Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 13.511
Filtrar
1.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445466

RESUMO

To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core-shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core-shell microparticles were of spherical appearance, with an average size of 14.65 µm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core-shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Microesferas , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Camundongos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Medicine (Baltimore) ; 100(31): e26801, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397833

RESUMO

RATIONALE: At present, the prognosis of patients with giant lung squamous cell carcinoma (LSCC) is poor, and there is no safe and effective treatment for elderly patients with large LSCC. PATIENT CONCERNS: Here, we reported a 77-year-old man admitted to the hospital with cough for 3 months and significant chest pain. Computed tomography (CT) imaging showed a large mass in the left lung with pleural effusion. DIAGNOSES: Chest CT scan revealed a 12.5 cm × 7.3 cm mass in the left upper lobe adjacent to the pulmonary vein, with left pleural effusion. Pulmonary tumor markers were significantly elevated, and CT-guided percutaneous lung mass biopsy specimens showed LSCC. INTERVENTIONS: After diagnosis, the patient was treated with sintilimab combined with endostar and nab-paclitaxel. After 2 cycles of treatment, the lung mass in the patient shrank rapidly and the clinical symptoms were relieved. OUTCOMES: The patient's tumor dramatically shrank, and the pleural effusion was decreased after 4 cycles of treatment without any adverse effects. Meanwhile, the high-level tumor marker resumed normal. LESSONS: Sintilimab combined with endostar and nab-paclitaxel may be a good treatment option for lung squamous cell cancer, especially for that in elderly patients.


Assuntos
Albuminas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma de Células Escamosas , Endostatinas/administração & dosagem , Neoplasias Pulmonares , Paclitaxel/administração & dosagem , Derrame Pleural , Proteínas Recombinantes/administração & dosagem , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biópsia/métodos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Estadiamento de Neoplasias , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/etiologia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Carga Tumoral
3.
Medicine (Baltimore) ; 100(32): e26845, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397891

RESUMO

RATIONALE: Despite the development of human papillomavirus vaccines and significant improvement in cervical cancer screening over the past few years, cervical cancer remains the fourth most common cancer in women of childbearing age after breast cancer, melanoma, and thyroid cancer. PATIENT CONCERNS: In this case report, the patients are all cervical cancer with stage IB2 and IB3 during pregnancy, the management constitutes a major medical challenge related to the impact of treatment on both maternal and fetal outcomes. Neoadjuvant chemotherapy (NACT) is an innovative option for cervical cancer patients with stage IB2 and IB3 before cesarean delivery and radical hysterectomy, and many chemotherapeutic agents are available, cisplatin plus paclitaxel yielded good maternal and fetal outcomes to the authors' knowledge. DIAGNOSES: Masses were discovered in the cervix of 4 pregnant women with a history of vaginal bleeding. Biopsy examination of the masses revealed cervical carcinoma, which was staged in accordance with the International Federation of Gynecology and Obstetrics (i.e., FIGO) system. INTERVENTIONS: The patients were treated with paclitaxel plus cisplatin, followed by cesarean delivery and radical hysterectomy. OUTCOMES: The 4 patients were treated successfully, with no recurrence during follow-up periods of 14 to 56 months, and all of the children were doing well with no anomalies. LESSONS: Although further data are required, in pregnant women with invasive cervical cancer, NACT with cisplatin plus paclitaxel followed by cesarean delivery and radical hysterectomy was a practical treatment option.


Assuntos
Cisplatino , Histerectomia/métodos , Paclitaxel , Complicações Neoplásicas na Gravidez , Neoplasias do Colo do Útero , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biópsia/métodos , Colo do Útero/patologia , Cesárea/métodos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Humanos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Complicações Neoplásicas na Gravidez/patologia , Complicações Neoplásicas na Gravidez/cirurgia , Resultado da Gravidez , Resultado do Tratamento , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia
4.
Biomed Pharmacother ; 139: 111716, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243618

