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1.
Biol Pharm Bull ; 46(2): 194-200, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36724948

RESUMO

Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, the increased systemic fPt levels do not increase oxaliplatin-induced toxicities. We hypothesized that renal dysfunction has minimal effect on the elimination rate of reactive fPt, and that the DNA-binding capacity is one of the properties of reactive Pt species. This study aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics. The pharmacokinetics of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The platinum concentrations were determined using inductively coupled plasma-mass spectrometry. The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA. Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after drug administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 35.9 and 7.3% at 2 and 14 d after treatment, respectively. The plasma level of DNA-reactive fPt also decreased to 1.9 and 0.6%, respectively, on these days. This study showed that severe renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.


Assuntos
Antineoplásicos , Nefropatias , Ratos , Animais , Oxaliplatina , Platina , Compostos Organoplatínicos/efeitos adversos , DNA , Nefropatias/induzido quimicamente
2.
Genes (Basel) ; 14(1)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36672910

RESUMO

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. METHODS: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. RESULTS: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1-12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8-12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5-21.1) and severe CIPN. CONCLUSIONS: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Doenças do Sistema Nervoso Periférico , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Platina/efeitos adversos , Estudos Prospectivos , Seguimentos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética
3.
BMC Med Genomics ; 16(1): 10, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653841

RESUMO

BACKGROUND: Leucine-rich repeat sequence domains are known to mediate protein‒protein interactions. Recently, some studies showed that members of the leucine rich repeat containing (LRRC) protein superfamily may become new targets for the diagnosis and treatment of tumours. However, it is not known whether any of the LRRC superfamily genes is expressed in the stroma of ovarian cancer (OC) and is associated with prognosis. METHODS: The clinical data and transcriptional profiles of OC patients from the public databases TCGA (n = 427), GTEx (n = 88) and GEO (GSE40266 and GSE40595) were analysed by R software. A nomogram model was also generated through R. An online public database was used for auxiliary analysis of prognosis, immune infiltration and protein‒protein interaction (PPI) networks. Immunohistochemistry and qPCR were performed to determine the protein and mRNA levels of genes in high-grade serous ovarian cancer (HGSC) tissues of participants and the MRC-5 cell line induced by TGF-ß. RESULTS: LRRC15 and LRRC32 were identified as differentially expressed genes from the LRRC superfamily by GEO transcriptome analysis. PPI network analysis suggested that they were most enriched in TGF-ß signalling. The TCGA-GTEx analysis results showed that only LRRC15 was highly expressed in both cancer-associated fibroblasts (CAFs) and the tumour stroma of OC and was related to clinical prognosis. Based on this, we developed a nomogram model to predict the incidence of adverse outcomes in OC. Moreover, LRRC15 was positively correlated with CAF infiltration and negatively correlated with CD8 + T-cell infiltration. As a single indicator, LRRC15 had the highest accuracy (AUC = 0.920) in predicting the outcome of primary platinum resistance. CONCLUSIONS: The LRRC superfamily is related to the TGF-ß pathway in the microenvironment of OC. LRRC15, as a stromal biomarker, can predict the clinical prognosis of HGSC and promote the immunosuppressive microenvironment. LRRC15 may be a potential therapeutic target for reversing primary resistance in OC.


Assuntos
Neoplasias Ovarianas , Platina , Humanos , Feminino , Platina/metabolismo , Platina/uso terapêutico , Leucina/metabolismo , Leucina/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prognóstico , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
5.
Asian Pac J Cancer Prev ; 24(1): 195-205, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36708568

