RESUMO
Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use.
Assuntos
Antineoplásicos , Neoplasias da Mama , Ácidos Carboxílicos , Sobrevivência Celular , Docetaxel , Sistemas de Liberação de Medicamentos , Fulerenos , Fulerenos/química , Fulerenos/administração & dosagem , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/farmacologia , Docetaxel/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Feminino , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Ácidos Carboxílicos/química , Tamanho da Partícula , Portadores de Fármacos/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Nanoconjugados/química , Ratos , Células MCF-7 , Disponibilidade BiológicaRESUMO
INTRODUCTION: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study. RESULTS: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X2 = 9.14, p < 0.05) and those below the age of 18 (X 2 = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models. CONCLUSION: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas , Desoxicitidina , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Osteossarcoma , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Humanos , Docetaxel/uso terapêutico , Docetaxel/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Taxoides/uso terapêutico , Taxoides/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Linhagem Celular Tumoral , Masculino , Feminino , Resultado do Tratamento , AnimaisRESUMO
Primary ovarian sarcoma is a rare malignancy, with primary ovarian leiomyosarcoma being even rarer because of the lack of smooth muscle in the ovaries. We herein report a case of primary ovarian leiomyosarcoma in a woman in her late 50s who presented with a 6-month history of abdominal pain. Imaging revealed a pelvic mass. The patient underwent surgery and was diagnosed with ovarian leiomyosarcoma. One month postoperatively, she began gemcitabine and docetaxel chemotherapy and continued this treatment for 6 months. Eight months postoperatively, however, recurrence was detected in the pelvic cavity. This case is reported with the aim of raising awareness about this rare disease.
Assuntos
Leiomiossarcoma , Neoplasias Ovarianas , Humanos , Feminino , Leiomiossarcoma/patologia , Leiomiossarcoma/cirurgia , Leiomiossarcoma/diagnóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/cirurgia , Pessoa de Meia-Idade , Docetaxel/uso terapêutico , Docetaxel/administração & dosagem , Gencitabina , Recidiva Local de Neoplasia/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Programmed cell death-1 (PD-1) blockade improves survival in patients with advanced esophageal squamous cell carcinoma (ESCC). However, the efficacy of taxanes after exposure to PD-1 blockade remains unclear in patients with advanced ESCC. METHODS: We retrospectively analyzed the clinical outcomes of advanced ESCC patients treated with taxanes (paclitaxel or docetaxel) with/without prior exposure to PD-1 blockade (Exposed /Naïve group) at National Cancer Center Hospital from June 2016 to December 2020. RESULTS: Ninety-nine patients (Exposed group, n = 32; Naïve group, n = 67) were included. The objective response rate (ORR) of the Exposed group was significantly higher than that of the Naïve group (37.5% vs. 13.4%, p = 0.009). The median progression-free survival was similar between the Exposed and Naïve groups (3.8 vs. 2.8 months, HR 1.12, 95% CI 0.65-1.86, p = 0.66). PD-1 blockade exposure independently predicated higher ORR to taxanes in multivariate analysis. Grade ≥ 3 adverse events were comparable between the Exposed and Naïve groups (45.8% vs. 40.3%, p = 0.64). CONCLUSIONS: Taxanes following PD-1 blockade in advanced ESCC showed a higher ORR but similar PFS compared to taxanes without prior PD-1 exposure.
