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1.
Saudi Med J ; 43(1): 37-44, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35022282

RESUMO

OBJECTIVES: To investigate the anti-tumor activity and tolerability of celecoxib as an adjuvant therapy for patients with metastatic colorectal cancer (CRC). METHODS: In this randomized controlled study, 54 patients with metastatic CRC were randomized into 2 groups; the control group (n=28) which received 6 cycles of folinic acid, fluorouracil and irinotecan (FOLFIRI) regimen (5-flourouracil, leucovorin, irinotecan), and the celecoxib group (n=26) which received 6 cycles of FOLFIRI regimen plus celecoxib 200 mg twice daily. The study duration was 3 months. Patients were assessed at baseline and at the end of intervention through the Response Evaluation Criteria in Solid Tumors objective response rate (ORR) and through evaluating the serum concentrations of vascular endothelial growth factor (VEGF), soluble factor-related apoptosis (sFAS), sFAS ligand (sFASL), and epithelial neutrophil-activating peptide -78 (ENA-78/CXCL5). Common Terminology Criteria for Adverse Events version 6.0 was used for evaluating drug-related toxicity. RESULTS: After intervention, celecoxib/FOLFIRI arm showed significant elevation in ORR as compared to FOLFIRI arm (p=0.001). As compared to FOLFIRI arm, celecoxib/FOLFIRI arm showed significantly lower VEGF (p<0.001), CXCL5 (p<0.001), and sFASL (p<0.001) serum levels and significantly higher sFAS serum level and sFAS/FASL ratio (p<0.001). Furthermore, celecoxib/FOLFIRI arm showed significantly higher progression-free survival and one-year overall survival when compared to FOLFIRI arm. CONCLUSION: Celecoxib plus chemotherapy may represent an effective and safe synergetic protocol for patients with metastatic CRC.Clinicaltrial.gov ID:NCT03645187.


Assuntos
Neoplasias Colorretais , Fator A de Crescimento do Endotélio Vascular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/uso terapêutico , Celecoxib/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila , Humanos , Leucovorina
2.
Int J Cancer ; 150(1): 112-123, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34431518

RESUMO

Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE-3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS-WT tumors (ie, wild-type in KRAS and NRAS exons 2-4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13-2.38; P = .0098) and progression-free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18-2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/mortalidade , Perda de Peso , Idoso , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
3.
J Colloid Interface Sci ; 609: 353-363, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34902672

RESUMO

Most carrier-based nano drug delivery systems (nano-DDSs) are subjected to complex preparation or purification processes, metabolic instability and potential systemic toxicity. To overcome these issues, it is urgent to develop a multifunctional carrier-free nano-DDS that can be fabricated by a simple approach for enhanced anticancer efficacy. In this work, the carrier-free supramolecular nanoprodrug (CF SNPD) based on lactose (Lac) functionalized dimeric camptothecin (CPT) was developed, in which Lac and CPT were conjugated by the aromatized thioacetal (ATA, a reactive oxygen species (ROS)-responsive bond). The obtained Lac-ATA-CPT2 prodrug and the photosensitizer Chlorin e6 (Ce6) formed CF SNPD (denoted as Ce6@Lac-ATA-CPT2 NPs) in water by supramolecular self-assembly. The design of dimeric CPT endowed Ce6@Lac-ATA-CPT2 NPs with ultrahigh drug-loading capacity (up to 94%) and excellent stability. The Lac-functionalized CF SNPD displayed active specific targetability to HepG2 cells resulting from the carbohydrate-protein interactions. Furthermore, the fluorescence signal of Ce6 facilitated the precise tracking and localization of Ce6@Lac-ATA-CPT2 NPs within the cell. Meanwhile, the ROS generated by Ce6 not only cleaved ATA linker to trigger on-demand CPT release, but also exhibited a killing effect on tumor cells, enabling synergistic therapy via CPT-mediated chemotherapy (CT) and Ce6-induced photodynamic therapy (PDT). Therefore, the multifunctional CF SNPD may be one of the promising therapeutic options for liver cancer.