RESUMO

BACKGROUND: A rare yet severe neoplasia called malignant pleural mesothelioma (MPM) typically manifests itself in advanced stages. Despite some improvements in the treatment of patients with MPM, this malignancy continues to have a detrimental prognosis . The primary goal of the present study was to assess the associatin between ERCC1, RRM1, and thymidylate synthase (TS) expression and disease outcome in patients with malignant pleural mesothelioma (MPM) treated with either pemetrexed plus cisplatin or gemcitabine plus cisplatin. METHODS: This prospective cohort study was done on ninety-one advanced MPM patients. The patients received either pemetrexed plus platinum (55 of 91) or gemcitabine plus platinum chemotherapy (36 of 91). Tissue biopsy was taken at time of diagnosis. Immunohistochemistry was used to assess the levels of ERCC1, RRM1, and TS transcription in tissue biopsies (paraffin embedded). RESULTS: Based on the findings, 70% of patients with low expression of TS had low expression of ERCC1, and 68% of patients with high expression of TS had high expression of ERCC1, suggesting  a significat association between ERCC1 expression and TS expression (p=0.005). However, there was no relation between ERCC1 and RRM1 expression patterns (p= 0.296). In patients underwen platinum-based theraphy (n 91), a significant correlation was detected between low ERCC1 median High-scoring and longer progression time (TTP;9.6 v 5.3 months;P< .001) or overall survival (OS) (OS;18.1 v 9.1 months; P<0.001). A significant correlation was found between low TS protein expression and longer time progression (TTP; 11.8 v 5.4 months; P< .001) or OS (OS; 19.8 v 8.5 months; P <0.001) in patients undergoing pemetrexed plus platinum chemotherapy (n 55). Low RRM1 expression was accompanied by high progression free survival (TTP; 10.6 v 3.8 months) and OS (OS; 20.6 v 8.6 months) in patients receiving gemcitabine plus platinum chemotherapy. Based on the multivariate test results, the independent variables significantly affecting OS were tumor stage (HR: 2.3; 95% CI: 1.1-4.9; p= 0.021) and ERCC1 (HR: 2.7; 95% CI: 1.7-4.3; p < 0.001). CONCLUSION: Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Humanos , Mesotelioma Maligno/tratamento farmacológico , Pemetrexede/uso terapêutico , Cisplatino , Platina/uso terapêutico , Timidilato Sintase/metabolismo , Estudos Prospectivos , Glutamatos/uso terapêutico , Guanina/uso terapêutico , Desoxicitidina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Endonucleases , Resultado do Tratamento , Neoplasias Pulmonares/patologia
6.
J Med Chem ; 66(1): 875-889, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36594812

RESUMO

Platinum drugs as primary chemotherapy drugs have been applied to various cancer patients. However, their therapeutic applicability is limited due to the adverse effects and immunosuppression. To minimize the side effects and boost the immune response, we designed and synthesized platinum(IV) prodrugs that introduced BRD4 inhibitor JQ-1. Among them, CJ2 had the most potent therapeutic activity and less toxicity. With the introduction of ligand JQ-1, CJ2-reduced PD-L1 protein was found in the cytoplasm and cytomembrane for the first time. By interfering with the PD-L1 synthesis, CJ2 could arouse the immune system and promote CD8+ T cell infiltration. Meanwhile, CJ2 could accelerate PD-L1 degradation in the cytoplasm to block DNA damage repair. In vivo, CJ2 markedly suppressed tumor growth by reversing the immunosuppression microenvironment and enhancing DNA damage. These findings provide an effective approach to improve the selectivity and activity of the platinum drugs with elevated immune response.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Pró-Fármacos , Humanos , Antígeno B7-H1 , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Platina/farmacologia , Platina/uso terapêutico , Proteínas Nucleares , Fatores de Transcrição , Imunoterapia , Citoplasma/metabolismo , Microambiente Tumoral , Linhagem Celular Tumoral , Proteínas de Ciclo Celular
7.
PeerJ ; 11: e14656, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36700004

RESUMO

Background: This in vitro investigation aimed to determine the influence of multiple autoclave cycles on the cyclic fatigue resistance of three heat-treated nickel-titanium (NiTi) files: EdgeTaper Platinum (ETP), ProTaper Gold (PTG), and TruNatomy Prime (TN). Materials: Sixty NiTi files, twenty of each NiTi file type: ETP 25/.06, PTG 25/.08, and TN 26/.04 were randomly divided into four equal subgroups (n = 5). The files for the control group were left un-autoclaved. Different autoclave sterilization cycles (one, five, and ten) were used for the other three groups. The files were then placed in a metal canal block and rotated according to the manufacturer's instructions until fracture. The length of the broken segment and the time taken for fracture were measured. The fractured surfaces were subsequently subjected to SEM imaging. The Kruskal-Wallis test was used to analyze the data, followed by Dunn-Bonferroni pairwise comparisons. Statistical significance was set at p < 0.05. Results: ETP showed significantly greater resistance to cyclic fatigue than TN in all autoclave groups and PTG after five autoclave cycles (p = 0.014). Fatigue resistance was not affected by the number of autoclaving cycles, except for ETP. After the first and tenth autoclaving cycles, they required significantly more rotations to failure than the non-sterilized files (p = 0.039 and p = 0.021, respectively). The fractured segments of the ETP files in these two groups were also longer than those in the control group (p = 0.010). Conclusion: The cyclic fatigue resistance of ETP was greater than that of TN in all tested conditions. Repeated autoclave cycles of sterilization improved the cyclic fatigue resistance of the ETP files only and did not affect the cyclic fatigue resistance of TN and PTG. However, the ETP files separated at a longer distance from the tip with increased autoclaving cycles.