Assuntos
Docetaxel , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Paclitaxel , Humanos , Masculino , Feminino , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Pessoa de Meia-Idade , Idoso , Docetaxel/uso terapêutico , Docetaxel/efeitos adversos , Docetaxel/administração & dosagem , Paclitaxel/uso terapêutico , Paclitaxel/efeitos adversos , Paclitaxel/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Taxoides/efeitos adversos , Taxoides/uso terapêutico , Intervalo Livre de Progressão , Resultado do Tratamento , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
A novel core-shell nanocarrier system has been designed for co-delivery of a small anticancer drug, docetaxel (DTX) and tumor suppressor (TS) miR-34a named as Exo(PAN34a+DTX). The core is formed by pH dependent polyamine salt aggregates (PSA) containing both the payloads and the shell is formed by RAW 264.7 cell derived exosomal fragments. Herein, phosphate driven polyallylamine hydrochloride (PAH, MW:17,500 Da) PSA was formed in presence of miR-34a and DTX to form PAN34a+DTX. The formulation exhibited pH dependent DTX release with only 33.55 ± 2.12% DTX release at pH 7.2 and 75.21 ± 1.8% DTX release till 144 h at pH 5.5. At 1.21 molar ratio of phosphate to the amine (known as R value), efficient complexation of miR-34a (3.6 µM) in the PAN particles was obtained. PAN34a+DTX demonstrated particle size (163.86 ± 12.89 nm) and zeta-potential value of 17.53 ± 5.10 mV which upon exosomal fragment layering changed to - 7.23 ± 2.75 mV which is similar to the zeta-potential of the exosomal fragments, i.e., - 8.40 ± 1.79 mV. The final formulation Exo(PAN34a+DTX), loaded with 40 ng/mL DTX and 50 nM miR-34a exhibited 48.20 ± 4.59% cytotoxicity in triple negative breast cancer (TNBC) cells, 4T1. Co-localization of CM-DiI (red fluorescence) stained exosomal fragments and FAM-siRNA (green fluorescence) in the cytoplasm of 4T1 cells after 6 h of Exo(PANFAM) treatment confirmed the efficiency of the designed system to co-deliver two actives. Exo(PAN34a+DTX) also reduced BCL-2 expression (target gene for miR-34a) by 8.98 folds in comparison to free DTX confirming promising co-delivery and apoptosis inducing effect of Exo(PAN34a+DTX) in 4T1.
Assuntos
Apoptose , Docetaxel , Exossomos , MicroRNAs , Poliaminas , MicroRNAs/genética , MicroRNAs/metabolismo , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Poliaminas/química , Humanos , Exossomos/metabolismo , Apoptose/efeitos dos fármacos , Animais , Camundongos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Células RAW 264.7 , Linhagem Celular Tumoral , Portadores de Fármacos/químicaRESUMO
The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (â¼95 %) and loading capacity (â¼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (â¼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.
Assuntos
Antineoplásicos , Docetaxel , Glutationa , Lipossomos , Camundongos Endogâmicos BALB C , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/farmacologia , Docetaxel/química , Animais , Camundongos , Glutationa/química , Feminino , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Taxoides/administração & dosagem , Taxoides/farmacologia , Taxoides/farmacocinética , Taxoides/química , Polissorbatos/química , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológicoRESUMO
BACKGROUND: Managing metastatic castration-resistant prostate cancer (mCRPC) in men aged ≥ 75 is challenging due to limited data. Regardless of age, in real-world clinical practice, most mCRPC still derive from failure of androgen deprivation therapy (ADT) with or without docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC). As abiraterone acetate plus prednisone (AA) and enzalutamide (Enza) are common first-line treatments for mCRPC. The impact of prior use of D for mCSPC on the efficacy and safety of AA or Enza in this older population remains unclear. METHODS: A cohort of patients aged ≥ 75 years starting AA or Enza as first-line therapy for mCRPC from January 2015 to April 2019 was identified from the registries of 10 institutions. Patients were categorized into 2 groups based on previous use of D for mCSPC. Primary endpoints were cancer-specific survival (CSS) from AA or Enza start, CSS from ADT onset, and safety. We used Kaplan-Meier method to estimate the endpoints distribution, including median values with 95% confidence intervals (95% CI). RESULTS: Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months. Median CSS from ADT or AA/Enza was not significantly different between ADT+D and ADT alone cohorts (71.9 vs. 52.7 months, P = .97; 25.4 vs. 27.2 months, P = .89, respectively). No statistically significant difference in adverse events (AEs) of any grade rate (58.3% vs. 52.1%, respectively; P = .67) or grade ≥ 3 (12.5% vs. 15.7%, respectively; P = 1.0) was found between ADT+D and ADT alone cohorts. CONCLUSIONS: Despite the innate limitations of a retrospective design and relatively small size of the ADT+D cohort, this analysis suggests that elderly men receiving AA or Enza as first-line therapy for mCRPC have similar survival outcomes and tolerability, regardless of previous D for mCSPC.