Assuntos
Nanopartículas , Fotoquimioterapia , Camptotecina/farmacologia , Linhagem Celular Tumoral , Lactose , Imagem Óptica , Água
4.
Bull Cancer ; 108(11S): 11S1-11S7, 2021 Dec.
Artigo em Francês | MEDLINE | ID: mdl-34969511

RESUMO

HER2, a human epidermal growth factor, being activated by amplification, is a negative prognostic factor in breast cancer. HER2 is the target of anti-HER2 antibodies (Trastuzumab, Pertuzumab…). For more than 10 years, breast cancers have been classified into HER2 positive and HER2 negative. However, the advent of new cytotoxic drugs combined with anti-HER2 antibodies, such as TDM1 or trastuzumab déruxtécan, have shown very promising therapeutic activity in patients with low HER2 expression breast cancer. These new therapeutic perspectives encourage a better identification of low HER2 tumours in order to identify patients who could benefit from them. Thus, the classification of breast tumours evolves to individualize HER2-negative tumours (score 0), HER2-positive tumours (score 3+ and 2+ amplified) and HER2-low tumours (scores 1+ and 2+ not-amplified). HER2-low tumours are common and represent more than half of all breast cancers. To identify these HER2-low tumours, pathology laboratories should not change their usual technique calibrated according to ASCO/CAP and GEFPICS recommendations. Until more clinical data about response to these new treatment strategies are available, GEFPICS does not require pathologists to identify this HER2-low category. Nevertheless, this designation will allow clinicians to identify patients whose tumours fall into this category in the very short term and offer them new treatment options.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Feminino , Amplificação de Genes , Genes erbB-2 , Humanos , Imunoconjugados/uso terapêutico , Recidiva Local de Neoplasia/química , Guias de Prática Clínica como Assunto , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico
5.
Bull Cancer ; 108(11S): 11S19-11S25, 2021 Dec.
Artigo em Francês | MEDLINE | ID: mdl-34969512

RESUMO

The emergence of a new tumor entity called HER2-low breast cancer leads us to reconsider therapeutic indications in patients whose tumors were usually considered as luminal or triple negative. The development of antibody-drug conjugates (ADCs) allows using HER2 as a vector of a cytoxic drug with significant clinical efficacy in breast cancer with low HER2 expression. Trastuzumab deruxtecan monotherapy is currently evaluated in phase III trials in HER2-low patients, but also in combination in earlier phase studies. Many ADCs are in development, with highly anticipated results. The toxicities of these various ADCs seem manageable and compatible with prolonged administration. Her2-low breast cancer subtype may benefit from dedicated therapeutic strategies in the next few years.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/química , Imunoconjugados/uso terapêutico , Receptor ErbB-2 , Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Terapia Neoadjuvante , Oligopeptídeos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Receptor ErbB-2/uso terapêutico , Trastuzumab/uso terapêutico
6.
Zhonghua Zhong Liu Za Zhi ; 43(11): 1177-1182, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34794220

RESUMO

Objective: To investigate the correlation between UGT1A1 polymorphisms and the irinotecan plus S-1 regimen-induced toxicities in Chinese advanced esophageal squamous cell carcinoma (ESCC) patients. Methods: A total of 46 recurrent or metastatic ESCC patients selected from ESWN 01 trial were randomly assigned to irinotecan plus S-1 group [intravenous infusion of irinotecan (160 mg/m(2)) on day 1 and oral S-1 (80-120 mg) on days 1-10, repeated every 14 days]. Peripheral venous blood at baseline was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6 and UGT1A1*28 were analyzed by polymerase chain reaction (PCR) amplification. Irinotecan plus S-1 regimen-induced toxicities of patients with different UGT1A1 polymorphisms were observed. The correlation between UGT1A1 polymorphisms and the adverse effects was analyzed. Results: Among the 46 patients, the numbers of UGT1A1*6 wild type genotype (GG), mutant heterozygote (GA) and mutant homozygote (AA) were 30, 15 and 1, while those with UGT1A1*28 wild type genotype (TA6/6), mutant heterozygote (TA6/7) and mutant homozygote (TA7/7) were 36, 8 and 2, respectively. Only one patient with UGT1A1*6 AA genotype occurred grade 3 diarrhea, while one of the 2 patients with UGT1A1*28 TA7/7 genotype occurred grade 4 diarrhea. No neutropenia was observed in the patient with UGT1A1*6 AA genotype, however, both of the two patients with UGT1A1*28 TA7/7 genotype occurred grade 3-4 neutropenia. Patients with UGT1A1*28 genetic polymorphism (TA 6/7 or TA7/7) had a higher response rate compared with wild-type TA6/6 carriers. (55.6% versus 26.5%). Conclusions: The homozygous genotype of UGT1A1*6 AA and UGT1A1*28 TA7/7 are rare (<5%) in Chinese ESCC population. Not all homozygous AA and TA7/7 carriers occur severe dose limited toxicities (DLT) when treated with irinotecan (160 mg/m(2)) plus S-1 regimen for 2 weeks. However, it's still necessary torigorously observe the occurrence of severe diarrhea and neutropenia in patients with UGT1A1*6 AA and UGT1A1*28 TA7/7 and adjust the dose timely.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Camptotecina/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Genótipo , Glucuronosiltransferase/genética , Humanos , Irinotecano/efeitos adversos , Polimorfismo Genético , Estudos Prospectivos
7.
Nihon Shokakibyo Gakkai Zasshi ; 118(11): 1063-1070, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34759103