Assuntos
Ouro , Platina , Estresse Mecânico , Falha de Equipamento , Teste de Materiais , Preparo de Canal Radicular , Esterilização/métodos
8.
In Vivo ; 37(1): 143-148, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593015

RESUMO

BACKGROUND/AIM: In clinical practice, platinum-based systemic chemotherapy works to shrink pelvic lymph nodes. Intra-arterial (IA) bolus infusion may result in more favorable results than systemic chemotherapy. In the present study, we investigated the distribution of cisplatin administrated by IA infusion in varying organs, specifically focusing on the node tissue, in comparison with the intravenous (IV) route. MATERIALS AND METHODS: Under anesthesia, cisplatin 0.42 mg/body was administrated by IA or IV infusion in rats to mimic a balloon-occluded arterial infusion model used in clinical practice. The kidney, bladder, lymphatic tissue, and peripheral blood were extracted to analyze the amount of cisplatin by inductively coupled plasma-mass spectrometry. RESULTS: Concertation of cisplatin by IA infusion was higher than that by the IV route in the peripheral blood and kidney. IA infusion led to a significantly high concentration of cisplatin in the bladder compared to IV infusion (1.3±0.452 vs. 0.2 ppb/mg ± 0.055, p=0.050). Furthermore, the IA method led to an extremely high concentration of cisplatin in the lymphatic tissue compared to the IV method (0.1±0.036 vs. 13.3±5.36, p=0.048). CONCLUSION: High cisplatin accumulation in the lymphatic tissue and bladder by IA administration may have a potential role for treating patients with node-positive bladder cancer.


Assuntos
Cisplatino , Neoplasias da Bexiga Urinária , Ratos , Animais , Cisplatino/uso terapêutico , Infusões Intra-Arteriais , Distribuição Tecidual , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Platina
9.
Int J Mol Sci ; 24(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36614297

RESUMO

Rhabdomyosarcoma (RMS) in adults is a rare and aggressive disease, which lacks standard therapies for relapsed or advanced disease. This retrospective study aimed to describe the activity of BOMP-EPI (bleomycin, vincristine, methotrexate and cisplatin alternating with etoposide, cisplatin and ifosfamide), an alternative platinum-based regimen, in adult patients with relapsed/metastatic RMS. In the study, 10 patients with RMS with a median age at diagnosis of 20.8 years and a female/male distribution of 6/4 received a mean of 2.5 cycles of BOMP-EPI. The best RECIST response was a complete response in 1/10 (10%) patients, a partial response in 5/10 (50%), stable disease in 3/10 (30%) and progression in 1/10 (10%). With a median follow-up in the alive patients from the start of therapy of 30.5 months (15.7-258), all patients progressed with a median progression-free survival of 8.47 months (95% CI 8.1-8.8), and 7/10 patients died with a median overall survival of 24.7 months (95% CI 13.7-35.6). BOMP-EPI was an active chemotherapy regimen in adults with pediatric-type metastatic RMS, with outcomes in terms of survival that seem superior to what was expected for this poor-prognosis population. Low HMGB1 expression level was identified as a predictive factor of better response to this treatment.


Assuntos
Proteína HMGB1 , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Humanos , Adulto , Masculino , Criança , Feminino , Cisplatino/uso terapêutico , Platina/uso terapêutico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/patologia , Etoposídeo/uso terapêutico , Vincristina/uso terapêutico
10.
Carbohydr Polym ; 303: 120463, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36657845

RESUMO

In recent years, nanocellulose-based bioinorganic nanohybrids have been exploited in numerous applications due to their unique nanostructure, excellent catalytic properties, and good biocompatibility. To the best of our knowledge, this is the first report on the simple and effective synthesis of graphene/cellulose (RGO/CNC) matrix-supported platinum nanoparticles (Pt NPs) for nonenzymatic electrochemical glucose sensing. The Pt/RGO/CNC nanohybrid presented a porous network structure, in which Pt NPs, RGO, and CNCs were integrated well. Here, cellulose nanocrystals act as a biocompatible framework for wrapped RGO and monodispersed Pt nanoparticles, effectively preventing the restacking of graphene during reduction. The superior glucose sensing performance of Pt/RGO/CNC modified glass carbon electrode (GCE) was achieved with a linear concentration range from 0.005 to 8.5 mM and a low detection limit of 2.1 µM. Moreover, the Pt/RGO/CNC/GCE showed remarkable sensitivity, selectivity, durability, and reproducibility. The obtained results indicate that the CNCs-based bioinorganic nanohybrids could be a promising electrode material in electrochemical biosensors.