Assuntos
Acetato de Abiraterona , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Docetaxel , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Sistema de Registros , Humanos , Masculino , Feniltioidantoína/administração & dosagem , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Feniltioidantoína/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Idoso , Acetato de Abiraterona/uso terapêutico , Acetato de Abiraterona/administração & dosagem , Nitrilas/administração & dosagem , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Idoso de 80 Anos ou mais , Sistema de Registros/estatística & dados numéricos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Prednisona/administração & dosagem , Prednisona/uso terapêuticoRESUMO
The treatment of metastatic castration-sensitive prostate cancer (mCSPC) has seen remarkable breakthroughs over the last few years. Diagnostic and therapeutic advances have given rise to debates about risk stratification and optimal first-line treatment selection, as well as to concerns about potential overtreatment in a disease state with a highly heterogeneous clinical behavior. Here, we use case reports from our practice to review the clinical trials exploring intensified triplet regimens combining androgen deprivation therapy with second-generation androgen receptor signaling inhibitors and docetaxel, and we offer our recommendations on how to best select candidates for these novel combinations. Furthermore, the growing adoption of PET imaging with increasingly sensitive and prostate tissue-specific tracers replacing conventional staging technologies has led to the identification of a subset of low-volume mCSPC with nodal metastases which would otherwise not be considered abnormal by RECIST criteria. We describe our PSA-adapted approach to treatment in this unique population with non-measurable low-volume mCSPC which has not been specifically investigated in any phase III clinical trials. We also discuss ongoing clinical trials evaluating treatment de-escalation strategies. Finally, we review how local treatment modalities directed at the prostate or distant sites of disease in oligometastatic CSPC may benefit patients, and how we incorporate metastasis-directed therapy in the management of mCSPC.
Assuntos
Metástase Neoplásica , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Antagonistas de Androgênios/uso terapêutico , Docetaxel/uso terapêutico , Docetaxel/administração & dosagemRESUMO
INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with prognoses varying from months to years at time of castration-resistant diagnosis. Optimal first-line therapy for those with different prognoses is unknown. METHODS: We conducted a retrospective cohort study of men in a national healthcare delivery system receiving first-line therapy for mCRPC (abiraterone, enzalutamide, docetaxel, or ketoconazole) from 2010 to 2017, with follow-up through 2019. Using commonly drawn prognostic labs at start of mCRPC therapy (hemoglobin, albumin, and alkaline phosphatase), we categorized men into favorable, intermediate, or poor prognostic groups depending on whether they had none, one to two, or all three laboratory values worse than designated laboratory cutoffs. We used Kaplan-Meier methods to examine prostate specific antigen (PSA) progression-free and overall survival (OS) according to prognostic group and first-line therapy, and multivariable cox regression to determine variables associated with survival outcomes. RESULTS: Among 4135 patients, median PSA progression-free survival (PFS) was 6.9 months (95% confidence interval [CI] 6.6-7.3), and median OS 18.8 months (95% CI 18.0-19.6), ranging from 5.7 months (95% CI 4.8-7.0) in the poor prognosis group to 31.3 months (95% CI 29.7-32.9) in the favorable group. OS was similar regardless of initial treatment received for favorable and intermediate groups, but worse for those in the poor prognostic group who received ketoconazole (adjusted hazard ratio 2.07, 95% CI 1.2-3.6). PSA PFS was worse for those who received ketoconazole compared to abiraterone across all prognostic groups (favorable HR 1.76, 95% CI 1.34-2.31; intermediate HR 1.78, 95% CI 1.41-2.25; poor HR 8.01, 95% CI 2.93-21.9). CONCLUSION: Commonly drawn labs at mCRPC treatment start may aid in predicting survival and response to therapies, potentially informing discussions with care teams. First-line treatment selection impacts disease progression for all men with mCRPC regardless of prognostic group, but impacted OS only for men with poor prognosis at treatment start.
