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1.
Trials ; 23(1): 29, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35012634

RESUMO

BACKGROUND: Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). The effect of neoadjuvant chemotherapy in advanced cervical cancer is controversial. Studies have shown that the addition of a weekly regimen of neoadjuvant chemotherapy (NACT) followed by CCRT may be superior to a thrice-weekly regimen of NACT and CCRT. Among patients who had not received prior cisplatin, a cisplatin and paclitaxel (TP) regimen resulted in longer overall survival than other regimens. This study aims to investigate the feasibility, safety, and efficacy of NACT with weekly TP followed by CCRT. METHODS: This is a prospective, randomized, open-labeled, multicentered phase III study. Based on a 65% of 2-year disease-free survival (DFS) rate in the CCRT group and 80% of that in NACT followed by CCRT group, and on prerequisite conditions including an 8% loss to follow-up, a two-sided 5% of type I error probability, and an 80% of power, a total of 300 cases were required for enrollment. Patients with IIB-IVA cervical cancer will be randomly allocated in a 1:1 ratio to one of two intervention arms. In the study arm, patients will receive dose-dense cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly for 4 cycles followed by CCRT (45 Gy in 5 weeks concurrent with cisplatin 40 mg/m2 weekly) plus image-guided adaptive brachytherapy (IGBRT). In the control arm, patients will undergo CCRT treatment. The primary endpoint of the study is 2-year disease-free survival (DFS); the secondary endpoints are 5-year overall survival (OS) and disease-free survival (DFS), the response rate 3 months after treatment completion, grade III/IV adverse effects, and quality of life, and potential biomarkers for predicting treatment response will also be studied. DISCUSSION: The data gathered from the study will be used to determine whether NACT with weekly TP followed by CCRT may become an optimized treatment for locally advanced cervical cancer. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900025327. Registered on 24 August 2019. medresman.org.cn ChiCTR1900025326.


Assuntos
Cisplatino , Neoplasias do Colo do Útero , Protocolos de Quimioterapia Combinada Antineoplásica , Quimiorradioterapia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante , Estadiamento de Neoplasias , Paclitaxel , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo do Útero/patologia
2.
Anticancer Res ; 42(1): 363-371, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34969746

RESUMO

BACKGROUND/AIM: To evaluate the clinical desire for pressurized intraperitoneal aerosol chemotherapy (PIPAC) in South Korea. PATIENTS AND METHODS: We performed an online survey on surgical oncologists between November and December 2019 using a questionnaire consisting of 20 questions. RESULTS: A total of 164 respondents answered the questionnaire. Among those specialized in ovarian cancer, pseudomyxoma peritonei, and malignant mesothelioma 41.7-50% preferred PIPAC for the curative treatment of primary diseases, whereas 32.7-33.3% majoring in colorectal and hepatobiliary cancers chose it for the palliative treatment of recurrent diseases. Furthermore, 66.7-95.2% considered PIPAC appropriate for the cancers they specialized in, and 76-78.7% expected a treatment response of more than 50% and considered grade 1 or 2 complications acceptable. Most respondents answered the reasonable costs to purchase and implement PIPAC once at between 1,000,000-5,000,000 South Korean Won (KRW). CONCLUSION: Most Korean surgical oncologists expected relatively high tumor response rates with minor toxicities through the repeated implementation of PIPAC.


Assuntos
Infusões Parenterais/métodos , Mesotelioma Maligno/cirurgia , Oncologistas/psicologia , Neoplasias Ovarianas/cirurgia , Pseudomixoma Peritoneal/cirurgia , Aerossóis/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Custos e Análise de Custo , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/patologia , Metástase Neoplásica , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Oxaliplatina/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/cirurgia , Pseudomixoma Peritoneal/tratamento farmacológico , Pseudomixoma Peritoneal/patologia , Inquéritos e Questionários , Resultado do Tratamento
3.
Life Sci ; 289: 120230, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34919900