Assuntos
Grafite , Nanopartículas Metálicas , Grafite/química , Nanopartículas Metálicas/química , Celulose , Reprodutibilidade dos Testes , Técnicas Eletroquímicas/métodos , Platina/química , Glucose
11.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675064

RESUMO

Pt (II) derivatives show anti-cancer activity by interacting with nucleobases of DNA, thus causing some spontaneous and non-spontaneous reactions. As a result, mono- and diaqua products are formed which further undergo complexation with guanine or adenine. Consequently, many processes are triggered, which lead to the death of the cancer cell. The theoretical and experimental studies confirm that such types of interactions can also occur with other chemical compounds. The vitamins from B group have a similar structure to the nucleobases of DNA and have aromatic rings with single-pair orbitals. Theoretical and experimental studies were performed to describe the interactions of B vitamins with Pt (II) derivatives such as cisplatin, oxaliplatin and carboplatin. The obtained results were compared with the values for guanine. Two levels of simulations were implemented at the theoretical level, namely, B3LYP/6-31G(d,p) with LANL2DZ bases set for platinum atoms and MN15/def2-TZVP. The polarizable continuum model (IEF-PCM preparation) and water as a solvent were used. UV-Vis spectroscopy was used to describe the drug-nucleobase and drug-B vitamin interactions. Values of the free energy (ΔGr) show spontaneous reactions with mono- and diaqua derivatives of cisplatin and oxaliplatin; however, interactions with diaqua derivatives are more preferable. The strength of these interactions was also compared. Carboplatin products have the weakest interaction with the studied structures. The presence of non-covalent interactions was demonstrated in the tested complexes. A good agreement between theory and experiment was also demonstrated.


Assuntos
Antineoplásicos , Neoplasias , Complexo Vitamínico B , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Cisplatino/química , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Carboplatina/química , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Platina/química , Complexo Vitamínico B/farmacologia , Complexo Vitamínico B/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/química , Neoplasias/tratamento farmacológico
12.
Dalton Trans ; 52(5): 1388-1392, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36637059

RESUMO

Pt(terpyridine) complexes are well-known DNA intercalators. The introduction of an NHC co-ligand rendered such a complex highly antiproliferative in cancer cells compared to its chlorido derivative. Despite the high potency, zebrafish embryos tolerated the compound well, especially compared to cisplatin. DNA interaction studies support a mode of action related to intercalation.


Assuntos
Antineoplásicos , Platina , Animais , Antineoplásicos/farmacologia , Ligantes , Peixe-Zebra , Linhagem Celular Tumoral , DNA
13.
Sci Prog ; 106(1): 368504221147173, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36718538

RESUMO

Colorectal cancer (CRC) can be resistant to platinum drugs, possibly through ferroptosis suppression, albeit the need for further work to completely understand this mechanism. This work aimed to sum up current findings pertaining to oxaliplatin resistance (OR) or resistance to ascertain the potential of ferroptosis to regulate oxaliplatin effects. In this review, tumor development relating to iron homeostasis, which includes levels of iron that ascertain cells' sensitivity to ferroptosis, oxidative stress, or lipid peroxidation in colorectal tumor cells that are connected with ferroptosis initiation, especially the role of c-Myc/NRF2 signaling in regulating iron homeostasis, coupled with NRF2/GPX4-mediated ferroptosis are discussed. Importantly, ferroptosis plays a key role in OR and ferroptotic induction may substantially reverse OR in CRC cells, which in turn could inhibit the imbalance of intracellular redox induced by oxaliplatin and ferroptosis, as well as cause chemotherapeutic resistance in CRC. Furthermore, fundamental research of small molecules, ferroptosis inducers, GPX4 inhibitors, or natural products for OR coupled with their clinical applications in CRC have also been summarized. Also, potential molecular targets and mechanisms of small molecules or drugs are discussed as well. Suggestively, OR of CRC cells could significantly be reversed by ferroptosis induction, wherein this result is discussed in the current review. Prospectively, the existing literature discussed in this review will provide a solid foundation for scientists to research the potential use of combined anticancer drugs which can overcome OR via targeting various mechanisms of ferroptosis. Especially, promising therapeutic strategies, challenges ,and opportunities for CRC therapy will be discussed.