RESUMO

Despite the advances in targeted therapies and immunotherapy for non-small cell lung cancer (NSCLC) patients, the intravenous administration of carboplatin (CARB) and paclitaxel (PTX) in well-spaced cycles is widely indicated for the treatment of NSCLC from stage II to stage IV. Our strategy was to add a controlled-release cisplatin-based dry-powder for inhalation (CIS-DPI-ET) to the conventional CARB-PTX-IV doublet, administered during the treatment off-cycles to intensify the therapeutic response while avoiding the impairment of pulmonary, renal and haematological tolerance of these combinations. The co-administration of CIS-DPI-ET (0.5 mg/kg) and CARB-PTX-IV (17-10 mg/kg) the same day showed a higher proportion of neutrophils in BALF (35 ± 7% vs 1.3 ± 0.8%), with earlier regenerative anaemia than with CARB-PTX-IV alone. A first strategy of CARB-PTX-IV dose reduction by 25% also induced neutrophil recruitment, but in a lower proportion than with the first combination (20 ± 6% vs 0.3 ± 0.3%) and avoiding regenerative anaemia. A second strategy of delaying CIS-DPI-ET and CARB-PTX-IV administrations by 24 h avoided both the recruitment of neutrophils in BALF and regenerative anaemia. Moreover, all these groups showed higher cytotoxicity (LDH activity, protein content) with no higher renal toxicities. These two strategies seem interesting to be assessed in terms of antitumor efficacy in mice.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Pós/administração & dosagem , Administração por Inalação , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
5.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208987

RESUMO

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Tinzaparina/administração & dosagem , Albuminas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Paclitaxel/farmacologia , Neoplasias Pancreáticas/metabolismo , Tinzaparina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299028

RESUMO

Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antipsicóticos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Sinergismo Farmacológico , Apoptose , Neoplasias da Mama/patologia , Proliferação de Células , Neoplasias do Colo/patologia , Quimioterapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas
7.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206347

RESUMO

In this study, an amphiphilic conjugate based on mPEG and cholesterol-modified chitosan with hydrazone bonds in the molecules (mPEG-CS-Hz-CH) was successfully synthesized. Using the polymer as the carrier, the paclitaxel (PTX)-loaded mPEG-CS-Hz-CH micelles were prepared by an ultrasonic probe method. The mean particle size and zeta potential of the optimized PTX-loaded micelles were 146 ± 4 nm and +21.7 ± 0.7 mV, respectively. An in vitro drug release study indicated that the PTX-loaded mPEG-CS-Hz-CH micelles were stable under normal physiological conditions (pH 7.4), whereas rapid drug release was observed in the simulated tumor intracellular microenvironment (pH 5.0). An in vitro cytotoxicity study demonstrated the non-toxicity of the polymer itself, and the PTX-loaded micelles exhibited superior cytotoxicity and significant selectivity on tumor cells. An in vivo antitumor efficacy study further confirmed that the PTX-loaded micelles could improve the therapeutic efficacy of PTX and reduce the side effects. All these results suggested that the mPEG-CS-Hz-CH micelles might be promising pH-sensitive nanocarriers for PTX delivery.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Micelas , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Células MCF-7 , Paclitaxel/uso terapêutico , Tamanho da Partícula , Polímeros
8.
Medicine (Baltimore) ; 100(25): e26342, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160399

