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1.
Life Sci ; 289: 120243, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34922941

RESUMO

Intestinal mucositis (IM) is a critical side-effect associated with antineoplastic therapy. Treatment available is only palliative and often not effective. However, alternative therapeutic strategies, such as probiotics, have attracted significant attention due to their immune-modulatory action in several diseases. Thus, the present study aims to elucidate the therapeutic potential of the probiotic strain Bifidobacterium longum 51A in a murine model of mucositis induced by irinotecan. Due to the scarcity of studies on dose-response and viability (probiotic vs paraprobiotic), we first evaluated which dose and cell viability would be most effective in treating mucositis. In this study, the oral pretreatment with viable B. longum 51A at a concentration of 1 × 109 CFU/mL reduced the daily disease activity index (p < 0.01), protected the intestinal architecture, preserved the length of the intestine (p < 0.05), and reduced intestinal permeability (p < 0.01), inflammation, and oxidative damage (p < 0.01) induced by irinotecan. Also, treatment with B. longum 51A increased the production of secretory immunoglobulin A (p < 0.05) in the intestinal fluid of mice with mucositis. Furthermore, B. longum 51A reversed the mucositis-induced increase in Enterobacteriaceae bacterial group in the gut (p < 0.01). In conclusion, these results showed that oral administration of B. longum 51A protects mice against intestinal damage caused by irinotecan, suggesting its use as a potential probiotic in therapy during mucositis.


Assuntos
Bifidobacterium longum , Microbioma Gastrointestinal/efeitos dos fármacos , Enteropatias , Irinotecano/efeitos adversos , Mucosite , Probióticos/farmacologia , Animais , Feminino , Enteropatias/induzido quimicamente , Enteropatias/microbiologia , Enteropatias/terapia , Irinotecano/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Mucosite/induzido quimicamente , Mucosite/microbiologia , Mucosite/terapia
2.
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
3.
Oncology ; 99(10): 665-672, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34515197

RESUMO

BACKGROUND: Due to few efficacious options in later lines of therapy in metastatic colorectal cancer (mCRC), there has been considerable interest in the possibility of retreatment with previously administered agents. This study investigated the efficacy and safety of irinotecan retreatment (IRI2) in patients with refractory mCRC. METHODS: We performed a retrospective analysis of patients with mCRC who were retreated with irinotecan-based regimens. The retreatment regimens with anti-epidermal growth factor receptor therapies were excluded. RESULTS: A total of 64 patients were included. Patients had a median age of 56 years and were offered mainly in the setting of third- or fourth-line therapy with IRI2. The disease control rate was 78.2% including an objective response of 23.5%. Median progression-free survival and overall survival were 5.5 and 19.3 months, respectively. The most frequent grade 3 or higher toxicities were nausea/vomiting (27.9%) and neutropenia (25%). CONCLUSION: IRI2 might be a reasonable option for heavily pretreated patients with mCRC who achieved disease control with prior irinotecan therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Pessoa de Meia-Idade , Metástase Neoplásica , Retratamento , Estudos Retrospectivos , Resultado do Tratamento
4.
Expert Opin Drug Metab Toxicol ; 17(10): 1157-1163, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34486919

RESUMO

INTRODUCTION: Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking. AREAS COVERED: This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients. EXPERT OPINION: Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Irinotecano/administração & dosagem , Farmacogenética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Genótipo , Glucuronosiltransferase/genética , Humanos , Irinotecano/efeitos adversos , Neutropenia/induzido quimicamente , Medicina de Precisão , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos
5.
Eur J Cancer ; 157: 21-30, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34464782

RESUMO

BACKGROUND: The efficacy of modified FOLFIRINOX (mFOLFIRINOX) as a second-line chemotherapy treatment for metastatic pancreatic adenocarcinoma (mPAC), remains unclear. This multi-center randomised phase III trial aimed to elucidate the efficacy of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients with good performance status. PATIENTS AND METHODS: Eighty mPAC patients (age, 19-75 years) refractory to first-line gemcitabine-based chemotherapy were randomly selected to receive mFOLFIRINOX or S-1. mFOLFIRINOX comprised oxaliplatin (65 mg/m2), irinotecan (135 mg/m2), and leucovorin (400 mg/m2) on day 1 and continuous 5-FU infusion (1000 mg/m2) over 24 h on days 1-2 every 2 weeks. S-1 comprised body surface area-dependent oral S-1, divided into two doses per day on days 1-28 every 6 weeks. RESULTS: Overall survival was the primary endpoint. The objective response and disease control rates were higher in the mFOLFIRINOX than in the S-1 group (15% versus 2%; p = .04 and 67% versus 37%; p = .007). The median progression-free survival rates were 5.2 and 2.2 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted hazard ratio [HR]: .4; 95% confidence interval [CI]: .2-.6; p < .001). The median overall survival rates were 9.2 and 4.9 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted HR: .4; 95% CI: .2-.7; p = .002). Grade 3-4 adverse events occurred in 56% and 17% of the patients in the mFOLFIRINOX and S-1 groups, respectively (p < .001). CONCLUSION: Administration of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients refractory to gemcitabine-based chemotherapy resulted in increased survival rates than S-1 treatment alone.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Ácido Oxônico/efeitos adversos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Qualidade de Vida , Tegafur/efeitos adversos
6.
Curr Oncol ; 28(3): 2296-2307, 2021 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-34203031

