of drugs on cell microstructure and mechanical properties, the average cell surface roughness and cell height are positively correlated with the concentration of docetaxel. Especially when the concentration was 100 ng/ml, the adhesion decreased by 37.04% and Young's modulus increased by 1.57 times compared with the control group. This may be because docetaxel leads to microtubule remodeling and membrane protein aggregation, which affects cell microstructure and increases cell strength, leading to significant changes in the mechanical properties of ovarian cells. This is of great significance to the study of the formation mechanism of tumor cell invasion and migration activities mediated by actin.


Assuntos
Citoesqueleto/efeitos dos fármacos , Docetaxel/farmacologia , Microtúbulos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Actinas/efeitos dos fármacos , Actinas/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Feminino , Humanos , Microtúbulos/metabolismo , Neoplasias Ovarianas/metabolismo
7.
Adv Ther ; 38(12): 5752-5762, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34699004

RESUMO

INTRODUCTION: Concurrent anthracycline and taxane is an effective and efficient way to deliver neoadjuvant chemotherapy for HER2-negative breast cancers. Data on efficacy and tolerance to 6 cycles of concurrent docetaxel, epirubicin, and cyclophosphamide (TEC) is limited. METHOD: All patients with HER2-negative breast cancers who received neoadjuvant TEC from January 2013 to December 2019 were reviewed. RESULTS: A total of 71 patients [57 luminal B disease; 14 triple negative breast cancer (TNBC)] received neoadjuvant TEC with prophylactic granulocyte colony-stimulating factor (G-CSF). The pathological complete response (pCR) rate was 26.3% and 28.6% for luminal B and TNBC, respectively. With median follow-up of 48.9 months, 3 years disease-free survival was 85.9%, and 3 years overall survival was 89.6%. Non-hematological toxicities were common but the majority was grade 1 or 2. The most common grade 3 or 4 toxicity were hematological, including neutropenia (26.8%) and anemia (15.5%). There was no cardiotoxicity observed. Half of the patients had at least one dose reduction but all patients completed the planned 6 cycles and had breast surgery done. CONCLUSION: Six cycles of TEC with prophylactic G-CSF is an effective and tolerable neoadjuvant regime for HER2-negative breast cancers. Hematological toxicities were the most common toxicities. Although many patients required dose reduction, all patients completed treatment and there was no observed cardiotoxicity.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Docetaxel/uso terapêutico , Epirubicina , Feminino , Humanos , Terapia Neoadjuvante , Receptor ErbB-2/uso terapêutico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
8.
BMC Cancer ; 21(1): 1086, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625033

RESUMO

BACKGROUND: Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. METHODS: RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. RESULTS: Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. CONCLUSIONS: These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Itália , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia
9.
BMC Cancer ; 21(1): 1073, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598694

RESUMO

BACKGROUND: This study aimed to evaluate the feasibility, safety, and efficacy of postoperative adjuvant chemotherapy with docetaxel/cisplatin/S-1 (DCS) following S-1 therapy in patients with stage III gastric cancer after curative gastrectomy. METHODS: Patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Adjuvant chemotherapy was initiated within 8 weeks of gastrectomy. The first cycle of chemotherapy consisted of S-1 monotherapy (day 1-14), followed by a 7-day rest period. Cycles 2 and 3 consisted of the following: S-1 (day 1-14) administration, followed by a 14-day rest period, and an intravenous infusion of cisplatin and docetaxel on days 1 and 15. After two cycles, S-1 was administered for up to 1 year. RESULTS: Thirty patients were enrolled between 2014 and 2017. Febrile neutropenia of grade 3 or higher was the most common hematological toxicity with 4 patients (13.3%). Other hematological toxicities of grade 3 or higher were as follows: neutropenia in 3 (10.0%), leukopenia in 3 (10.0%), and anemia in 2 (6.7%) patients. Most frequent non-hematological toxicity of grade 3 was anorexia (n = 4, 13.3%) and general fatigue (n = 3, 10.0%); no grade 4 non-hematological toxicities were observed. Twenty-five patients (83.3%) completed two cycles of DCS treatment and 18 (60.0%) completed subsequent S-1 treatment for 1 year. The relative dose intensity of docetaxel and cisplatin was 0.86 and that of S-1 was 0.88. CONCLUSION: The DCS regimen can be acceptable as an adjuvant chemotherapy and offers an effective postoperative treatment option for stage III gastric cancer patients. TRIAL REGISTRATION NUMBER: UMIN000012785 . DATE OF REGISTRY: 08/01/2014.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Anemia/induzido quimicamente , Anorexia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Neutropenia Febril Induzida por Quimioterapia/etiologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Esquema de Medicação , Combinação de Medicamentos , Fadiga/induzido quimicamente , Estudos de Viabilidade , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Cooperação do Paciente , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tegafur/administração & dosagem , Tegafur/efeitos adversos
10.
Medicine (Baltimore) ; 100(39): e27361, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596147