Assuntos
Neoplasias Colorretais , Ferroptose , Humanos , Platina/farmacologia , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Procedimentos Clínicos , Ferro/metabolismo , Ferro/farmacologia , Neoplasias Colorretais/tratamento farmacológico
14.
J Comp Eff Res ; 12(2): e220016, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36621905

RESUMO

Introduction: In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. Materials & methods: A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Results: Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Conclusion: Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Docetaxel/uso terapêutico , Pemetrexede/uso terapêutico , Metanálise em Rede , Platina/uso terapêutico , Teorema de Bayes , Imunoterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
15.
ACS Sens ; 8(1): 381-387, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36600539

RESUMO

Combined detection of multiple markers related to the same disease could improve the accuracy of disease diagnosis. However, the abundance levels of multiple markers of the same disease varied widely in real samples, making it difficult for the traditional detection method to meet the requirements of a wide detection range. Herein, three kinds of cardiac biomarkers, cardiac troponin I (cTnI), myoglobin (Myo), and C-reaction protein (CRP), which were from the pM level to the µM level in real samples, were selected as model targets. Valency-controlled signal probes based on DNA tetrahedron nanostructures (DTNs) and platinum nanoparticles (PtNPs) were constructed for tunable cardiac biomarker detection. PtNPs with high horseradish peroxidase-like activity and stability served as signal molecules, and DTNs with unique spatial structure and sequence specificity were used for precisely controlling the number of connected PtNPs. By controlling the number of PtNPs connected to DTNs, monovalent, bivalent, and trivalent signal probes were obtained and were used for the detection of cardiac markers in different concentration ranges. The limit of detection of cTnI, Myo, and CRP was 3.0 pM, 0.4 nM, and 6.7 nM, respectively. Furthermore, it performed satisfactorily for the detection of cardiac markers in 10% human serum. It was anticipated that the design of valency-controlled signal probes based on DTNs and nanozymes could be extended to the construction of other multi-target detection platforms, thus providing a basis for the development of a new precision medical detection platform.


Assuntos
Nanopartículas Metálicas , Humanos , Nanopartículas Metálicas/química , Platina/química , DNA , Troponina I , Mioglobina
16.
ACS Appl Mater Interfaces ; 15(3): 3882-3893, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36629473

RESUMO

The catalytic and antioxidant properties of platinum nanoparticles (PtNPs) make them promising candidates for several applications in nanomedicine. However, an open issue, still shared among most nanomaterials, is the understanding on how internalized PtNPs, which are confined within endo-lysosomal compartments, can exert their activities. To address this problem, here we study the protective effect of 5 nm PtNPs on a human hepatic (HepG2) cell line exposed to dichlorodiphenylethylene (DDE) as a model of oxidative stress. Our results indicate that PtNPs are very efficient to reduce DDE-induced damage in HepG2 cells, in an extent that depends on DDE dose. PtNPs can contrast the unbalance of mitochondrial dynamics induced by DDE and increase the expression of the SOD2 mitochondrial enzyme that recovers cells from oxidative stress. Interestingly, in cells treated with PtNPs─alone or in combination with DDE─mitochondria form contact sites with a rough endoplasmic reticulum and endo-lysosomes containing nanoparticles. These findings indicate that the protective capability of PtNPs, through their intrinsic antioxidant properties and modulating mitochondrial functionality, is mediated by an inter-organelle crosstalk. This study sheds new light about the protective action mechanisms of PtNPs and discloses a novel nano-biointeraction mechanism at the intracellular level, modulated by inter-organelle communication and signaling.


Assuntos
Antioxidantes , Nanopartículas Metálicas , Humanos , Antioxidantes/farmacologia , Platina/farmacologia , Transdução de Sinais , Mitocôndrias/metabolismo
17.
ACS Sens ; 8(1): 141-149, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36640268