RESUMO

OBJECTIVE: To evaluate the therapeutic efficacy and safety of S1 monotherapy or combination with nab-paclitaxel for the treatment of elderly patients with metastatic or locally advanced pancreatic adenocarcinoma. METHOD: PubMed, Embase, Cochrane Central Library, China Biology Medicine, and China National Knowledge Infrastructure databases were searched without time limits according to the inclusion criteria. RevMan (Version 5.3) software was used for data extraction and meta-analysis. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate therapeutic effects while side effects including leukopenia, thrombocytopenia, neurotoxicity, vomit, and alopecia were extracted for evaluation. There was no need for ethical review in this study because no ethical experiments were conducted and all data used were public data. All relevant data are within the paper and its Supporting Information files. RESULTS: Four retrospective studies comprising 308 elderly patients with metastatic or locally advanced pancreatic adenocarcinoma were included in the analysis. One hundred fifty-one patients underwent S1 monotherapy and 157 received S1 combined nab-paclitaxel. Meta-analysis indicated that compared with S1 monotherapy, S1 combined with nab-paclitaxel had higher ORR (OR 2.25, 95% CI: 1.42-3.55; P = .0005) and DCR (OR 2.94, 95% CI: 1.55-5.58; P = .0009). The adverse reaction of leukopenia was higher in the combined therapy group (OR 1.85, 95% CI: 1.09-3.13, P = .02), but no significant difference was found in thrombocytopenia, neurotoxicity, vomiting, and alopecia between the 2 groups (P > .05). CONCLUSION: Nab-paclitaxel plus S1 was more efficient in terms of ORR and DCR than S1 monotherapy in elderly pancreatic ductal adenocarcinoma patients while the side effect was controllable with a higher probability of leukopenia. Thus, combined nab-paclitaxel and S1 could be safely used in elderly patients.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Leucopenia/epidemiologia , Ácido Oxônico/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Combinação de Medicamentos , Humanos , Leucopenia/induzido quimicamente , Estadiamento de Neoplasias , Ácido Oxônico/efeitos adversos , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Tegafur/efeitos adversos
9.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069042

RESUMO

OBJECTIVES: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. METHODS: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. RESULTS: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. CONCLUSION: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Granulócitos/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Morfolinas/administração & dosagem , Paclitaxel/administração & dosagem , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinas/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Tiazóis/administração & dosagem , Resultado do Tratamento , Triazinas/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Expert Opin Drug Metab Toxicol ; 17(7): 785-801, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34128748

RESUMO

Introduction: Paclitaxel is a microtubule stabilizer that is currently one of the most utilized chemotherapeutic agents. Its efficacy in breast, uterine, lung and other neoplasms made its safety profile enhancement a subject of great interest. Neurotoxicity is the most common paclitaxel-associated toxicities. In addition, hypersensitivity reactions, hematological, gastrointestinal, and cardiac toxicities are all encountered.Areas covered: The current review explores paclitaxel-induced toxicities mechanisms and risk factors. Studies investigating these toxicities pharmacogenomic biomarkers are reviewed and summarized. There is a limited margin of consistency between the retrieved associations. Variants in genes related to neuro-sensitivity are the most promising candidates for future studies.Expert opinion: Genome-wide association studies highlighted multiple-candidate biomarkers relevant to neuro-sensitivity. Most of the identified paclitaxel-neurotoxicity candidate genes are derived from congenital neuropathy and diabetic-induced neurotoxicity pathways. Future studies should explore these sets of genes while considering the multifactorial nature of paclitaxel-induced neurotoxicity. In the absence of certain paclitaxel-toxicity biomarkers, future research should avoid earlier studies' caveats. Genes in paclitaxel's pharmacokinetic pathways could not provide consistent results in any of its associated toxicities. There is a need to dig deeper into toxicity-development mechanisms and personal vulnerability factors, rather than targeting only the genes suspected to affect drug exposure.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Paclitaxel/efeitos adversos , Farmacogenética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Biomarcadores/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética
11.
Int J Nanomedicine ; 16: 4087-4104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163161