RESUMO

ABSTRACT: The aim of this study is to investigate the association between baseline neutrophil-to-lymphocyte ratio (NLR) and progression-free survival (PFS), overall survival (OS) and radiological response in castration-resistant prostate cancer patients treated with docetaxel.Forty-one prostate cancer patients who were treated with docetaxel were selected. Univariable and multivariable Cox regression models were used to predict the association of baseline NLR as a dichotomous variable with PFS and OS after chemotherapy initiation.In Kaplan-Meier analysis, the median PFS (9.8 vs 7.5 months, P = .039, Fig. 1) and OS (17.6 vs 14.2 months, P = .021, Fig. 2) was higher in patients who did not have an elevated NLR than in those with an elevated NLR. In univariate analysis, the pretreatment NLR was significantly associated with PFS (P = .049) and OS (P = .023). In multivariable analysis, patients with a NLR of >3 were at significantly higher risk of tumor progress (hazard ratio 2.458; 95% confidence interval 1.186-5.093; P = .016) and death (hazard ratio 3.435; 95% CI 1.522-7.750; P = .003)than patients with a NLR of ⩽3.NLR may be an independent predictor of PFS and OS in castration-resistant prostate cancer patients treated with docetaxel. The findings require validation in further prospective, big sample-sized studies.


Assuntos
Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Linfócitos/citologia , Neutrófilos/citologia , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Fatores Etários , Idoso , China , Intervalo Livre de Doença , Complexo IV da Cadeia de Transporte de Elétrons , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Gradação de Tumores , Modelos de Riscos Proporcionais , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida
11.
ESMO Open ; 6(5): 100277, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34626918

RESUMO

BACKGROUND: Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS: In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS: Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS: The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.


Assuntos
Cisplatino , Neoplasias Esofágicas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Docetaxel/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/efeitos adversos , Alimentos Formulados , Humanos , Estudos Prospectivos
12.
In Vivo ; 35(6): 3509-3519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697189