RESUMO

Real-time monitoring of cell temperature fluctuation can help researchers better understand physiological phenomena and the effects of drug treatment on cells, which is a novel and important tool for cellular informatics. The platinum (Pt) temperature sensor is widely used in temperature measurement with the advantages of strong stability, great accuracy, and high sensitivity. However, the commercially available Pt sensors have large thermal resistance and heat capacity which are difficult to be applied for cell temperature measurement because only a very small amount of heat flux is generated by live cells. In this study, we designed a system using precision Pt thin-film temperature sensors with low heat capacity and thermal resistance. The Pt thin-film sensors are covered by a silicon nitride insulation layer grafted with a self-assembled multilayer silane film for promoting cell adhesion. The temperature coefficient of resistance of the Pt temperature sensor was about 2100 ppm/°C. The four-wire lead design next to the sensor detection area ensured maximum accuracy, resulting in a system noise below 0.01 °C over a long time. HEK-293T and HeLa cells were cultured on the sensor surface, respectively. The temperature fluctuation of 293T cells was monitored in a cell culture medium, showing a temperature increase of about 0.05-0.12 °C. The temperature fluctuation of HeLa cells treated with cisplatin was also measured and recorded, indicating a temperature decrease of 0.01 °C first and then a gradual temperature increase of 0.04 °C. The Pt sensor system we developed demonstrated high sensitivity and long stability for cell temperature fluctuation monitoring, which can be widely used in cell activity and cellular informatics studies.


Assuntos
Temperatura Alta , Platina , Humanos , Temperatura , Células HeLa , Técnicas de Cultura de Células
18.
Eur J Cancer ; 180: 117-124, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592506

RESUMO

BACKGROUND: For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice. METHODS: We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy. RESULTS: Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3-26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6-34.6) and 66.9% (95% CI: 59.6-75.2%), respectively. The incidence of grade 3-5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma. CONCLUSIONS: Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias Epiteliais e Glandulares , Neoplasias do Timo , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/patologia , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/patologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Platina/uso terapêutico
19.
Eur J Med Chem ; 248: 115044, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36621139

RESUMO

In cancer cells, Pol η allows DNA replication and cell proliferation even in the presence of chemotherapeutic drug-induced damages, like in the case of platinum-containing drugs. Inhibition of Pol η thus represents a promising strategy to overcome drug resistance and preserve the effectiveness of chemotherapeutic drugs. Here, we report the discovery of a novel class of Pol ƞ inhibitors, with 35 active close analogs. Compound 21 (ARN24964) stands out as the best inhibitor, with an IC50 value of 14.7 µM against Pol η and a good antiproliferative activity when used in combination with cisplatin - with a synergistic effect in three different cancer cell lines (A375, A549, OVCAR3). Moreover, it is characterized by a favorable drug-like profile in terms of its aqueous kinetic solubility, plasma and metabolic stability. Thus, ARN24964 is a promising compound for further structure-based drug design efforts toward developing drugs to solve or limit the issue of drug resistance to platinum-containing drugs in cancer patients.


Assuntos
Neoplasias Ovarianas , Platina , Humanos , Feminino , Apoptose , Linhagem Celular Tumoral , Replicação do DNA , Dano ao DNA
20.
Med Oncol ; 40(2): 80, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650399

RESUMO

Urinary bladder cancer (UBC) holds a potentially profound social burden and affects over 573,278 new cases annually. The disease's primary risk factors include occupational tobacco smoke exposure and inherited genetic susceptibility. Over the past 30 years, a number of treatment modalities have emerged, including cisplatin, a platinum molecule that has demonstrated effectiveness against UBC. Nevertheless, it has severe dose-limiting side effects, such as nephrotoxicity, among others. Since intracellular accumulation of platinum anticancer drugs is necessary for cytotoxicity, decreased uptake or enhanced efflux are the root causes of platinum resistance and response failure. Evidence suggests that genetic variations in any transporter involved in the entry or efflux of platinum drugs alter their kinetics and, to a significant extent, determine patients' responses to them. This review aims to consolidate and describe the major transporters and their polymorphic variants in relation to cisplatin-induced toxicities and resistance in UBC patients. We concluded that the efflux transporters ABCB1, ABCC2, SLC25A21, ATP7A, and the uptake transporter OCT2, as well as the organic anion uptake transporters OAT1 and OAT2, are linked to cisplatin accumulation, toxicity, and resistance in urinary bladder cancer patients. While suppressing the CTR1 gene's expression reduced cisplatin-induced nephrotoxicity and ototoxicity, inhibiting the expression of the MATE1 and MATE2-K genes has been shown to increase cisplatin's nephrotoxicity and resistance. The roles of ABCC5, ABCA8, ABCC10, ABCB10, ABCG1, ATP7B, ABCG2, and mitochondrial SLC25A10 in platinum-receiving urinary bladder cancer patients should be the subject of further investigation.


Assuntos
Antineoplásicos , Neoplasias da Bexiga Urinária , Humanos , Cisplatino/efeitos adversos , Platina , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Transportadores de Ácidos Dicarboxílicos
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