RESUMO

The application of atmospheric pressure low-temperature plasma (LTP) in medical treatment has received extensive attention owing to its redox regulatory and anti-inflammatory properties. Nephrotoxicity due to oxidative stress and inflammation is the main adverse effect of cisplatin. In the present study, rats with cisplatin-induced nephrotoxicity were treated with LTP to investigate its potential protective effect. The results showed that LTP treatment has multiple protective effects on cisplatin-induced nephrotoxicity. It significantly improved clinical indicators such as survival rate, water intake, food intake, body weight, and mobility, as well as physiological indexes such as reduced renal index and levels of serum urea, creatinine, and total bilirubin; pathological indicators such as reduced tubular injury, inflammatory infiltration, tubulointerstitial fibrosis, and apoptosis; cell survival indicators such as decreased protein levels of Caspase-3 and Bax and increased Bcl-2; anti-oxidation status such as reduced malondialdehyde content and increased activities of catalase, superoxide dismutase, and glutathione peroxidase; and reduced inflammatory factors such as TNF-α in kidney tissues. Specially, LTP treatment did not influence the anticancer effect of cisplatin as observed in the solid tumor mouse model established by subcutaneously inoculating H22 cells. Moreover, LTP did not influence the physiological and pathological indicators of normal rats, suggesting its biological safety. In conclusion, LTP can protect against cisplatin-induced nephrotoxicity through its anti-oxidation, anti-inflammation, and anti-apoptosis effects, without influencing the anticancer effect of cisplatin.


Assuntos
Cisplatino , Regulação da Expressão Gênica/efeitos dos fármacos , Nefropatias , Rim , Gases em Plasma/farmacologia , Animais , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ratos , Ratos Wistar
4.
Oncol Rep ; 47(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34935060

RESUMO

The efficacy of cisplatin (CDDP) has been demonstrated in the treatment of various cancers as monotherapy and combination therapy with immunotherapy. However, acquired CDDP resistance is a major obstacle to successful treatment. In the present study, the mechanisms underlying acquired CDDP resistance were examined using ACR20 cells, which are CDDP­resistant cells derived from A549 lung cancer cells. CDDP induces cytotoxicity by binding nuclear DNA and generating reactive oxygen species (ROS). Contrary to our expectation, ROS levels were elevated in ACR20 cells not treated with CDDP. Pretreatment with an ROS inhibitor enhanced the sensitivity of ACR20 cells to CDDP and prevented the activation of nuclear factor (NF)­ÐºB signaling and upregulation of inhibitor of apoptosis proteins (IAPs). Notably, evaluation of the mitochondrial oxygen consumption rate and mitochondrial superoxide levels revealed a deterioration of mitochondrial function in ACR20 cells. Mitochondrial DNA PCR­RFLP analysis revealed four mutations with varying percentage levels in ACR20 cells. In addition, in cytoplasmic hybrids with mitochondria from ACR20 cells, intrinsic ROS levels were elevated, expression of IAPs was increased, and complex I activity and sensitivity to CDDP were decreased. Analysis of three­dimensional structure data indicated that a mutation (ND2 F40L) may impact the proton translocation pathway, thereby affecting mitochondrial complex I activity. Together, these findings suggest that intrinsic ROS levels were elevated by mitochondrial DNA mutations, which decreased the sensitivity to CDDP via activation of NF­κB signaling and induction of IAP expression in ACR20 cells. These findings indicate that newly identified mutations in mitochondrial DNA may lead to acquired cisplatin resistance in cancer.


Assuntos
Cisplatino/farmacologia , DNA Mitocondrial/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Humanos , Mutação , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
5.
Gene ; 809: 146003, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34648915

RESUMO

OBJECTIVE: Chronotherapy, a promising therapy, may build up the chemotherapy efficacy through thinking about timing of therapy. Here, we observed the roles of period circadian regulator 2 (PER2) on cervical cancer progression and the therapeutic efficacy of cisplatin (DDP) based on the circadian rhythm of PER2. METHODS: When Hela/DDP and SiHa/DDP transfected with pcDNA3.1-PER2 and/or treated with human epidermal growth factor (hEGF), viability, apoptosis, migration, and nuclear translocation of NF-κB p65 were detected by CCK-8, flow cytometry, transwell, immunofluorescence and western blot. Furthermore, the expression of circadian rhythm regulators, multidrug resistance, and epithelial-mesenchymal transition (EMT) proteins was detected by western blot. Hela/DDP cells-induced tumor formation in nude mice was constructed. The expression of PER2 was measured at different time point by RT-qPCR. Cisplatin was separately injected into mice with cervical cancer at the highest and lowest expression of PER2. After 5 weeks, tumor volume was measured and tumor proliferation was assessed by immunohistochemistry. RESULTS: Overexpression of PER2 significantly reduced proliferative and migrated capacities and nuclear translocation of NF-κB p65 as well as enhanced apoptosis in Hela/DDP and SiHa/DDP cells. Meanwhile, its overexpression elevated the expression of circadian rhythm regulators as well as lowered the expression of multidrug resistance proteins and EMT pathway activation by suppressing PI3K/AKT pathway. PER2 was rhythmically expressed in cervical cancer tissues. Compared to cisplatin treatment at the lowest expression of PER2, tumor growth and proliferation of tumor cells were distinctly suppressed in mice treated with cisplatin at the highest expression of PER2. CONCLUSION: Our findings confirmed the circadian rhythm of PER2 in cervical cancer and its overexpression restrained the resistance to cisplatin in cervical cancer by PI3K/AKT pathway. It may improve cisplatin efficacy through considering the circadian rhythm of PER2.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Circadianas Period/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cronoterapia Farmacológica , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Nus , Proteínas Circadianas Period/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Arch Oral Biol ; 133: 105317, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34823152