RESUMO

BACKGROUND/AIM: Docetaxel has been widely used in metastatic Castration-resistant Prostate Cancer (mCRPC) patients for decades. The purpose of the study was to evaluate the efficacy of docetaxel rechallenge in patients with mCRPC. PATIENTS AND METHODS: We retrospectively compared patients who had received either first-line docetaxel and rechallenge after Androgen Receptor-axis Targeted therapies (ARAT), to those without rechallenge docetaxel. Multivariate cox-regression analysis was used to evaluate survival. RESULTS: Out of the 204 patients with mCRPC enrolled in the study, 24 patients received docetaxel rechallenge and 180 did not. The median overall survival was 50.11 months in the rechallenge group, as compared to 26.36 months in the non-rechallenge group (p of log rank=0.044). In the multivariate model, doxetaxel rechallenge was an independent risk factor for overall survival [hazard ratio (HR)=0.59, 95% confidence interval (CI)=0.32-0.99], together with the performance status score 2 (HR=2.46, 95%CI=1.32-4.58), hormone-sensitive state duration (HR=0.99, 95%CI=0.99-0.999), liver (HR=1.90, 95%CI=1.04-3.47) and brain metastases (HR=2.23, 95%CI=1.26-5.46). The advantage of rechallenge was addressed in the androgen receptor-axis-targeted (ARAT) non-responsive patients (HR=0.36, 95%CI=0.17-0.78). Adverse events were at 29.17% with Grade 3/4 neutropenia and at 20.83% with Grade 1/2 neutropenia in the docetaxel rechallenge group. CONCLUSION: The docetaxel rechallenge improved survival in patients with mCRPC failure of first-line docetaxel and subsequent abiraterone acetate or enzalutamide. Independent predictive factors for overall survival included i) the performance status, ii) hormone-sensitive state duration, iii) liver and iv) brain metastases. Patients non-responsive to ARATs will benefit from docetaxel rechallenge with regards to overall survival.


Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/efeitos adversos , Humanos , Masculino , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento
13.
J Egypt Natl Canc Inst ; 33(1): 35, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674048

RESUMO

BACKGROUND: Squamous cell carcinoma of the esophagus ranks as the most common cause of cancer incidence and mortality in males and the second most common in females. Surgery alone is associated with poor long-term survival. Neoadjuvant chemoradiation and perioperative chemotherapy without radiation have been tried to improve survival rates. METHODS: We retrospectively evaluated the neoadjuvant chemotherapy in forty-eight patients with non-metastatic, non-cervical squamous cell carcinoma of the esophagus with a docetaxel-based three-drug regimen to improve complete pathological response rates. RESULTS: The median age of presentation was 52 years, with male preponderance. All the patients received three cycles of docetaxel-cisplatin-fluorouracil-based chemotherapy. A complete pathological response to neoadjuvant chemotherapy was seen in 8 patients (17%). Rates of grade 3 hematological toxicities were seen in 12% of patients, with no observed grade 4 toxicity. The most common non-hematological toxicity was grade 3 alopecia (seen in 40%) and grade 2 nausea/vomiting in 8% of patients. At a median follow-up of 26.5 months, 2-year survival for the patients receiving chemotherapy and surgery is 66%. CONCLUSIONS: Preoperative chemotherapy with a taxane-based triple-drug regimen is a reasonable approach in squamous cell carcinoma of the esophagus, associated with improvement in complete pathological response rates, increases complete resection rates, with manageable toxicity.


Assuntos
Carcinoma de Células Escamosas , Docetaxel , Neoplasias Esofágicas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/epidemiologia , Docetaxel/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/epidemiologia , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Resultado do Tratamento
14.
Oncoimmunology ; 10(1): 1971418, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616588

RESUMO

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m2] plus docetaxel [25 mg/m2] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9-24.5), OS and PFS time ranged from 8.2-28.5 and 4.0-28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c+ dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias de Cabeça e Pescoço , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Docetaxel/uso terapêutico , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Humanos , Qualidade de Vida
15.
Chin J Nat Med ; 19(9): 656-665, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34561076

RESUMO

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Docetaxel , Composição de Medicamentos , Paclitaxel , Taxoides
16.
Int J Mol Sci ; 22(18)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34576262