RESUMO

An advanced small bowel mucinous adenocarcinoma with Peutz-Jeghers syndrome was resected, and we started capecitabine plus oxaliplatin (CapeOX) as adjuvant therapy. However, local recurrence was noted, and the tumor increased even after CapeOX plus bevacizumab and fluorouracil plus leucovorin plus irinotecan plus panitumumab (FOLFIRI plus panitumumab). Pembrolizumab was administered after confirming high-frequency microsatellite instability, and the tumor shrank markedly and remained shrunk for 20 months.


Assuntos
Adenocarcinoma Mucinoso , Neoplasias Colorretais , Síndrome de Peutz-Jeghers , Adenocarcinoma Mucinoso/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Recidiva Local de Neoplasia , Síndrome de Peutz-Jeghers/tratamento farmacológico
8.
Front Cell Infect Microbiol ; 11: 710945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722328

RESUMO

Irinotecan (CPT11) and its active metabolite ethyl-10-hydroxy-camptothecin (SN38) are broad-spectrum cytotoxic anticancer agents. Both cause cell death in rapidly dividing cells (e.g., cancer cells, epithelial cells, hematopoietic cells) and commensal bacteria. Therefore, CPT11 can induce a series of toxic side-effects, of which the most conspicuous is gastrointestinal toxicity (nausea, vomiting, diarrhea). Studies have shown that the gut microbiota modulates the host response to chemotherapeutic drugs. Targeting the gut microbiota influences the efficacy and toxicity of CPT11 chemotherapy through three key mechanisms: microbial ecocline, catalysis of microbial enzymes, and immunoregulation. This review summarizes and explores how the gut microbiota participates in CPT11 metabolism and mediates host immune dynamics to affect the toxicity and efficacy of CPT11 chemotherapy, thus introducing a new concept that is called "microbiota-host-irinotecan axis". Also, we emphasize the utilization of bacterial ß-glucuronidase-specific inhibitor, dietary interventions, probiotics and strain-engineered interventions as emergent microbiota-targeting strategies for the purpose of improving CPT11 chemotherapy efficiency and alleviating toxicity.


Assuntos
Antineoplásicos , Microbioma Gastrointestinal , Camptotecina , Inibidores Enzimáticos , Irinotecano
9.
Phys Chem Chem Phys ; 23(34): 18999-19010, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34612438