RESUMO

OBJECTIVE: Cisplatin, a platinum-based anticancer drug, produces reactive oxygen species (ROS) in many cell types and induces mechanical allodynia in the hands and/or feet (chemotherapy-induced painful neuropathy: CIPN). In this study, we examined the possibility of inducing neuropathy in the oral region using oral keratinocytes and rats. METHODS: Human oral keratinocytes (HOKs) were used to evaluate ROS generation after cisplatin application by a ROS-reactive fluorescent assay. In rats, after cisplatin administrations (two times), the trigeminal ganglion (TG) was investigated by electron microscopy and quantitative RT-PCR. Using our proprietary assay system, oral pain-related behaviors were observed in cisplatin-treated rats. RESULTS: In rats, cisplatin administration reduced food intake and body weight. In electron microscopic analysis, glycogen granules in the TG were depleted following administration, although organelles were intact. In HOK cells, cisplatin significantly increased ROS generation with cell death, similar to glycolysis inhibitors. Cisplatin administration did not show any effects on Trpa1 mRNA levels in the TG. However, the same procedure induced hypersensitivity to mechanical stimulation and the TRPA1 agonist allyl isothiocyanate in the oral mucosa. Mechanical hypersensitivity was inhibited by the antioxidative drug α-lipoic acid and the TRPA1 antagonist HC-030031, similar to that of the hind paw. CONCLUSION: The present findings suggest that cisplatin induces TRPA1-mediated CIPN due to ROS generation in the oral region. This study will provide a better understanding of persistent oral pain in cancer patients.


Assuntos
Cisplatino , Doenças do Sistema Nervoso Periférico , Animais , Cisplatino/toxicidade , Humanos , Hiperalgesia/induzido quimicamente , Mucosa Bucal , Ratos , Canal de Cátion TRPA1
7.
Anticancer Res ; 42(1): 195-203, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34969725

RESUMO

BACKGROUND: Histopathological tumor regression grade is applied not to lymph nodes but primary tumors modified by preoperative treatments. This study focused on patients whose pathological examination at the time of surgery showed no residual tumor after chemo(radio)therapy in the primary lesion (ypT0) or lymph nodes (ypN0). PATIENTS AND METHODS: A total of 87 patients with clinical stage II/III thoracic esophageal cancer underwent esophagectomy following preoperative treatments to evaluate significances between pathological response and clinical outcomes; 51 patients with clinically definitive lymph node metastasis (cN+) were analyzed as a subgroup. RESULTS: ypT0 rates were 20.7% and 23.5%, and ypN0 rates were 47.1% and 27.5% in the whole cohort and in the cN+ subgroup, respectively. Disease-free survival, from surgery to relapse or death, was significantly influenced by ypN status (p=0.035) but not by ypT status in the 51 patients with definitive cN+ disease. Preoperative chemoradiation was an independent favorable factor for achievement of ypN0 in the 51 patients (odds ratio=0.09; p=0.007). CONCLUSION: ypN status was a predictive factor for DFS in patients treated with docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy, superior to ypT status, especially in patients with definitive cN+ disease.


Assuntos
Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Linfonodos/cirurgia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Quimiorradioterapia Adjuvante/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfonodos/efeitos da radiação , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Gradação de Tumores , Cuidados Pré-Operatórios/efeitos adversos
8.
Anticancer Res ; 42(1): 205-209, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34969726

RESUMO

BACKGROUND/AIM: We retrospectively evaluated the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) for T3 N0 glottic carcinoma without vocal cord fixation. PATIENTS AND METHODS: Twenty-five patients underwent TPF-CCRT without elective nodal irradiaion (ENI). After the RT of 40 Gy, five patients (20%) without tumor regression underwent surgery. Others underwent RT with a median total dose of 66 Gy. RESULTS: Of the five patients who underwent surgery after the RT of 40 Gy, two showed residual carcinoma pathologically and the other three were confirmed to have complete pathological response to the treatment. The 5-year local control rate was 87%. No patients exhibited regional failure. No acute toxicities of grade 5 or late toxicities ≥grade 3 were observed. CONCLUSION: TPF-CCRT provides excellent tumor control with acceptable toxicities. CCRT while omitting ENI is a reasonable approach for T3 N0 glottic carcinoma without vocal cord fixation.


