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
OBJECTIVES: The high costs of cancer care can cause significant harm to patients and society. Prostate cancer, the leading nonskin malignancy in men, is responsible for the second-highest out-of-pocket (OOP) payments among all malignancies. Multiple first-line treatment options exist for metastatic castration-resistant prostate cancer (mCRPC); although their costs vary substantially, comparative effectiveness data are limited. There is little evidence of how gross payments made by insurers and OOP payments made by patients differ by treatment and health plan type and how these payment differences relate to utilization. STUDY DESIGN: Retrospective cohort study. METHODS: We used IBM MarketScan databases from 2013-2019 to identify men with prostate cancer who initiated treatment with 1 of 6 drugs approved for first-line treatment of mCRPC. We calculated and compared gross and OOP payments and drug utilization across drug and insurance plan types. RESULTS: We identified 4298 patients who met our inclusion criteria. Insurer payments varied substantially by first-line therapy but were similar across different health plan types, except for docetaxel. OOP payments for a given first-line therapy, in contrast, varied by health plan type. Utilization of first-line therapies varied by plan type in unadjusted analyses, but not after adjusting for patient characteristics. CONCLUSIONS: The extent to which patient OOP payments for drugs reflect differences in gross payments made by insurers varies across health insurance plan types. However, even though OOP payments for the same treatment differ across plan types, treatment choice is not significantly different across type of health insurance after controlling for patient characteristics.
Assuntos
Gastos em Saúde , Seguro Saúde , Humanos , Masculino , Estudos Retrospectivos , Idoso , Gastos em Saúde/estatística & dados numéricos , Estados Unidos , Seguro Saúde/economia , Seguro Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/economia , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/economia , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Docetaxel/uso terapêutico , Docetaxel/economiaRESUMO
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: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI. METHODS: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan-Meier method. RESULTS: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel (p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively. CONCLUSIONS: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC.
Assuntos
Docetaxel , Neoplasias de Próstata Resistentes à Castração , Taxoides , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Docetaxel/uso terapêutico , Taxoides/uso terapêutico , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Resultado do Tratamento , Metástase Neoplásica , Antineoplásicos/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
Docetaxel is a commonly used taxane chemotherapeutic agent in the treatment of a variety of cancers, including breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer. Docetaxel exerts its anti-cancer effects through inhibition of the cell cycle and induction of proapoptotic activity. However, docetaxel also impacts rapidly proliferating normal cells in the scalp hair follicles (HFs), rendering the HFs vulnerable to docetaxel-induced cell death and leading to chemotherapy-induced alopecia (CIA). In severe cases, docetaxel causes persistent or permanent CIA (pCIA) when hair does not grow back completely six months after chemotherapy cessation. Hair loss has severe negative impacts on patients' quality of life and may even compromise their compliance with treatment. This review discusses the notable prevalence of docetaxel-induced CIA and pCIA, as well as their prevention and management. At this moment, scalp cooling is the standard of care to prevent CIA. Treatment options to promote hair regrowth include but are not limited to minoxidil, photobiomodulation (PBMT), and platelet-rich plasma (PRP). In addition, a handful of current clinical trials are exploring additional agents to treat or prevent CIA. Research models of CIA, particularly ex vivo human scalp HF organ culture and in vivo mouse models with human scalp xenografts, will help expedite the translation of bench findings of CIA prevention and/or amelioration to the clinic.