RESUMO

One major problem in the pharmaceutical industry is the aqueous solubility of newly developed orally administered drug candidates. More than 50% of newly developed drug molecules suffer from low aqueous solubility. The therapeutic effects of drug molecules are majorly dependent on the bioavailability and, in essence, on the solubility of the used drug molecules. Thus, enhancement of drug solubility of sparingly soluble drug molecules is a need of modern times. Considering the high importance of drug solubility, we have computationally shown the enhancement of drug solubility for seven class II (poorly water-soluble) drug molecules in a water medium. The uses of supramolecular macrocycles have immense importance in the same field. Thus, we have used two synthetic supramolecular receptors named host-1a and host-1b to enhance the water solubility of fluorouracil, albendazole, camptothecin, clopidogrel, indomethacin, melphalan, and tolfenamic acid drug molecules. Biomedical engagements of a supramolecular receptor commence with the formation of stable host-drug complexes. These complexations enhance the water solubility of drug molecules and sustain the release rate and bioavailability of drug molecules. Thus, in this work, we focus on the formation of stable host-drug complexes in water medium. Molecular dynamics simulation is applied to analyze the structural features and the energetics involved in the host-drug complexation process. The information obtained at the atomistic level helps us gain better insights into the key interactions that operate to produce such highly stable complexes. Thus, we can propose that these two supramolecular receptors may be used as drug solubilizing agents, and patients will benefit from this theragnostic application shortly.


Assuntos
Simulação de Dinâmica Molecular , Albendazol/química , Camptotecina/química , Clopidogrel/química , Indústria Farmacêutica , Fluoruracila/química , Indometacina/química , Melfalan/química , Solubilidade , Água/química , ortoaminobenzoatos/química
10.
Molecules ; 26(20)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34684807

RESUMO

Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced A. aegypti larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC50 of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to A. aegypti adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.


Assuntos
Aedes/efeitos dos fármacos , Aedes/virologia , Camptotecina/análogos & derivados , Inseticidas/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/virologia , Aedes/fisiologia , Animais , Antivirais/farmacologia , Camptotecina/farmacologia , Descoberta de Drogas , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Resistência a Inseticidas , Larva/efeitos dos fármacos , Larva/fisiologia , Atividade Motora/efeitos dos fármacos , Pandemias/prevenção & controle , Inibidores da Topoisomerase I/farmacologia , Doenças Transmitidas por Vetores/epidemiologia , Doenças Transmitidas por Vetores/prevenção & controle , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos
11.
Molecules ; 26(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34500845

RESUMO

Molecular crosstalk between the cellular epigenome and genome converge as a synergistic driver of oncogenic transformations. Besides other pathways, epigenetic regulatory circuits exert their effect towards cancer progression through the induction of DNA repair deficiencies. We explored this mechanism using a camptothecin encapsulated in ß-cyclodextrin-EDTA-Fe3O4 nanoparticles (CPT-CEF)-treated HT29 cells model. We previously demonstrated that CPT-CEF treatment of HT29 cells effectively induces apoptosis and cell cycle arrest, stalling cancer progression. A comparative transcriptome analysis of CPT-CEF-treated versus untreated HT29 cells indicated that genes controlling mismatch repair, base excision repair, and homologues recombination were downregulated in these cancer cells. Our study demonstrated that treatment with CPT-CEF alleviated this repression. We observed that CPT-CEF exerts its effect by possibly affecting the DNA repair mechanism through epigenetic modulation involving genes of HMGB1, APEX1, and POLE3. Hence, we propose that CPT-CEF could be a DNA repair modulator that harnesses the cell's epigenomic plasticity to amend DNA repair deficiencies in cancer cells.


Assuntos
Antineoplásicos Fitogênicos/química , Camptotecina/química , Neoplasias do Colo/tratamento farmacológico , Reparo do DNA/efeitos dos fármacos , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanocápsulas/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Sequência de Bases , Camptotecina/farmacologia , Linhagem Celular Tumoral , Ciclodextrinas/química , DNA Polimerase III/genética , DNA Polimerase III/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Composição de Medicamentos , Liberação Controlada de Fármacos , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica , Biblioteca Gênica , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Nucleoproteínas/genética , Nucleoproteínas/metabolismo
12.
Future Oncol ; 17(30): 3911-3924, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467774