Assuntos
Carcinoma/tratamento farmacológico , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Prega Vocal/efeitos dos fármacos , Adulto , Idoso , Carcinoma/patologia , Carcinoma/radioterapia , Carcinoma/cirurgia , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/cirurgia , Estadiamento de Neoplasias , Prega Vocal/efeitos da radiação , Prega Vocal/cirurgia
9.
J Toxicol Environ Health A ; 85(1): 29-42, 2022 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-34445936

RESUMO

The aim of this study was to investigate changes in the intracellular metabolism resulting from cisplatin (CDDP)-induced nephrotoxicity in normal kidney tubular epithelial NRK-52E cells. Cytotoxicity, cell cycle analysis, and apoptotic cell death were all evaluated in NRK-52E cells treated with CDDP. Subsequently, proton nuclear magnetic resonance (1H-NMR) spectroscopy was used to investigate cellular metabolic profiles. CDDP-induced nephrotoxicity was determined in vivo model. Cytotoxicity in the NRK-52E cells significantly rose following treatment with CDDP and these increases were found to be concentration-dependent. Both p53 and Bax protein expression was increased in CDDP-treated NRK-52E cells, correlating with enhanced cellular apoptosis. In addition, a number of metabolites were altered in both media and cell lysates in these cells. In cell lysates, citrate, creatinine, and acetate levels were dramatically reduced following treatment with 20 µM CDDP concentrations, while glutamate level was elevated. Lactate and acetate levels were significantly increased in culture media but citrate concentrations were reduced following high 20 µM CDDP concentrations incubation. In addition, excretion of clusterin, calbindin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), selenium binding protein 1 (SBP1), and pyruvate kinase M2 (PKM2) into the culture media was significantly increased in CDDP-treated cells while expression of acetyl CoA synthetase 1 (AceCS1) was markedly reduced in these cells. These findings suggest that acetate-dependent metabolic pathway may be a reliable and useful biomarker for detecting CDDP-induced nephrotoxicity. Taken together, data demonstrate that the discovery of novel biomarkers by metabolite profiling in target cells may contribute to the detection of nephrotoxicity and new drug development.


Assuntos
Injúria Renal Aguda/metabolismo , Cisplatino/toxicidade , Acetatos/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Metabolômica , Modelos Biológicos , Ratos
10.
BMC cancer ; 21(1): 575-678, May., 2021. ilus, graf, tab
Artigo em Inglês | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1224518

RESUMO

BACKGROUND: No biomarker is available for identifying cancer patients at risk of developing nephrotoxicity when treated with cisplatin. METHODS: We performed microRNA (miRNA) sequencing using plasma collected 5 days after cisplatin treatment (D5) from twelve patients with head and neck cancer with and without nephrotoxicity (grade ≥ 2 increased serum creatinine). The most differentially expressed miRNAs between the two groups were selected for quantification at baseline and D5 in a larger cohort of patients. The association between miRNAs and nephrotoxicity was evaluated by calculating the odds ratio (OR) from univariate logistic regression. Receiver operating characteristic curves (ROC) were used to estimate the area under the curve (AUC), sensitivity, and specificity. RESULTS: MiR-3168 (p = 1.98 × 10− 8 ), miR-4718 (p = 4.24 × 10− 5 ), and miR-6125 (p = 6.60 × 10− 5 ) were the most differentially expressed miRNAs and were further quantified in 43, 48, and 53 patients, respectively. The baseline expression of miR-3168 (p = 0.0456, OR = 1.03, 95% CI: 1.00­1.06) and miR-4718 (p = 0.0388, OR = 1.56, 95% CI: 1.03­ 2.46) were associated with an increased risk of nephrotoxicity, whereas miR-6125 showed a trend (p = 0.0618, OR = 1.73, 95% CI: 0.98­3.29). MiR-4718 showed the highest AUC (0.77, 95% CI: 0.61­0.93) with sensitivity of 66.76 and specificity of 79.49. CONCLUSIONS: We have provided evidence of baseline plasmatic expression of miR-3168, miR-6125, and miR-4718 as potential predictors of cisplatin-induced nephrotoxicity.


Assuntos
Cisplatino , MicroRNAs , Nefropatias , Neoplasias
11.
Int J Mol Sci ; 22(24)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34948109

RESUMO

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.