Assuntos
Androstenos , Docetaxel , Cetoconazol , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/sangue , Idoso , Estudos Retrospectivos , Cetoconazol/uso terapêutico , Prognóstico , Pessoa de Meia-Idade , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Docetaxel/uso terapêutico , Docetaxel/administração & dosagem , Androstenos/uso terapêutico , Antígeno Prostático Específico/sangue , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estimativa de Kaplan-MeierRESUMO
BACKGROUND: The association between recurrence timing and prognosis in patients with locally advanced resectable esophageal cancer undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy remains unclear. This study aimed to clarify this association using multicenter prospective clinical trial data. METHODS: Among 162 patients enrolled in a NAC phase II study comparing the efficacy of cisplatin and fluorouracil plus docetaxel with cisplatin and fluorouracil plus adriamycin, 64 patients with recurrence after R0 resection were included in this study. We evaluated the association between recurrence timing and overall survival after recurrence (OSr), along with clinicopathological factors associated with recurrence timing and OSr. RESULTS: Among 64 patients, 46 (71.9%) and 59 (92.2%) experienced recurrence within 1 and 2 years after surgery, respectively. Groups based on recurrence timing, including ≤ 6, 6-12, and > 12 months, had median OSr of 3.6, 13.9, and 13.4 months, respectively. The prognosis was significantly poorer for patients with recurrence ≤ 6 months after surgery than for other patients (P < 0.001). Multivariate analysis revealed pathological lymph node staging as an independent factor associated with early recurrence (odds ratio: 3.46, 95% confidence interval: 1.47-8.02, P = 0.0045). On the other hand, multivariate analysis for factors associated with OSr revealed pT (hazard ratio [HR]: 1.91, 95%CI 1.26-2.88, P = 0.0022), early recurrence (HR: 6.88, 95%CI 2.68-17.6, P < 0.001), and treatment after recurrence, with both local treatment (HR: 0.47, 95%CI 0.22-0.98, P = 0.043) and chemotherapy (HR: 0.25, 95%CI 0.11-0.58, P = 0.0011) as independent prognostic factors. CONCLUSION: Patients with advanced esophageal cancer experiencing recurrence within 6 months after esophagectomy following NAC have an extremely poor prognosis, suggesting that an advanced pN stage is associated with early recurrence.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Neoplasias Esofágicas , Esofagectomia , Fluoruracila , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Humanos , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Esofagectomia/métodos , Prognóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Terapia Neoadjuvante/métodos , Fatores de Tempo , Estudos Prospectivos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Docetaxel/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Taxoides/uso terapêutico , Taxoides/administração & dosagem , Estadiamento de Neoplasias , Quimioterapia Adjuvante/métodos , AdultoRESUMO
The invasion and metastasis of tumors pose significant challenges in the treatment of ovarian cancer (OC), making it difficult to cure. One potential treatment approach that has gained attention is the use of matrix metalloproteinase reactive controlled release micelle preparations. In this study, we developed a novel PEG5000-PVGLIG-hyaluronic acid docetaxel/bakuchiol (PP-HA-DTX/BAK) micelles formulation with desirable characteristics such as particle size, narrow polydispersity index, and a ZETA potential of approximately -5 mV. The surface modification with HA facilitates tumor penetration into the tumor interior, while the incorporation of DSPE-PEG2000-PVGLIG-PEG5000helps conceal DSPE-PEG2000-HA, reducing off-target effects and prolonging drug circulation timein vivo. Bothin vitroandin vivoexperiments demonstrated that these micelles effectively inhibit proliferation, invasion, and metastasis of OC cells while promoting apoptosis. Therefore, our findings suggest that PP-HA-DTX/BAK micelles represent a safe and effective therapeutic strategy for treating OC.