RESUMO

Background and Purpose: Cisplatin-paclitaxel (TP) combination chemotherapy as the first-line therapy for numerous cancers is hindered by its inadequate accumulation in tumors and severe side effects resulting from non-specific distribution. The aim of this study is to explore whether TMTP1-modified, cisplatin and paclitaxel prodrugs co-loaded nanodrug could improve cervical cancer chemotherapy and relieve its side effects through active and passive tumor targeting accumulation and controlled drug release. Methods: TDNP, with capacities of active targeting for tumors and controlled drug release, was prepared to co-deliver cisplatin and paclitaxel prodrugs. The characteristics were investigated, including the diameter, surface zeta potential, stability and tumor microenvironment (TME) dependent drug release profiles. Cellular uptake, cytotoxicity, drug accumulation in tumors, antitumor effects and safety analysis were evaluated in vitro and in vivo. Results: The oxidized cisplatin and the paclitaxel linked to the polymer achieved a high loading effciency of over 80% and TME-dependent sustained drug release. Moreover, TMTP1 modification enhanced cellular uptake of TDNP and further improved the cytotoxicity of TDNP in vitro. In vivo, TDNP showed an extended blood circulation and increased accumulation in SiHa xenograft models with the aid of TMTP1. More importantly, TDNP controlled tumor growth without life-threatening side effects. Conclusion: Our study provided a novel TP co-delivery platform for targeted chemotherapy of cervical cancer, which was promising to improve the therapeutic effcacy of TP and may also have application in other tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Pró-Fármacos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/metabolismo , Cisplatino/farmacologia , Feminino , Humanos , Paclitaxel/administração & dosagem , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Polímeros/química , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Biochem Pharmacol ; 188: 114587, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33932471

RESUMO

The standard chemotherapy regimens of ovarian cancer are platinum-based chemotherapy (carboplatin and paclitaxel) and bevacizumab (BEV). However, the effects of BEV alone or combined with carboplatin and paclitaxel on mitochondrial dynamics, mitochondrial function, mitophagy, apoptosis, inflammation and vascular endothelial growth factor (VEGF) in human ovarian cancer mitochondria and cells have not yet been investigated. Therefore, we aimed to test the hypothesis that 1) platinum-based chemotherapy and BEV equally damage isolated mitochondria from human ovarian cancers, and ovarian cancer cells through inducing mitochondrial dynamics dysregulation, mitochondrial dysfunction, increased mitophagy and apoptosis, as well as altered inflammation and VEGF; and 2) combined therapies exert greater damage than monotherapy. Each isolated human ovarian cancer mitochondria (n = 16) or CaOV3 cells (n = 6) were treated with either platinum-based chemotherapy (carboplatin 10 µM and paclitaxel 5 µM), BEV (2 mg/mL) or combined platinum-based chemotherapy and BEV for 60 min or 24 h, respectively. Following the treatment, mitochondrial dynamics, mitochondrial function, mitophagy, apoptosis, cytotoxicity, inflammation and VEGF were determined. Platinum-based chemotherapy caused ovarian cancer mitochondria and cell damage through mitochondrial dysfunction, increased cell death with impairment of membrane integrity, and enhanced VEGF reduction, while BEV did not. BEV caused deterioration of ovarian cancer mitochondria and cells through mitochondrial-dependent apoptosis, but it had no effect on cell viability. Interestingly, combined platinum-based chemotherapy and BEV treatments had no addictive effects on all parameters except mitochondrial maximal respiration, when compared to monotherapy. Collectively, these findings suggest that platinum-based chemotherapy and BEV caused human ovarian cancer mitochondrial and cell damage through different mechanisms.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Paclitaxel/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Platina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
13.
J Oncol Pharm Pract ; 27(5): 1245-1247, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34018861

RESUMO

The present analysis was conducted to assess the pharmacological costs of atezolizumab as first-line treatment in triple negative metastatic breast cancer (mBC). Pivotal phase III randomized controlled trial (RCT) was considered. Nine hundred and two patients were included. Differences in costs between the 2 arms (atezolizumab plus nabpaclitaxel versus placebo plus nab-paclitaxel) was 17 398 €, with a cost of 7564 €per month of OS-gain in the overall population and 2485 €per month of OS-gain in PD-L1-positive (≥1) population. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, atezolizumab could be considered cost-effective in first-line treatment for triple-negative mBC only in PD-L1-positive population, but a reduction of costs is mandatory.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Albuminas/administração & dosagem , Antígeno B7-H1 , Análise Custo-Benefício , Humanos , Paclitaxel/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias de Mama Triplo Negativas/patologia
14.
Int J Biol Macromol ; 183: 1270-1282, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34004196