RESUMO

Chemoembolization with irinotecan-loaded microspheres has proven effective in the treatment of unresectable liver metastases in the course of colorectal cancer (CRC). Most researchers recommend slowly administering the embolizate at the level of the lobar arteries, without obtaining visible stasis. However, there are reports of a relationship between postoperative embolizate retention in metastatic lesions and the response to treatment. To retain residual embolizate throughout the entire neoplastic lesion requires a temporary flow stop (stasis) within all supply vessels, which may cause temporary stasis in subsegmental or even segmental vessels. OBJECTIVE: To assess the risk of complications and post-embolization syndrome severity following chemoembolization of CRC metastatic liver lesions with microspheres loaded with Irinotecan, with regard to hepatic-artery branch level of temporary stasis. PATIENTS AND METHODS: The study included 52 patients (29 female, 23 male) with liver metastases from CRC, who underwent 202 chemoembolization treatments (mean: 3.88 per patient) with microspheres loaded with 100 mg irinotecan. Postembolization syndrome (PES) severity and complication occurrence were assessed with regard to the hepatic-artery branch level of temporary stasis. Adverse events were assessed according to Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events. RESULTS: Median survival from the start of chemoembolization was 13 months. From 202 chemoembolization sessions, 15 (7.4%) significant complications were found. The study found a significant relationship between the branch level of temporary stasis and the presence of complications (p < 0.001), with the highest number of complications observed with temporary stasis in segmental vessels. PES was diagnosed after 103 (51%) chemoembolization treatments. A significant association was found between PES severity and the branch level of temporary stasis (p < 0.001). CONCLUSIONS: The branch level of temporary stasis affected the severity of post-embolization syndrome. A significant association was found between the branch level of temporary stasis obtained in chemoembolization procedures and the presence of complications. The apparent lack of change in numbers of complications when stasis was applied at tumor supply vessels or subsegmental arteries may indicate the safe use of temporary stasis in some cases where colorectal cancer metastases are treated. Further research is needed to determine the most effective chemoembolization technique.


Assuntos
Quimioembolização Terapêutica , Neoplasias Colorretais , Neoplasias Hepáticas , Artérias , Quimioembolização Terapêutica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Irinotecano/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Microesferas
7.
BMC Cancer ; 21(1): 674, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34098908

RESUMO

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Irinotecano/administração & dosagem , Panitumumabe/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Irinotecano/efeitos adversos , Japão , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Panitumumabe/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento , Proteínas ras/sangue , Proteínas ras/genética
8.
Cancer Chemother Pharmacol ; 88(3): 543-553, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34117512

RESUMO

PURPOSE: SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan. METHODS: We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry. RESULTS: Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1. CONCLUSION: The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.


Assuntos
Irinotecano/administração & dosagem , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Neoplasias/tratamento farmacológico , Insuficiência Renal/fisiopatologia , Idoso , Área Sob a Curva , Cromatografia Líquida , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular , Humanos , Irinotecano/efeitos adversos , Irinotecano/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Estudos Prospectivos , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacocinética
9.
Biomolecules ; 11(6)2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067288

RESUMO

FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GN) are the most common chemotherapy regimens in first-line treatment of metastatic pancreatic cancer (PC). They have not been compared each other in a prospective trial, but only in retrospective studies, which can thus be affected by several biases. In order to overcome these biases, we took advantage of matching-adjusted indirect comparison (MAIC), that allows an indirect comparison by reducing cross-trial differences, and compared data from 268 patients treated with GN in a real-world setting with data from the 171 patients included in the FFX arm of the PRODIGE trial. Survival outcomes did not differ between the two populations. Overall survival was 11.1 months for both treatments (hazard ratio (HR) of FFX 1.10, 95% confidence interval (CI) 0.81-1.49; p = 0.527). Progression-free survival was 6.0 months with GN and 6.4 months with FFX (HR of FFX 1.11, 95% CI 0.82-1.50; p = 0.520). On the other hand, we observed a difference in the toxicity profiles: grade 3/4 anemia was more frequent with GN, whereas a higher occurrence of grade 3/4 vomiting and diarrhea was reported with FFX. FFX and GN show an equivalent efficacy but different safety profiles in the first-line therapy of metastatic pancreatic cancer. Searching for reliable predictive biomarkers is advised in order to improve therapeutic strategy in metastatic PC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Taxa de Sobrevida
10.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074038