RESUMO

Sacituzumab Govitecan (also known by the brand name TRODELVY®) is a new and available treatment for metastatic triple-negative breast cancer, or mTNBC for short. Metastatic breast cancer means the breast cancer has spread to other parts of the body. Triple negative means the breast cancer does not have 3 common proteins on the cell surface called receptors. This is a summary of the ASCENT study, published in the New England Journal of Medicine in April 2021. This study compared Sacituzumab Govitecan with standard chemotherapy. Chemotherapy is a treatment that kills cancer cells or stops them from dividing. 529 people with mTNBC took part in the study across 7 countries. All who took part had already received 2 previous chemotherapies, which stopped working for their cancer. The study showed that patients who took Sacituzumab Govitecan lived longer than those who took a different chemotherapy while on the study. Tumors shrank in more patients who took Sacituzumab Govitecan than in patients who took chemotherapy. In general, patients who took Sacituzumab Govitecan experienced more side effects. This included low levels of a type of white blood cell known as neutrophils (neutropenia) and loose or watery stool (diarrhea). Use of supportive care lessened these side effects. This summary also includes insights and perspectives from 2 breast cancer patient advocates. ClinicalTrials.gov NCT number: NCT02574455. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here.


Assuntos
Imunoconjugados , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Camptotecina/análogos & derivados , Humanos , Idioma , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
13.
J Control Release ; 338: 358-366, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34481018

RESUMO

FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.


Assuntos
Neoplasias do Colo , Neoplasias Pancreáticas , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Leucovorina/uso terapêutico , Camundongos , Microbolhas , Oxaliplatina , Neoplasias Pancreáticas/tratamento farmacológico , Resultado do Tratamento , Uridina/análogos & derivados
14.
Anticancer Res ; 41(9): 4505-4513, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475076

RESUMO

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Angiografia por Tomografia Computadorizada , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
15.
Crit Rev Oncol Hematol ; 166: 103457, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34428555

RESUMO

Malignant tumors in young patients present a significant therapeutic challenge for physicians, partially due to their rarity and a relative lack of data, at least compared to adult tumors. As a result, there is an urgent need to explore new possible therapeutic regimens, either by introducing novel agents or by exploring combinations of existing agents. Vincristine, Temozolomide and Irinotecan are chemotherapeutic drugs which have emerged over the last six decades as monotherapy or as part of therapeutic regimens in various solid tumors. Combining these agents can yield strong synergistic effects, as suggested by preclinical data and results from clinical trials. Furthermore, adding novel molecules, such as anti-VEGF factor Bevacizumab to the aforementioned regimens, has shown efficacy in a limited number of trials, which are thoroughly analyzed throughout this review. Data presented throughout this paper suggest that VIT(b) regimen should be further explored in solid tumors in pediatric and adolescent patients.


Assuntos
Neoplasias Encefálicas , Neoplasias , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/uso terapêutico , Criança , Dacarbazina/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Neoplasias/tratamento farmacológico , Temozolomida/uso terapêutico , Vincristina
16.
Sci Rep ; 11(1): 16891, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413454

RESUMO

Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8+ T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of CXCL9/10/11 in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC.


Assuntos
Camptotecina/análogos & derivados , Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoconjugados/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Trastuzumab/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/metabolismo , Fatores Quimiotáticos/farmacologia , Dano ao DNA , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacos
17.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443490

RESUMO

Hydroxycamptothecin (SN38) is a natural plant extract isolated from Camptotheca acuminate. It has a broad spectrum of anticancer activity through inhibition of DNA topoisomerase I, which could affect DNA synthesis and lead to DNA damage. Thus, the action of SN38 against cancers could inevitably affect endogenous levels of ribonucleotide (RNs) and deoxyribonucleotide (dRNs) that play critical roles in many biological processes, especially in DNA synthesis and repair. However, the exact impact of SN38 on RNs and dRNs is yet to be fully elucidated. In this study, we evaluated the anticancer effect and associated mechanism of SN38 in human colorectal carcinoma HCT 116 cells. As a result, SN38 could decrease the cell viability and induce DNA damage in a concentration-dependent manner. Furthermore, cell cycle arrest and intracellular nucleotide metabolism were perturbed due to DNA damage response, of which ATP, UTP, dATP, and TTP may be the critical metabolites during the whole process. Combined with the expression of deoxyribonucleoside triphosphates synthesis enzymes, our results demonstrated that the alteration and imbalance of deoxyribonucleoside triphosphates caused by SN38 was mainly due to the de novo nucleotide synthesis at 24 h, and subsequently the salvage pathways at 48 h. The unique features of SN38 suggested that it might be recommended as an effective supplementary drug with an anticancer effect.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Neoplasias Colorretais/metabolismo , DNA/metabolismo , Ribonucleotídeos/metabolismo , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Células HCT116 , Humanos , Irinotecano/farmacologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Ribonucleotídeo Redutases/metabolismo
18.
Molecules ; 26(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34443689