Assuntos
Alopecia , Antineoplásicos , Docetaxel , Alopecia/induzido quimicamente , Alopecia/prevenção & controle , Humanos , Docetaxel/uso terapêutico , Antineoplásicos/efeitos adversos , Prevalência , Neoplasias/tratamento farmacológico , Animais , Taxoides/efeitos adversos , Taxoides/uso terapêuticoRESUMO
BACKGROUND: QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. MATERIALS AND METHODS: This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab). RESULTS: Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups. CONCLUSION: QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Medicamentos Biossimilares , Neoplasias da Mama , Docetaxel , Receptor ErbB-2 , Trastuzumab , Humanos , Trastuzumab/uso terapêutico , Trastuzumab/farmacologia , Docetaxel/uso terapêutico , Docetaxel/farmacologia , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Método Duplo-Cego , Adulto , Medicamentos Biossimilares/uso terapêutico , Medicamentos Biossimilares/farmacologia , Medicamentos Biossimilares/administração & dosagem , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , IdosoRESUMO
Docetaxel is commonly used for treatment of castration-resistant prostate cancer. Unfortunately, many prostate cancer patients develop resistance to docetaxel. Clinical markers less invasive than biopsies, such as blood samples, would be ideal for monitoring and predicting patient treatment outcomes to docetaxel. Lipid alterations are often associated with the progression of many cancers, including prostate cancer. This study investigated the use of lipids from whole blood as clinical markers for docetaxel resistance in a small cohort of patients with prostate cancer. Qualitative lipidomics was performed by liquid chromatography-tandem mass spectrometry to assess the lipid composition of prostate cancer cells exposed to docetaxel as well as whole blood from prostate cancer patients before, during and after docetaxel treatment. Three patients had castration resistant prostate cancer, three had castration sensitive prostate cancer, and four had de novo prostate cancer during the extent of the study. Mean decrease accuracy and classical univariate receiving operating characteristic curve analyses were performed to identify potential biomarkers. In total, 245 and 221 altered lipids were identified from a second stage of mass spectrometry analysis of prostate cancer cells and clinical blood samples, respectively. Both models indicated that docetaxel treatment altered ether-linked phosphatidylcholines, lysophosphatidylcholine, diacylglycerols, ceramides, hexosylceramides, and sphingomyelins. The results also indicated several lipid changes were associated with sphingolipid signaling and metabolism, and glycerophospholipid metabolism. Collectively, these data suggest the potential usage of identified lipid species as indicators of docetaxel resistance in prostate cancer.
Assuntos
Biomarcadores Tumorais , Docetaxel , Lipidômica , Lipídeos , Neoplasias da Próstata , Humanos , Masculino , Docetaxel/uso terapêutico , Docetaxel/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Lipidômica/métodos , Biomarcadores Tumorais/sangue , Lipídeos/sangue , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Linhagem Celular Tumoral , Espectrometria de Massas em TandemRESUMO
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
Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often accompanies prostate cancer progression. Attempts to overcome resistance to docetaxel by combining docetaxel with other biological agents have been mostly unsuccessful. A better understanding of the mechanisms underlying docetaxel resistance may provide new avenues for the treatment of advanced PCa. We have previously found that the fatty acid-binding protein 12 (FABP12)-PPARγ pathway modulates lipid-related bioenergetics and PCa metastatic transformation through induction of Slug, a master driver of epithelial-to-mesenchymal transition (EMT). Here, we report that the FABP12-Slug axis also underlies chemoresistance in PCa cells. Cell sensitivity to docetaxel is markedly suppressed in FABP12-expressing cells, along with induction of Survivin, a typical apoptosis inhibitor, and inhibition of cleaved PARP, a hallmark of programmed cell death. Importantly, Slug depletion down-regulates Survivin and restores cell sensitivity to docetaxel in FABP12-expressing cells. Finally, we also show that high levels of Survivin are associated with poor prognosis in PCa patients, with FABP12 status determining its prognostic significance. Our research identifies a FABP12-Slug-Survivin pathway driving docetaxel resistance in PCa cells, suggesting that targeting FABP12 may be a precision approach to improve chemodrug efficacy and curb metastatic progression in PCa.