Assuntos
Injúria Renal Aguda , Antígeno B7-H1 , Cisplatino/efeitos adversos , Células Epiteliais/metabolismo , Técnicas de Transferência de Genes , Túbulos Renais Proximais/metabolismo , Regulação para Cima , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/terapia , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/genética , Linfócitos T CD4-Positivos/metabolismo , Cisplatino/farmacologia , Modelos Animais de Doenças , Macrófagos/metabolismo , Camundongos
12.
Int J Mol Sci ; 22(24)2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34948122

RESUMO

The pro-apoptotic tumor suppressor BIN1 inhibits the activities of the neoplastic transcription factor MYC, poly (ADP-ribose) polymerase-1 (PARP1), and ATM Ser/Thr kinase (ATM) by separate mechanisms. Although BIN1 deficits increase cancer-cell resistance to DNA-damaging chemotherapeutics, such as cisplatin, it is not fully understood when BIN1 deficiency occurs and how it provokes cisplatin resistance. Here, we report that the coordinated actions of MYC, PARP1, and ATM assist cancer cells in acquiring cisplatin resistance by BIN1 deficits. Forced BIN1 depletion compromised cisplatin sensitivity irrespective of Ser15-phosphorylated, pro-apoptotic TP53 tumor suppressor. The BIN1 deficit facilitated ATM to phosphorylate the DNA-damage-response (DDR) effectors, including MDC1. Consequently, another DDR protein, RNF8, bound to ATM-phosphorylated MDC1 and protected MDC1 from caspase-3-dependent proteolytic cleavage to hinder cisplatin sensitivity. Of note, long-term and repeated exposure to cisplatin naturally recapitulated the BIN1 loss and accompanying RNF8-dependent cisplatin resistance. Simultaneously, endogenous MYC was remarkably activated by PARP1, thereby repressing the BIN1 promoter, whereas PARP inhibition abolished the hyperactivated MYC-dependent BIN1 suppression and restored cisplatin sensitivity. Since the BIN1 gene rarely mutates in human cancers, our results suggest that simultaneous inhibition of PARP1 and ATM provokes a new BRCAness-independent synthetic lethal effect and ultimately re-establishes cisplatin sensitivity even in platinum-refractory cancer cells.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Proteínas Quinases/química
13.
JAMA Netw Open ; 4(12): e2138470, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34928359

RESUMO

Importance: Nedaplatin-based concurrent chemoradiotherapy (CCRT) regimen at 2 years was noninferior to cisplatin-based regimen in patients with locoregional, stage II to IVB nasopharyngeal carcinoma (NPC) and was associated with fewer late adverse events, but longer-term outcomes and toxicity are unclear. Objective: To evaluate the 5-year outcomes and late toxicity profile of nedaplatin-based CCRT in patients with locoregional, stage II to IVB NPC. Design, Settings, and Participants: This 5-year follow-up secondary analysis of an open-label, noninferiority, multicenter randomized clinical trial enrolled patients with nonkeratinizing stage II to IVB NPC between January 16, 2012, and July 16, 2014, with a median follow-up duration of 78 months (IQR, 3-99 months). Data analysis was conducted from November 10, 2020, to July 8, 2021. Interventions: Patients were randomly assigned (1:1) to receive nedaplatin (100 mg/m2)- or cisplatin (100 mg/m2)-based chemotherapy every 3 weeks for 3 cycles concurrently with intensity-modulated radiotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS). Secondary end points were overall survival, distant metastasis-free survival, and locoregional relapse-free survival. Results: A total of 402 eligible participants were enrolled (median [IQR] age, 45 [18-65] years; 302 [75.1%] male). Patients were randomly assigned to receive nedaplatin- or cisplatin-based CCRT (n = 201 for each): 196 patients (97.5%) started nedaplatin-based CCRT and 197 patients (98.0%) started cisplatin-based CCRT. Intention-to-treat analysis demonstrated a 5-year progression-free survival rate of 81.4% (95% CI, 75.9%-86.9%) for the cisplatin group and 79.8% (95% CI, 74.1%-85.5%) for nedaplatin group, with a difference of 1.6% (95% CI, -6.3% to 9.5%; P = .002 for noninferiority). No significant survival differences were observed between the cisplatin and nedaplatin groups for 5-year overall survival (89.4% vs 88.8%, P = .63), distant metastasis-free survival (85.9% vs 90.4%, P = .17), and locoregional relapse-free survival (92.6% vs 89.6%, P = .17) rates. The cisplatin group had a higher incidence of grade 3 and 4 auditory toxic effects than the nedaplatin group (35 [17.7%] vs 21 [10.5%], P = .04). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, long-term analysis confirmed that nedaplatin-based CCRT could be regarded as an alternative doublet treatment strategy to cisplatin-based CCRT in stage II to IVB NPC. Trial Registration: ClinicalTrials.gov Identifier: NCT01540136.