Assuntos
Docetaxel , Micelas , Invasividade Neoplásica , Neoplasias Ovarianas , Fenóis , Polietilenoglicóis , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Polietilenoglicóis/química , Fenóis/química , Fenóis/farmacologia , Camundongos , Apoptose/efeitos dos fármacos , Ácido Hialurônico/química , Taxoides/química , Taxoides/farmacologia , Taxoides/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Camundongos Nus , Tamanho da Partícula , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Portadores de Fármacos/químicaRESUMO
Purpose: Docetaxel (DTX) is a valuable anti-tumor chemotherapy drug with limited oral bioavailability. This study aims to develop an effective oral delivery system for DTX using natural nanoparticles (Nnps) derived from Coptidis Rhizoma extract. Methods: DTX-loaded self-assembled nanoparticles (Nnps-DTX) were created using an optimized heat-induction strategy. Nnps-DTX's shape, size, Zeta potential, and in vitro stability were all carefully examined. Additionally, the study investigated the encapsulation efficiency, loading capacity, crystal form, and intermolecular interactions of DTX in Nnps-DTX. Subsequently, the solubility, release, cellular uptake, metabolic stability, and preclinical pharmacokinetics of DTX in Nnps-DTX were systematically evaluated. Finally, the cytotoxicity of Nnps-DTX was assessed in three tumor cell lines. Results: Nnps-DTX was spherical in shape, 138.6 ± 8.2 nm in size, with a Zeta potential of -20.8 ± 0.6 mV, a DTX encapsulation efficiency of 77.6 ± 8.5%, and a DTX loading capacity of 6.8 ± 1.9%. Hydrogen bonds, hydrophobic interactions, and electrostatic interactions were involved in the formation of Nnps-DTX. DTX within Nnps-DTX was in an amorphous form, resulting in enhanced solubility (23.3 times) and release compared to free DTX. Following oral treatment, the mice in the Nnps-DTX group had DTX peak concentrations 8.8, 23.4, 44.6, and 5.7 times higher in their portal vein, systemic circulation, liver, and lungs than the mice in the DTX group. Experiments performed in Caco-2 cells demonstrated a significant increase in DTX uptake by Nnps-DTX compared to free DTX, which was significantly inhibited by indomethacin, an inhibitor of caveolae-mediated endocytosis. Furthermore, compared to DTX, DTX in Nnps-DTX demonstrated better metabolic stability in liver microsomes. Notably, Nnps-DTX significantly reduced the viability of MCF-7, HCT116, and HepG2 cells. Conclusion: The novel self-assembled nanoparticles considerably enhanced the cellular absorption, solubility, release, metabolic stability, and pharmacokinetics of oral DTX and demonstrated strong cytotoxicity against tumor cell lines.
Assuntos
Docetaxel , Nanopartículas , Animais , Docetaxel/farmacocinética , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Humanos , Administração Oral , Nanopartículas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Camundongos , Linhagem Celular Tumoral , Coptis chinensis , Tamanho da Partícula , Masculino , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Disponibilidade Biológica , Solubilidade , Ratos Sprague-Dawley , Camundongos Endogâmicos BALB CRESUMO
Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond.
Assuntos
Antineoplásicos , Docetaxel , Neoplasias Pulmonares , Fator 2 Relacionado a NF-E2 , Pró-Fármacos , Espécies Reativas de Oxigênio , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Humanos , Animais , Pró-Fármacos/uso terapêutico , Pró-Fármacos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Docetaxel/farmacologia , Docetaxel/farmacocinética , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas , Terapia Combinada , Camundongos Nus , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Células A549 , Liberação Controlada de Fármacos , FemininoRESUMO
Herein, we reported novel docetaxel-decorated solid lipid nanoparticle (DCT-SLN)-loaded dual thermoreversible system (DCT-DRTS) for intramuscular administration with reduced burst effect, sustained release and improved antitumor efficacy. The optimized DCT-DRTs was subjected to in-vitro and in-vivo analyses. Antitumor evaluation of the DCT-DRTS was executed and compared with DCT-hydrogel, and DCT-suspension trailed by the histopathological and immune-histochemical analyses. The DCT-SLN gave a mean particle size of 157 nm and entrapment efficiency of 93 %. It was a solid at room temperature, and changed to liquid at physiological temperature due to its melting point of about 32 °C. Unlikely, poloxamer mixture remained liquefied at 25-27 °C, however converted to gel at physiological temperature. This behavior demonstrated opposed reversible property of the DCT-SLN and poloxamer hydrogel in DCT-DRTS system, making it ideal for intramuscular administration and quick gelation inside the body. The DCT-DRTS sustained the drugs release and unlike DCT-hydrogel, the preliminary plasma concentration of DCT-DRTS was significantly reduced, overcoming the burst release. A meaningfully enhanced antitumor efficacy and improved survival rate was observed from DCT-DRTS in tumor cell xenograft athymic nude mice. Additionally, increased apoptotic and reduced proliferation markers were observed in DCT-DRTS treated tumor masses. It was concluded that DCT-DRTS may be a suitable choice for intramuscular administration of DCT with sustained release, improved bioavailability, reduced toxicity and enhanced antitumor effects.