RESUMO

Multidrug resistance (MDR) remains the primary issue leading to the failure of chemotherapy. In this study, a d-α-tocopherol polyethylene 1000 glycol succinate (TPGS) and chondroitin sulfate (CS) dual-modified lipid-albumin nanosystem was constructed for targeted delivery of paclitaxel (PTX) in treating MDR cancer. The obtained nanosystem (TLA/PTX@CS) had an average size of around 176 nm and a negative zeta potential of around -18 mV. TPGS was confirmed to improve the intracellular accumulation of PTX and facilitate the mitochondrial-targeting of lipid-albumin nanosystem. Functionalized with the outer CS shell, TLA/PTX@CS entered MDR breast cancer (MCF-7/MDR) cells via CD44 receptor-mediated endocytosis. CS shell was degraded by concentrated hyaluronidase in the lysosomes, thereby releasing PTX into cytoplasm and inhibiting cell proliferation. In vivo studies revealed that TLA/PTX@CS possessed prolonged blood circulation, resulting in elevated tumor accumulation, excellent antitumor efficacy with a tumor inhibition ratio of 75.3%, and significant survival benefit in MCF-7/MDR tumor-bearing mice. Hence, this TPGS and CS dual-modified lipid-albumin nanosystem provides a promising strategy for targeted delivery of chemotherapeutic drug and reversal of MDR in cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sulfatos de Condroitina/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Paclitaxel/administração & dosagem , Vitamina E/química , Albuminas/química , Animais , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Lipídeos/química , Células MCF-7 , Camundongos , Nanopartículas , Paclitaxel/química , Paclitaxel/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Radiother ; 25(5): 441-446, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33958272

RESUMO

PURPOSE: The aim of this study was to evaluate the efficacy of liposome-paclitaxel and carboplatin combination chemoradiotherapy for patients with locally advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Seventy-nine consecutive patients treated with liposome-paclitaxel based concurrent chemoradiotherapy between January 2015 and December 2019 at Cancer hospital of the University of Chinese Academy of Sciences (Zhejiang cancer hospital) were enrolled in this study. The overall response, toxicities, progression-free survival and overall survival were analyzed with SPSS software. RESULTS: A total of 302 cycles of weekly chemotherapy were delivered, with a median 4 courses. After concurrent chemoradiotherapy (CCRT), the efficacy was classified as CR in 4 cases (5.1%), PR in 22 cases (28.2%) and SD in 51 cases (65.4%). The median PFS and OS time were 18.2 months and 23.4 months. The 3-year PFS and OS rates were 45.1% and 43.6%, respectively. CONCLUSIONS: Liposome-paclitaxel and carboplatin concurrent with radiotherapy is a safe and effective modality for locally advanced ESCC. Further clinical investigation are warranted to evaluate the efficacy of this regimen.


Assuntos
Carboplatina/administração & dosagem , Quimiorradioterapia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/terapia , Paclitaxel/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Lipossomos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada
16.
Anticancer Res ; 41(5): 2597-2603, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952489

RESUMO

BACKGROUND/AIM: Platinum-based chemotherapy with pemetrexed or paclitaxel/bevacizumab are regimens used in combination with checkpoint inhibitors in non-squamous non-small cell lung cancer (NSCLC) treatment. We conducted a real-world study to compare the outcomes of these chemotherapeutic regimens. PATIENTS AND METHODS: We investigated 1,534 patients with advanced non-squamous NSCLC treated with platin/pemetrexed (n=1212) or platin/paclitaxel/bevacizumab (n=322) in 9 cancer centres in the Czech Republic. RESULTS: The regimen containing platin/paclitaxel/bevacizumab showed significantly better overall response rate (ORR) compared to the platin/pemetrexed [40.8% vs. 32.7% (p=0.008)] in the overall population and [55.0% vs. 38.8% (p=0.002)] in the Eastern Cooperative Oncology Group performance status 0 group. There was no significant improvement in progression-free survival (PFS) and overall survival (OS) in either of these two groups of patients. CONCLUSION: In our real-world data analysis, patients treated with platin/paclitaxel/bevacizumab had better overall response rate (ORR), but not PFS or OS. Thus, both treatment regimens are similarly effective. Their selection should therefore be based on the potential side effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Pemetrexede/administração & dosagem , Pemetrexede/efeitos adversos , Intervalo Livre de Progressão
17.
Nat Commun ; 12(1): 3187, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045459