Assuntos
Quimiorradioterapia/efeitos adversos , Cisplatino/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Compostos Organoplatínicos/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Quimiorradioterapia/métodos , Cisplatino/toxicidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/toxicidade , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
14.
BMC Res Notes ; 14(1): 454, 2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34922615

RESUMO

OBJECTIVE: Cisplatin is a conventional anticancer drug that generates reactive oxygen species and causes apoptosis. However, many cancer cells develop alterations in the ATP binding cassette transporter responsible for the uptake and efflux process, which leads to resistance. Many natural products have shown potential to compete with ATP binding cassette transporter and may sensitize resistant cells to cisplatin. Studies have shown pro-oxidant effect of carotenoids that promote apoptosis of cancer cells. Bixin and fucoxanthin are well-known carotenoids with known antioxidant properties, however their bioactivity in lung cancer cells, clinically known to develop resistance due to ATP binding cassette transporter, has been minimally studied. This study is the first to investigate the potential of bixin and fucoxanthin to sensitize human lung cancer cell line, A549 and cervical cancer cell line, HeLa, to cisplatin. Drug combination method developed by Chou and Talalay theorem was employed. RESULT: Employing the best combination ratio, this study shows selective sensitization of cancer cells to cisplatin after bixin and fucoxanthin treatment. Further study on the mechanism of action in specific types of cancer cells is warranted. It may improve cisplatin sensitivity in tumors and rational use of cancer drugs.


Assuntos
Neoplasias Pulmonares , Neoplasias do Colo do Útero , Carotenoides , Cisplatino/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Xantofilas
15.
BMC Vet Res ; 17(1): 350, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34784920

RESUMO

BACKGROUND: Gentamicin (GM) is a low-cost, low-resistance antibiotic commonly used to treat gram-negative bacterial diseases. Cisplatin (Csp) is a platinum-derived anti-neoplastic agent. This experiment aimed to identify the early signs of gentamicin and cisplatin-induced nephrotoxicity in rats. Thirty Wistar rats were divided into three groups of 10: a control group, which received no treatment; a gentamicin group administered by a dose of (100 mg/kg, IP) for 7 consecutive days, and a cisplatin group was administered intraperitoneal in a dose of (1.5 mg/kg body weight) repeated twice a week for 3 weeks. RESULTS: Both experimental groups exhibited increased levels of creatinine, urea, and uric acid, with the cisplatin-treated group showing higher levels than the gentamicin group. Experimental groups also exhibited significantly increased Malondialdehyde (MDA), reduced glutathione (GSH), and glutathione peroxidase (GSH-Px) with more pronounced effects in the cisplatin-treated group. Further, both experimental groups exhibited significant up-regulation of Tumor Necrosis Factor α (TNF-α), caspase-3, and Bax and down regulation of Bcl-2. CONCLUSION: These findings confirm the use of necrotic, apoptotic genes as early biomarkers in the detection of tubular kidney damage. Further, cisplatin was shown to have a greater nephrotoxic effect than gentamicin; therefore, its use should be constrained accordingly when co-administered with gentamicin.


Assuntos
Cisplatino/toxicidade , Gentamicinas/toxicidade , Nefropatias/induzido quimicamente , Animais , Antibacterianos/toxicidade , Antineoplásicos/toxicidade , Apoptose/genética , Biomarcadores , Caspase 3/genética , Genes bcl-2/genética , Nefropatias/patologia , Masculino , Necrose/genética , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Proteína X Associada a bcl-2/genética
16.
Zhonghua Wei Chang Wai Ke Za Zhi ; 24(11): 977-983, 2021 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-34823298