Assuntos
Antineoplásicos , Preparações de Ação Retardada , Docetaxel , Hidrogéis , Nanopartículas , Animais , Hidrogéis/química , Hidrogéis/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Humanos , Injeções Intramusculares , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Nanopartículas/química , Nanopartículas/administração & dosagem , Preparações de Ação Retardada/química , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Temperatura , Camundongos Nus , Poloxâmero/química , Camundongos , Sistemas de Liberação de Medicamentos , Feminino , Lipídeos/química , Lipídeos/administração & dosagem , Masculino , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Taxoides/administração & dosagem , Taxoides/farmacocinética , Taxoides/química , LipossomosRESUMO
BACKGROUND/AIM: The COVID-19 pandemic brought many challenges in healthcare systems globally. Pegylated granulocyte colony stimulating factor (PEG-GCSF) is recommended to reduce febrile neutropenia (FN), however there are a few reports that G-CSF might worsen COVID-19 disease, and its appropriate use during the COVID-19 pandemic remains uncertain. This retrospective study aimed to analyze the association between PEG-GCSF use and COVID-19 infection and severity. PATIENTS AND METHODS: Breast cancer patients who received chemotherapy at the Nagoya Tokushukai General Hospital between October 2020 and April 2023 were included. Patients with suspected COVID-19 symptoms during each chemotherapy cycle underwent COVID-19 antigen testing. To assess the potential impact of PEG-GCSF on COVID-19 severity, we collected data on patient background, chemotherapy regimens, PEG-GCSF use, COVID-19 antigen tests, and COVID-19 infection from their medical records. RESULTS: Thirty patients received chemotherapy. In total, 71 cycles were administered comprising adriamycin and cyclophosphamide (AC; 37 cycles), docetaxel (DTX; 26 cycles) and docetaxel and cyclophosphamide (TC; eight cycles). Among those patients, suspected COVID-19 symptoms were observed in only one of 62 cycles of the three regimens (1.6%) with PEG-GCSF compared to two of nine cycles (22.2%) without PEG-GCSF (p=0.0405). However, because none developed COVID-19 infection during chemotherapy, we could not assess COVID-19 severity and PEG-GCSF use. CONCLUSION: A potential role of PEG-GCSF in reducing suspected COVID-19 symptoms during chemotherapy, reducing the anxiety and need for hospital visits, thus improving patients' quality of life, is suggested. These insights could contribute to optimizing the care of breast cancer patients in situations like the current pandemic.
Assuntos
Neoplasias da Mama , COVID-19 , Fator Estimulador de Colônias de Granulócitos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/química , Pandemias , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/química , Estudos Retrospectivos , SARS-CoV-2RESUMO
Docetaxel (DTX) is a recommended treatment in patients with metastasic prostate cancer (PCa), despite its therapeutic efficacy is limited by strong systemic toxicity. However, in localized PCa, intratumoral (IT) administration of DTX could be an alternative to consider that may help to overcome the disadvantages of conventional intravenous (IV) therapy. In this context, we here present the first in vivo preclinical study of PCa therapy with nanomedicines of mesoporous silica nanoparticles (MSN) and DTX by IT injection over a xenograft mouse model bearing human prostate adenocarcinoma tumors. The efficacy and tolerability, the biodistribution and the histopathology after therapy have been investigated for the DTX nanomedicine and the free drug, and compared with the IV administration of DTX. The obtained results demonstrate that IT injection of DTX and DTX nanomedicines allows precise and selective therapy of non-metastatic PCa and minimize systemic diffusion of the drug, showing superior activity than IV route. This allows reducing the therapeutic dose by one order and widens substantially the therapeutic window for this drug. Furthermore, the use of DTX nanomedicines as IT injection promotes strong antitumor efficacy and drug accumulation at the tumor site, improving the results obtained with the free drug by the same route.