RESUMO

Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form "micro-thrombi" with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of "micro-thrombi", and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Neoplasias Mamárias Experimentais/terapia , Metástase Neoplásica/terapia , Nanomedicina Teranóstica/métodos , Animais , Anti-Inflamatórios/administração & dosagem , Anticoagulantes/administração & dosagem , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/cirurgia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Nanopartículas/química , Células Neoplásicas Circulantes/efeitos dos fármacos , Paclitaxel/administração & dosagem , Estudo de Prova de Conceito , Ratos , Estilbenos/administração & dosagem
18.
Toxicol Appl Pharmacol ; 423: 115576, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000264

RESUMO

Metastatic breast cancer is a prevalent life-threatening disease. Paclitaxel (PTX) is widely used in metastatic breast cancer therapy, but the side effects limit its chemotherapeutic application. Multidrug strategies have recently been used to maximize potency and decrease the toxicity of a particular drug by reducing its dosage. Therefore, we have evaluated the combined anti-cancerous effect of PTX with tested natural compounds (andrographolide (AND), silibinin (SIL), mimosine (MIM) and trans-anethole (TA)) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue dye exclusion assay, proliferating cell nuclear antigen (PCNA) staining, network pharmacology, molecular docking, molecular dynamics (MD) and in vivo chick chorioallantoic membrane (CAM) angiogenesis assay. We observed a reduction in the IC50 value of PTX with tested natural compounds. Further, the network pharmacology-based analysis of compound-disease-target (C-D-T) network showed that PTX, AND, SIL, MIM and TA targeted 55, 61, 56, 31 and 18 proteins of metastatic breast cancer, respectively. Molecular docking results indicated that AND and SIL inhibited the C-D-T network's core target kinase insert domain receptor (KDR) protein more effectively than others. While MD showed that the binding of AND with KDR was stronger and more stable than others. In trypan blue dye exclusion assay and PCNA staining, AND and SIL along with PTX were found to be more effective than PTX alone. CAM assay results suggested that AND, SIL and TA increase the anti-angiogenic potential of PTX. Thus, natural compounds can be used to improve the anti-cancer potential of PTX.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Produtos Biológicos/metabolismo , Neoplasias da Mama/metabolismo , Paclitaxel/metabolismo , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Produtos Biológicos/administração & dosagem , Produtos Biológicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Embrião de Galinha , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Simulação de Acoplamento Molecular/métodos , Paclitaxel/administração & dosagem , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Resultado do Tratamento
19.
Cancer Med ; 10(9): 3045-3058, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811746

RESUMO

BACKGROUND: In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum-based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor). METHODS: Following primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III-IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression-free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA-sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD-L1 expression was scored by immunohistochemistry (IHC). RESULTS: A total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss-of-function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD-L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD-L1 protein expression in the GR group. CONCLUSIONS: Our research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Antígeno B7-H1/metabolismo , Carboplatina/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Procedimentos Cirúrgicos de Citorredução , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Genes BRCA1 , Genes BRCA2 , Genes p53 , Humanos , Proteína do Locus do Complexo MDS1 e EVI1/genética , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Intervalo Livre de Progressão , Proteínas Repressoras/metabolismo , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Sequenciamento Completo do Exoma
20.
Cancer Med ; 10(9): 3068-3076, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33826243

RESUMO

BACKGROUND: Paclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients. METHODS: Early breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18-24.9 kg/m2 and overweight/obese, ≥25 kg/m2 , respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software. RESULTS: Eighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2 , mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two-sample t-test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2-sample t-test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, -0.009; p > 0.05). CONCLUSION: When dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under-dosing of this drug. TRIAL REGISTRATION: This study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , Paclitaxel/farmacocinética , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Área Sob a Curva , Peso Corporal , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Sobrepeso/metabolismo , Paclitaxel/administração & dosagem , Estudos Prospectivos , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...