RESUMO

Effective intracerebral delivery is key for glioma treatment. However, the drug delivery system within the brain is largely limited by its own adverse physical and chemical properties, low targeting efficiency, the blood-brain barrier and the blood-brain tumor barrier. Herein, we developed a simple, safe and efficient biomimetic nanosuspension. The C6 cell membrane (CCM) was utilized to camouflaged the 10-hydroxycamptothecin nanosuspension (HCPT-NS) in order to obtain HCPT-NS/CCM. Through the use of immune escape and homotypic binding of the cancer cell membrane, HCPT-NS/CCM was able to penetrate the blood-brain barrier and target tumors. The HCPT-NS is only comprised of drugs, as well as a small amount of stabilizers that are characterized by a simple preparation method and high drug loading. Similarly, the HCPT-NS/CCM is able to achieve targeted treatment of glioma without any ligand modification, which leads it to be stable and efficient. Cellular uptake and in vivo imaging experiments demonstrated that HCPT-NS/CCM is able to effectively cross the blood-brain barrier and was concentrated at the glioma site due to the natural homing pathway. Our results reveal that the glioma cancer cell membrane is able to promote drug transport into the brain and enter the tumor via a homologous targeting mechanism.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Membrana Celular/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Nanopartículas/química , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Ratos , Suspensões , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento
19.
Biomolecules ; 11(8)2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34439774

RESUMO

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.


Assuntos
Inibidores de Checkpoint Imunológico/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Compostos Fitoquímicos/química , Receptor de Morte Celular Programada 1/metabolismo , Animais , Antígenos CD/metabolismo , Antineoplásicos/farmacologia , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Camptotecina/química , Diterpenos/química , Compostos de Epóxi/química , Flavonoides/química , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Imunoterapia , Isotiocianatos/química , Camundongos , Fenantrenos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Receptores Imunológicos/metabolismo , Saponinas/química , Sulfóxidos/química , Terpenos/química , Microambiente Tumoral/efeitos dos fármacos
20.
Environ Res ; 201: 111564, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34228950

RESUMO

Endophytic wild fungal strain Phyllosticta elongata MH458897 isolated from medicinal plant Cipadessa baccifera from the Western Ghats region of Sathyamangalam Tiger Reserve Forest. This endophytic fungus has potential of effective anticancer drug Camptothecin (CPT). Endophytic fungi act as key symbionts in-between plants and ecosystem in the biosphere. This recently identified microbial population inside the plants produces many defence metabolites against plant pathogens. Among these defense metabolites, CPT gained much attention because of its effective anticancer activity. The maximum yield of CPT produced by optimizing the various factors like DEKM07 medium, pH 5.6, incubation time using Response Surface Methodology based on Central Composite Design. Extracted CPT is characterized using High Performance Liquid Chromatography and Electrospray ionization-Mass spectrometry. The highest yield of CPT was 0.747 mg/L was produced at optimized factors of dextrose - 50 g L-1, peptone - 5.708 g L-1, magnesium sulphate - 0.593 g L-1, and incubation time - 14 days. In-vitro MTT assay revealed the CPT derivatives were cytotoxic to A-549 cancer cell line (IC50 58.28 µg/ml) as nearly compared to the (IC50 51.08 µg/ml) standard CPT. CPT producing strain P. elongata from C. baccifera has the potential of CPT biosynthesis, and could be an effective anticancer bio metabolite. This compound has been described in the literature to be an effective anticancer metabolite. Our findings support the novel lifesaving anticancer drug from endophytic fungus in forest ecosystem concludes effective utilization of key symbionts will safeguard the humans and forest ecosystem.


Assuntos
Camptotecina , Plantas Medicinais , Ascomicetos , Ecossistema , Humanos , Índia
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