Assuntos
Antineoplásicos , Docetaxel , Nanopartículas , Neoplasias da Próstata , Dióxido de Silício , Ensaios Antitumorais Modelo de Xenoenxerto , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Animais , Dióxido de Silício/química , Dióxido de Silício/administração & dosagem , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Nanopartículas/administração & dosagem , Nanopartículas/química , Distribuição Tecidual , Linhagem Celular Tumoral , Camundongos , Nanomedicina/métodos , Injeções Intralesionais , Camundongos Nus , Porosidade , Portadores de Fármacos/química , Portadores de Fármacos/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologiaRESUMO
BACKGROUND/AIM: In patients with metastatic castration-sensitive prostate cancer (mCSPC), upfront treatment intensification with the addition of new hormonal agents and/or docetaxel to androgen deprivation therapy (ADT) is recommended. However, this modality is potentially excessive in a subset of these patients. This study aimed to identify patients who may be eligible to omit upfront treatment intensification. PATIENTS AND METHODS: Patients with mCSPC who underwent ADT were enrolled. The association between undetectable prostate-specific antigen (PSA) (<0.2 ng/ml) after ADT initiation and overall or castration-resistance-free survival was evaluated. RESULTS: Ninety-seven out of the 242 enrolled patients had low-risk and/or low-volume cancer and were further analyzed. Of these, 45 (46.4%) patients achieved undetectable PSA. The median follow-up period after ADT initiation was 70 months. The median overall survival among patients with undetectable PSA was quite long, reaching 226 months and significantly longer than that among patients with detectable PSA [71 months, hazard ratio (HR)=0.27, 95% confidence interval (CI)=0.15-0.49, p<0.001]. Time to development of castration-resistance was also long and significantly longer in the undetectable PSA group than that in the detectable PSA group (median: 124 vs. 17 months, HR=0.20, 95% CI=0.12-0.34, p<0.001). CONCLUSION: Patients with low-risk and/or low-volume mCSPC showed long-term survival when undetectable PSA was achieved during conventional ADT. In these patients, skipping upfront treatment intensification does not seem to negatively impact survival.
Assuntos
Antagonistas de Androgênios , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Idoso , Antígeno Prostático Específico/sangue , Pessoa de Meia-Idade , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Androgênios/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Resultado do Tratamento , Metástase Neoplásica , Idoso de 80 Anos ou mais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/mortalidade , Docetaxel/administração & dosagem , Docetaxel/uso terapêuticoRESUMO
INTRODUCTION: Docetaxel plus ramucirumab (DTX + RAM) therapy is a standard treatment for previously treated lung cancer, but many adverse events have been reported. This retrospective study was conducted to examine if the side effects of DTX + RAM therapy can be minimized by the combined use of oral dexamethasone (DEX), and to assess the therapeutic effect of DTX + RAM in patients with recurrent lung cancer. METHODS: Forty patients with relapsed non-small cell lung cancer who underwent DTX + RAM therapy were divided into two groups based on the concomitant use of oral DEX, and the therapeutic effects and toxicities in the two groups were compared. RESULTS: The objective response rate (ORR) was significantly better in the DEX group (P = 0.0203). The median progression-free survival (PFS) was 5.20 months vs 2.87 months (P = 0.064) in the DEX and non-DEX groups, respectively. However, the median overall survival (OS) was significantly better in the DEX group (15.17 months vs 7.37 months, P = 0.0317). The frequency of fluid retention within six months of the start of treatment was 10.0% vs 42.5% in the DEX and non-DEX groups, respectively, with the fluid retention rate being significantly higher in the non-DEX group (P = 0.039).Conclusion: Concomitant use of oral DEX during DTX + RAM therapy may facilitate the long-term continuation of treatment and contribute to OS prolongation.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Dexametasona , Docetaxel , Neoplasias Pulmonares , Ramucirumab , Humanos , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Masculino , Feminino , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Estudos Retrospectivos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Adulto , Administração Oral , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do TratamentoRESUMO