RESUMO

Glioblastoma multiforme (GBM) has remained one of the most lethal and challenging cancers to treat. Previous studies have shown encouraging results when irinotecan was used in combination with temozolomide (TMZ) for treating GBM. However, irinotecan has a narrow therapeutic index: a slight dose increase in irinotecan can induce toxicities that outweigh its therapeutic benefits. SN-38 is the active metabolite of irinotecan that accounts for both its anti-tumor efficacy and toxicity. In our previous paper, we showed that SN-38 embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs) provides an efficient delivery and sustained release of SN-38 from SMPs in the brain tissues of rats. These properties of SMPs give them potential for therapeutic application due to their high efficacy and low toxicity. In this study, we tested the anti-tumor activity of SMP-based interstitial chemotherapy combined with TMZ using TMZ-resistant human glioblastoma cell line-derived xenograft models. Our data suggest that treatment in which SMPs are combined with TMZ reduces tumor growth and extends survival in mice bearing xenograft tumors derived from both TMZ-resistant and TMZ-sensitive human glioblastoma cell lines. Our findings demonstrate that combining SMPs with TMZ may have potential as a promising strategy for the treatment of GBM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Irinotecano/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Temozolomida/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Irinotecano/efeitos adversos , Camundongos , Microplásticos/química , Microscopia Eletrônica de Varredura , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J. coloproctol. (Rio J., Impr.) ; 41(2): 188-192, June 2021. tab, graf, ilus
Artigo em Inglês | LILACS | ID: biblio-1286991

RESUMO

Abstract Objective The present study aimed to evaluate the relationship between UGT1A1*28 gene polymorphism and the prevalence of neutropenia in patients with colorectal cancer treated with irinotecan. Method Thirteen studies were included. These papers were selected from the Virtual Health Library, Scientific Electronic Library Online, International Health Sciences Literature and PubMed, and their data were collected and evaluated using the BioEstat 5.3 software (BioEstat, Belém, PA, Brazil). Results Three genotypes were analyzed, namely 6/6 (wild type), 6/7, and 7/7. In total, 2,146 patients were included in the present study; of these, 55.6% (n=1,193) had 6/6 genotype, 37.3% (n=801) were heterozygous (6/7), and 7.1% (n=152) had the 7/7 genotype. A total of 1,672 (77.9%) patients displayed mild neutropenia, whereas 474 (22.1%) had severe neutropenia. When contrasting the 6/7 and 7/7 genotypes with the 6/6 genotype using statistical tests for meta-analysis, patients with the 7 allele, either Conclusion The analysis of the UGT1A1*28 gene polymorphism can aid the choice of treatment for patients with colorectal cancer in personalized medicine, increasing the chances of therapeutic success.


Resumo Objetivo Avaliar a relação do polimorfismo do gene UGT1A1*28 com a prevalência de neutropenia em pacientes com câncer colorretal submetidos a tratamento com o irinotecano. Método Foram incluídos 13 estudos sobre o tema proposto, selecionados nas bases de dados da Biblioteca Virtual de Saúde, Scientific Electronic Library Online, International Health Sciences Literature e PubMed.Os dados foramcoletados dos artigos científicos selecionados e avaliados com o auxílio do software BioEstat 5.3 (BioEstat, Belém, PA, Brasil). Resultados Osgenótipos analisados foram6/6 (tipo selvagem), 6/7 e 7/7. Foramincluídos 2.146 pacientes. Destes, 55,6% (n=1.193) apresentaram genótipo 6/6, 37,3% (n=801) eramheterozigotos (6/7) e 7,1%(n=152) tinhamo genótipo 7/7.Umtotal de 1.672 (77,9%) pacientes apresentou neutropenia leve e 474 (22,1%) neutropenia severa. Ao contrastar os genótipos 6/7 e 7/7 como 6/6, percebeu-se, coma execução dos testes estatísticos demetaanálise, que os pacientes como alelo 7, emhomozigose ou heterozigose, tinhammaior risco de desenvolver neutropenia severa que pacientes com o genótipo 6/6 (razão de chances =1,559; intervalo de confiança de 95%=1,163-2,090; p=0,003). Conclusão A análise do polimorfismo do gene UGT1A1*28 pode auxiliar na escolha do tratamento do paciente comcâncer colorretal, no contexto da medicina personalizada, ampliando, assim, as chances de sucesso terapêutico.