RESUMO

Objective: To investigate the effects of radical radiotherapy combined with different chemotherapy regimens (fluorouracil-based versus docetaxel plus cisplatin) on the incidence of radiation intestinal injury and the prognosis in patients with non-metastatic anal squamous cell carcinoma. Methods: A retrospective cohort study was conducted to recruit non-metastatic anal squamous cell carcinoma patients who underwent chemoradiotherapy in the Sixth Affiliated Hospital of Sun Yat-sen University and Nanfang Hospital from July 2013 to January 2021. Inclusion criteria: (1) newly diagnosed anal and perianal squamous cell carcinoma; (2) completed radical radiotherapy combined with concurrent chemotherapy; (3) tumor could be evaluated before radiotherapy. Exclusion criteria: (1) no imaging evaluation before treatment, or the tumor stage could not be determined; (2) patients undergoing local or radical resection before radiotherapy; (3) distant metastasis occurred before or during treatment; (4) recurrent anal squamous cell carcinoma. A total of 55 patients (48 from the Sixth Affiliated Hospital of Sun Yat-sen University and 7 from Nanfang Hospital) were given fluorouracil (the 5-FU group, n=34) or docetaxel combined with the cisplatin (the TP group, n=21). The evaluation of radiation intestinal injury, hematological toxicity and 3-year disease-free survival (DFS) rate were compared between the two groups. The effects of chemotherapy regimen and other clinicopathological factors on the incidence and severity of acute and chronic radiation intestinal injury were analyzed. The assessment of radiation intestinal injury was based on the American Cancer Radiotherapy Cooperation Group (RTOG) criteria. Results: During radiotherapy and within 3 months after radiotherapy, a total of 45 patients developed acute radiation intestinal injury, including 18 cases of grade 1 (32.7%), 22 cases of grade 2 (40.0%) and 5 cases of grade 3 (9.1%). No patient developed chronic radiation intestinal injury. Among the 34 patients in the 5-FU group, 21 had grade 2-3 radiation intestinal injury (21/34, 61.8%), which was significantly higher than that in the TP group (6/21, 28.6%) (χ(2)=5.723, P=0.017). Multivariate analysis showed that 5-FU chemotherapy regimen was an independent risk factor for radiation intestinal injury (HR=4.038, 95% CI: 1.250-13.045, P=0.020). With a median follow-up period of 26 (5-94) months, the 3-year DFS rate of patients in TP group and 5-FU group was 66.8% and 77.9%, respectively, whose difference was not significant (P=0.478). Univariate analysis showed that the DFS rate was associated with sex, age, tumor location, T stage, N stage, and induction chemotherapy (all P<0.05), while the DFS rate was not associated with chemotherapy regimen or radiation intestinal injury (both P>0.05). Multivariate analysis revealed that age ≥ 50 years old was an independent risk factor affecting the prognosis of patients (HR=8.301, 95% CI: 1.130-60.996, P=0.038). Conclusions: For patients with non-metastatic anal squamous cell carcinoma, radical radiotherapy combined with TP chemotherapy regimen can significantly reduce the incidence of radiation intestinal injury as compared to 5-FU regimen. However, due to the short follow-up time, the effect of different chemotherapy regimens on the prognosis is not yet clear.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapia , Carcinoma de Células Escamosas/radioterapia , Quimiorradioterapia , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Retrospectivos
17.
Hinyokika Kiyo ; 67(10): 475-477, 2021 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-34742174

RESUMO

Malignant peritoneal mesothelioma is generally characterized by chief complaints such as abdominal mass and abdominal pain. We report a case of malignant peritoneal mesothelioma diagnosed as an inguinal mass. A 69-year-old man was referred to our hospital complaining of abdominal distension and swelling in the right inguinal region. Abdominal/pelvic contrast-enhanced computed tomography revealed a 22 cm tumor from the right inguinal canal to the peritoneal cavity and a large amount of ascites. Because imaging analyses revealed no metastasis, we planned tumor resection. We resected the tumor with the peritoneum and right testis and sampled some nodules in the mesentery. Histopathological examination of the tumor led to the diagnosis of epithelial malignant mesothelioma. Adhering to chemotherapy guidelines for pleural malignant mesothelioma, six courses of pemetrexed and cisplatin combination chemotherapy were performed. He is alive with no evidence of new local tumor or nodules in the mesentery 1 year postoperatively.


Assuntos
Mesotelioma Maligno , Mesotelioma , Neoplasias Peritoneais , Idoso , Cisplatino , Humanos , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/tratamento farmacológico , Pemetrexede , Neoplasias Peritoneais/diagnóstico por imagem
18.
Ann Palliat Med ; 10(10): 10575-10583, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34763504