INTRODUCTION: Radiation recall reaction (RRR) is a rare inflammatory reaction developing in a previously irradiated field after a triggering agent. In pediatric patients, it is poorly understood and deficiently studied. Gemcitabine-docetaxel (G/D) in childhood cancer is mainly used as a salvage regimen for sarcomas. We aim to describe RRR triggered by G/D in children. PATIENTS AND METHODS: Retrospective review of 21 patients receiving G/D along with radiotherapy at two hospitals from 2010 until 2022. RRR was considered as any toxicity occurring after G/D administration in a previously irradiated field. RRR features were described. Fisher's and Mann-Whitney tests were utilized to analyze the risk factors involved. RESULTS: Sixteen episodes of RRR developed in 16 (76.2%) patients. RRR mainly involved deep layers of the skin (58%) and occurred predominantly after two G/D cycles. The mean time between radiotherapy and chemotherapy was 28.5 days (0-1359 days), and the mean radiation volume 391 mL (157-1810 mL) for RRR. RRR treatment was mainly systemic steroids, with partial responses in six of 11 (58%) patients. Re-exposure to G/D was associated with a high rate of recurrence in nine of 15 (56.2%), prompting drug discontinuation. The major risk factors for RRR after G/D include, without statistical significance, a larger volume of the irradiated field and a shorter interval between chemotherapy and radiotherapy. CONCLUSIONS: The incidence of RRR after G/D in the pediatric population is higher than previously reported. Drug re-exposure is usually followed by recurrence. Higher irradiated volumes and a shorter time to the start of chemotherapy could be related with an increased risk of RRR.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Docetaxel , Gencitabina , Humanos , Estudos Retrospectivos , Masculino , Feminino , Criança , Desoxicitidina/análogos & derivados , Desoxicitidina/efeitos adversos , Docetaxel/efeitos adversos , Docetaxel/administração & dosagem , Adolescente , Fatores de Risco , Pré-Escolar , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Seguimentos , Lactente , Radiodermite/etiologia , Radiodermite/patologia , PrognósticoRESUMO
BACKGROUND: Based on the JCOG1109 trial, it is suggested that the combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) could potentially become a standard neoadjuvant chemotherapy regimen, alongside the conventional 5-fluorouracil and cisplatin (CF) therapy, for esophageal cancer. However, there are few reports on the impact of body composition changes associated with neoadjuvant chemotherapy on prognosis. AIM: Our study aimed to explore the effect of different neoadjuvant chemotherapy regimens on body composition during treatment and the impacts of body composition changes on their prognosis. METHODS AND RESULTS: This is a retrospective study of 215 patients with advanced thoracic esophageal cancer who had surgery after neoadjuvant chemotherapy from 2013 to 2019. Computed tomography scans were performed before and after neoadjuvant chemotherapy to assess body composition. Skeletal muscle mass index (SMI) was calculated by dividing total skeletal muscle mass at the 3rd lumbar level by the square of height, while visceral and subcutaneous fat masses were measured at the level of umbilicus. Patients in the lowest 25% of both sexes were classified into the low visceral fat and low subcutaneous fat groups, respectively. Of the patients enrolled, 178 were male and 37 were female. Among them, 91 had clinical Stage II disease, and 124 had clinical Stage III disease. Additionally, 146 patients received neoadjuvant chemotherapy CF, and 69 received neoadjuvant chemotherapy DCF. Comparing the DCF and CF groups, the DCF group consisted of significantly younger patients (p < .01), a higher proportion of males (p = .03), and a greater number of clinical Stage III cases (p < .01). However, although percent change in SMI and visceral fat mass was not significantly different between two regimens, percent change in subcutaneous fat mass was significant in the DCF group. The major prognostic factors for patients undergoing surgery after neoadjuvant chemotherapy for thoracic esophageal cancer were clinical Stage III, transition to low visceral fat, and response rating (SD/PD), while the specific neoadjuvant chemotherapy regimen did not significantly influence the outcomes. CONCLUSION: This study suggests that prevention of the shift to low visceral fat throughout the neoadjuvant chemotherapy process should improve patient outcomes.