RESUMO

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN-38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after the treatments were assessed via flow cytometry. The molecular mechanisms of CBD and the most promising combinations were investigated via label-free quantification proteomics. A strong synergy was observed across all synergy models at different molar ratios of CBD in combination with SN-38 and VIN. Intriguingly, synergy was observed for CBD with all chemotherapeutic drugs at a molar ratio of 636:1 in almost all synergy models. However, discording synergy trends warranted the validation of the selected combinations against different models. Enhanced apoptosis was observed for all synergistic CBD combinations compared to monotherapies or negative controls. A shotgun proteomics study highlighted 121 dysregulated proteins in CBD-treated MCF7 cells compared to the negative controls. We reported the inhibition of topoisomerase II ß and α, cullin 1, V-type proton ATPase, and CDK-6 in CBD-treated MCF7 cells for the first time as additional cytotoxic mechanisms of CBD, alongside sabotaged energy production and reduced mitochondrial translation. We observed 91 significantly dysregulated proteins in MCF7 cells treated with the synergistic combination of CBD with SN-38 (CSN-38), compared to the monotherapies. Regulation of telomerase, cell cycle, topoisomerase I, EGFR1, protein metabolism, TP53 regulation of DNA repair, death receptor signalling, and RHO GTPase signalling pathways contributed to the proteome-wide synergistic molecular mechanisms of CSN-38. In conclusion, we identified significant synergistic interactions between CBD and the five important chemotherapeutic drugs and the key molecular pathways of CBD and its synergistic combination with SN-38 in MCF7 cells. Further in vivo and clinical studies are warranted to evaluate the implementation of CBD-based synergistic adjuvant therapies for breast cancer.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Canabidiol/química , Proteômica/métodos , Adenocarcinoma/metabolismo , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Neoplasias da Mama/metabolismo , Canabidiol/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Dactinomicina/análogos & derivados , Dactinomicina/farmacologia , Docetaxel/química , Docetaxel/metabolismo , Doxorrubicina/química , Doxorrubicina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Irinotecano/química , Irinotecano/metabolismo , Células MCF-7 , Paclitaxel/química , Paclitaxel/metabolismo , Proteoma , Vinorelbina/química , Vinorelbina/metabolismo
17.
Mater Sci Eng C Mater Biol Appl ; 128: 112305, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474856

RESUMO

In spite of established evidence of the synergistic combination of hydrophobic anticancer molecule and microRNA for breast cancer treatment, their in vivo delivery has not been realized owing to their instability in the biological milieu and varied physicochemical properties. The present work reports folate targeted hybrid lipo-polymeric nanoplexes for co-delivering DTX and miR-34a. These nanoplexes exhibited a mean size of 129.3 nm with complexation efficiency at an 8:1 N/P ratio. The obtained nanoplexes demonstrated higher entrapment efficiency of DTX (94.8%) with a sustained release profile up to 85% till 48 h. Further, an improved transfection efficiency in MDA-MB-231 and 4T1 breast cancer cells was observed with uptake primarily through lipid-raft and clathrin-mediated endocytosis. Further, nanoplexes showed improved cytotoxicity (~3.5-5 folds), apoptosis (~1.6-2.0 folds), and change in expression of apoptotic genes (~4-7 folds) compared to the free treatment group in breast cancer cells. In vivo systemic administration of FA-functionalized DTX and FAM-siRNA-loaded nanoplexes showed an improved area under the curve (AUC) as well as circulation half-life compared to free DTX and naked FAM-labelled siRNA. Acute toxicity studies of the cationic polymer showed no toxicity at a dose equivalent to 10 mg/kg based on the hematological, biochemical, and histopathological examination.


Assuntos
Antineoplásicos , Neoplasias da Mama , MicroRNAs/administração & dosagem , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Docetaxel/farmacologia , Portadores de Fármacos/uso terapêutico , Feminino , Ácido Fólico , Humanos , MicroRNAs/genética , Polímeros/uso terapêutico
18.
Expert Rev Clin Pharmacol ; 14(10): 1295-1303, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34488513