Assuntos
Docetaxel , Proteínas de Ligação a Ácido Graxo , Neoplasias da Próstata , Fatores de Transcrição da Família Snail , Survivina , Humanos , Masculino , Docetaxel/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Survivina/metabolismo , Survivina/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição da Família Snail/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Morte Celular/efeitos dos fármacosRESUMO
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
BACKGROUND/AIM: Lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) accounts for the majority of non-small cell lung cancer (NSCLC), and overexpression of programmed death ligand 1 (PD-L1) in these cells is known to induce tumor immune evasion or drug resistance. However, detailed studies are needed to determine whether microRNAs (miRNAs) that reduce PD-L1 expression can suppress drug resistance in NSCLC. MATERIALS AND METHODS: Kaplan Meier plotter and Receiver Operating Characteristic plotter were used to determine the effect of specific miRNAs on survival and chemotherapy response in NSCLC patients. Cell viability, colony formation and invasion assays, and qPCR analyses were also performed. RESULTS: The expression of miRNA-140-3p (miR-140-3p) was lower in LUAD patients, compared to the normal group, and low expression of miR-140-3p was associated with poor survival of LUAD patients, but not in LUSC. The miR-140-3p mimic inhibited proliferation, colony formation, and invasion of LUAD cells. Interestingly, the expression of miR-140-3p was significantly lower in the group of LUAD patients who did not respond to docetaxel. In LUAD cells, combined treatment with miR-140-3p and docetaxel significantly reduced cell viability as well as the expression of ABCG2 and MVP, genes associated with drug resistance, compared to either treatment alone. Additionally, combined injection of miR-140-3p mimic and docetaxel significantly inhibited tumor growth compared to treatment with docetaxel alone. CONCLUSION: These results suggest that the high expression of miR-140-3p in LUAD is correlated with good patient prognosis and may contribute to the treatment of LUAD, especially by increasing responsiveness to docetaxel.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Adenocarcinoma de Pulmão , Antígeno B7-H1 , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , Proteínas de Neoplasias , Humanos , Docetaxel/farmacologia , MicroRNAs/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Masculino , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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
The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.
Assuntos
Plaquetas , Docetaxel , Micelas , Nanopartículas , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Animais , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Nanopartículas/química , Camundongos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Camundongos Endogâmicos BALB C , Humanos , Feminino , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismoRESUMO
BACKGROUND: Anthracycline-taxane is the standard chemotherapy strategy for treating high-risk early breast cancer despite the potentially life-threatening adverse events caused by anthracyclines. Commonly, the combination of docetaxel and cyclophosphamide (TC) is considered an alternative option. However, the efficacy of TC compared to anthracycline-taxane chemotherapy is unclear. This study compares disease-free survival (DFS), overall survival (OS) and cardiotoxicity between adjuvant TC and anthracycline-taxane for stages I-III, HER2-negative breast cancer. METHODS: A systematic search on MEDLINE, Embase and Cochrane CENTRAL for randomized-controlled trials published until 11 March 2024, yielded 203 studies with 11,803 patients, and seven trials were included. RESULTS: TC results in little to no difference in DFS (HR 1.09, 95% CI 0.98-1.20; moderate-certainty of evidence); OS (1.02, 95% CI 0.89-1.16; high-certainty of evidence); and cardiotoxicity (RR 0.54, 95% CI 0.16-1.76; high-certainty of evidence), compared to anthracycline-taxane. In the subgroup analysis, patients with ≥4 lymph nodes had improved DFS from anthracycline-taxane over TC. CONCLUSIONS: Overall, there was no difference between TC and anthracycline-taxane in DFS, OS and cardiotoxicity. In women with ≥4 nodes, anthracycline-taxane was associated with a substantial reduction in relapse events, compared to TC. Our study supports the current standard of practice, which is to use anthracycline-taxane and TC chemotherapy as a reasonable option in select cases.
Assuntos
Antraciclinas , Neoplasias da Mama , Humanos , Neoplasias da Mama/tratamento farmacológico , Feminino , Antraciclinas/uso terapêutico , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Taxoides/uso terapêutico , Docetaxel/uso terapêuticoRESUMO
Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.