RESUMO

BACKGROUND: To analyze the clinical effect of bevacizumab combined with cisplatin in the treatment of malignant pleural effusion and ascites. METHODS: A total of 86 patients with malignant pleural effusion and ascites admitted from June 2018 to September 2020 were selected as the research participants and randomly divided into a control group and observation group, with 43 cases in each group. The control group was given cisplatin intracavitary perfusion scheme, and the observation group was given bevacizumab combined with cisplatin intracavitary perfusion scheme. The Symptom Checklist 90 (SCL-90), Hamilton Depression Scale (HAM-D), and Hamilton Anxiety Scale (HAM-A) were used to evaluate participants' self-perceived negative symptoms, depression, and anxiety. The therapeutic effect and adverse reactions of the 2 groups were compared. The t-test was used for measurement data, and c2 test was used for enumeration data. Statistical significance was considered at P<0.05. RESULTS: After treatment, the serum levels of hypoxia inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF) in the observation group were significantly decreased and statistically lower than those in the control group (both P<0.05); the malignant pleural and abdominal water volume, average urine volume, and average chest circumference of the observation group were improved, and the difference was statistically significant compared with the control group (all P<0.05). The scores of each factor of SCL-90 in the observation group were decreased, among which the scores of somatization, interpersonal sensitivity, depression, anxiety, hostility, and terror in the observation group were significantly lower than those in the control group (all P<0.05); after treatment, the HAMD and HAMA scores of the observation group decreased, and the scores of HAMD (13.71±5.98) and HAMA (17.62±3.98) of the observation group were significantly lower than the score of (16.52±5.75) and (21.54±4.77) of the control group (both P<0.05). CONCLUSIONS: In the clinical treatment of malignant pleural effusion and ascites, bevacizumab combined with cisplatin intracavitary perfusion can improve the clinical treatment effect, reduce the depression and anxiety of patients, optimize patient quality of life, and improve the safety of treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100048959.


Assuntos
Neoplasias Pulmonares , Derrame Pleural Maligno , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ascite/tratamento farmacológico , Ascite/etiologia , Bevacizumab/uso terapêutico , Cisplatino/efeitos adversos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Derrame Pleural Maligno/tratamento farmacológico , Qualidade de Vida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular
19.
Otolaryngol Clin North Am ; 54(6): 1101-1115, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34774227

RESUMO

Ototoxicity refers to damage to the inner ear that leads to functional hearing loss or vestibular disorders by selected pharmacotherapeutics as well as a variety of environmental exposures (eg, lead, cadmium, solvents). This article reviews the fundamental mechanisms underlying ototoxicity by clinically relevant, hospital-prescribed medications (ie, aminoglycoside antibiotics or cisplatin, as illustrative examples). Also reviewed are current strategies to prevent prescribed medication-induced ototoxicity, with several clinical or candidate interventional strategies being discussed.


Assuntos
Orelha Interna , Ototoxicidade , Aminoglicosídeos/efeitos adversos , Antibacterianos/efeitos adversos , Cisplatino/efeitos adversos , Humanos
20.
Am J Case Rep ; 22: e933906, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34725317

RESUMO

BACKGROUND Peritoneal metastasis is a common progression of abdominal-pelvic cancers, and it is associated with poorer oncological prognosis when compared to other metastasis sites. Its treatment has limited results, mainly because of poor bioavailability of chemotherapy within the abdominal cavity after systemic administration. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been proposed as a novel method to deliver chemotherapy directly into the peritoneal surface; it combines the effectiveness and response of an intraperitoneal therapy with benefits of a minimally invasive approach. The laparoscopic capnoperitoneum is used to instill chemotherapy particles in a more efficient way for distribution and penetration when compared to peritoneal lavage. In the present study, we describe the first PIPAC performed in Brazil, according to the standard technique previously described with the Capnopen® nebulizer device, as well as technique details based on our literature review. CASE REPORT A 67-year-old man with pancreatic adenocarcinoma metastatic to the liver at first diagnosis underwent systemic treatment with the FOLFIRINOX protocol. After a major clinical response due to systemic treatment, pancreaticoduodenectomy was performed with resection and radiofrequency ablation of hepatic nodules. After 7 months of follow-up, the patient's condition evolved with symptomatic relapse in the peritoneum. Aiming at better control of this site, multiple PIPAC procedures were performed, showing excellent control of the peritoneal cavity disease. The patient had a sustained response in the peritoneal cavity and showed systemic disease progression 6 months after the first PIPAC procedure, which deceased at 20 months after the first PIPAC procedure and 42 months after the primary diagnosis. CONCLUSIONS This report shows that the PIPAC procedure is reproducible elsewhere, with safety and good functional results.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Neoplasias Peritoneais , Aerossóis/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Brasil , Cisplatino/uso terapêutico , Humanos , Masculino , Nebulizadores e Vaporizadores , Recidiva Local de Neoplasia , Neoplasias Peritoneais/tratamento farmacológico
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