RESUMO

BACKGROUND: This study aimed to quantitatively evaluate factors influencing the efficacy and safety of the docetaxel-platinum regimen to provide reliable information for optimizing chemotherapy regimens. RESEARCH DESIGN AND METHODS: A parametric survival function model was used to describe the time course of overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) receiving a docetaxel-platinum regimen. A random-effects model in a single-arm meta-analysis was used to analyze the objective response rate and grade 3-4 adverse event rates based on various docetaxel-platinum regimens. RESULTS: The model revealed that the risk of death in East Asians was approximately 1.5-fold higher than that in non-East Asians, with a median OS of 13.7 (95% confidence interval [CI]: 12.8-14.7) months and 9.3 (95% CI: 7.7-11.1) months, respectively. No significant impact of different administration regimens on OS was found. However, when drug exposure increased, the incidence of grade 3-4 anemia or neutropenia significantly increased. CONCLUSIONS: The docetaxel-platinum regimen has different efficacies in the treatment of advanced NSCLC between East Asian and non-East Asian populations. A better benefit-risk ratio can be obtained with a lower exposure regimen of docetaxel combined with platinum.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Carcinoma Pulmonar de Células não Pequenas/patologia , Docetaxel/administração & dosagem , Humanos , Neoplasias Pulmonares/patologia , Modelos Estatísticos , Compostos de Platina/administração & dosagem , Análise de Sobrevida , Taxa de Sobrevida
19.
Nanoscale ; 13(35): 15010-15020, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34533174

RESUMO

For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are attractive cancer targets as they can present peptides from tumour-selective proteins on the cell surface, which can be recognised by T cells via T cell receptors (TCRs). In this study, docetaxel-loaded polymeric NPs were conjugated to recombinant affinity-enhanced TCRs to target breast cancer cells presenting a tumour-selective peptide-HLA complex. The TCR-conjugated nanoparticles enabled enhanced delivery of docetaxel and induced cell death through tumour-specific peptide-HLA targeting. These in vitro data demonstrate the potential of targeting tumour-restricted peptide-HLA epitopes using high affinity TCR-conjugated nanoparticles, representing a novel treatment strategy to deliver therapeutic drugs specifically to cancer cells.


Assuntos
Nanopartículas , Receptores de Antígenos de Linfócitos T , Antígenos de Neoplasias , Linhagem Celular Tumoral , Docetaxel , Humanos , Linfócitos T
20.
Lung Cancer ; 161: 122-127, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34583220

RESUMO

INTRODUCTION: Advanced non-squamous non-small cell lung cancer (NsqNSCLC) progressing at the induction of a first-line of platin-based chemotherapy is a subgroup of patients with poor prognosis and few second-line treatment options. MATERIALS AND METHODS: This single-stage phase II prospective multicenter open-label trial performed in platin-based refractory (i.e. progressing during induction phase of first-line platin-based chemotherapy) advanced NsqNSCLC assessed the efficacy of the nintedanib-docetaxel combination in second-line treatment. The primary endpoint was progression-free survival (PFS) rates at 12 weeks with a cut-off at 30% for ineffectiveness and 50% for minimal efficacy. RESULTS: A total of 59 patients from 23 centers were included (mean age, 58.5 years; male gender, 73.6%; performance status 0-1, 100%; former/current smokers, 92.5%; adenocarcinoma, 92.5%, median platin-based first-line chemotherapy, 2). Nintedanib-docetaxel combination was administered for a median of 4 cycles. The rate of PFS at 12 weeks was 39.6% (95% CI, 28.2-56.8). Median PFS was 2.7 (95% CI, 1.4-4.1) months and one-year PFS was 11.8% (95% CI, 4.8-22.2). Median overall survival (OS) was 6.9 (95% CI, 4.3-8.2) months and 12-month OS was 32.1% (95% CI, 19.8-45.0); 18-month OS was 27.6% (95% CI, 16,1-40.4). Twenty-nine (53.7%) patients reported at least one serious treatment-related adverse events leading to permanent discontinuation of at least one study drug in 12 (22.2%) patients. CONCLUSION: The predefined minimal efficacy was not demonstrated. However, a number of NsqNSCLC patients refractory to first-line platin-based chemotherapy appeared to benefit from this combination.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxoides/uso terapêutico , Resultado do Tratamento
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