Assuntos
Humanos , Polimorfismo Genético , Neoplasias Colorretais/tratamento farmacológico , Neutropenia/epidemiologia , Prevalência , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico
12.
Eur J Cancer ; 151: 14-24, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33957442

RESUMO

BACKGROUND: This open-label, phase I/II study evaluated safety and efficacy for first-line liposomal irinotecan + oxaliplatin + 5-fluorouracil + leucovorin (NALIRIFOX). METHODS: Patients (aged ≥18 years) had locally advanced/metastatic pancreatic ductal adenocarcinoma (mPDAC), with an Eastern Cooperative Oncology Group performance status score of 0/1 and adequate organ function. Primary objectives were to determine the maximum tolerated dose (MTD) and to evaluate safety and tolerability. Treatment-emergent adverse events (TEAEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Efficacy end-points included progression-free survival (PFS) and overall survival (OS); disease assessments used Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: The MTD (liposomal irinotecan 50 mg/m2 [free-base equivalent], oxaliplatin 60 mg/m2, 5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2 every 2 weeks) was based on dose-limiting toxicities and cumulative safety data in four dose-exploration cohorts. The MTD was received by 32 of 56 patients, seven during dose exploration and 25 during dose expansion (median age 58.0 years [range, 39-76], 28 [87.5%] with metastatic disease at diagnosis [29 at study entry], and one receiving study treatment at data cutoff [26 February 2020]). Of these patients, 22 of 32 had grade ≥3 treatment-related TEAEs, most commonly neutropenia (31.3%), febrile neutropenia (12.5%) and hypokalaemia (12.5%); ten had serious treatment-related TEAEs; and three died from TEAEs considered unrelated to treatment. Median PFS and OS were 9.2 (95% CI: 7.69-11.96) and 12.6 (8.74-18.69) months, respectively. CONCLUSION: First-line NALIRIFOX for patients with locally advanced/mPDAC was generally manageable and tolerable. A randomised, controlled phase III study is underway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Fluoruracila/uso terapêutico , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Feminino , Fluoruracila/efeitos adversos , Humanos , Irinotecano/efeitos adversos , Leucovorina/efeitos adversos , Lipossomos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Espanha , Fatores de Tempo , Estados Unidos
13.
Eur J Cancer ; 151: 3-13, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33951545

RESUMO

BACKGROUND: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed. METHODS: We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX. RESULTS: In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329). CONCLUSION: This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.


Assuntos
Albuminas/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Cuidados Paliativos , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Albuminas/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Áustria , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Pontuação de Propensão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
14.
BMC Cancer ; 21(1): 537, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33975561

RESUMO

BACKGROUND: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GnP) have been recommended as the first-line chemotherapy for metastatic pancreatic cancer (mPC). However, the evidence is lacking comparing not only two regimens, but also sequential treatment (FFX-GnP vs. GnP-FFX). METHODS: Data of 528 patients (FFX, n = 371; GnP, n = 157) with mPC were collected retrospectively. Propensity score matching was conducted to alleviate imbalance of the two groups. Overall survival (OS), progression free survival (PFS), and toxicity of patients were analyzed. RESULTS: In the whole population, OS (12.5 months vs. 10.3 months, P = 0.05) and PFS (7.1 months vs. 5.8 months, P = 0.02) were longer in the FFX group before matching and after matching (OS: 11.8 months vs. 10.3 months, P = 0.02; PFS: 7.2 months vs. 5.8 months, P <  0.01). For sequential treatment, OS and PFS showed no significant difference. Interruptions of chemotherapy due to toxicities were more frequent (6.8 vs. 29.3%, P <  0.001) in the GnP group, and cessation of chemotherapy showed a significant association with mortality (z = - 1.94, P = 0.03). CONCLUSIONS: FFX achieved a longer overall survival than GnP in mPC, but not in the comparison for sequential treatment. More frequent adverse events followed by treatment interruptions during GnP might lead to a poor survival outcome. Therefore, FFX would be a better first-line treatment option than GnP for mPC.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pontuação de Propensão
15.
BMC Cancer ; 21(1): 564, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001059

RESUMO

BACKGROUND: The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. METHODS: FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, ß = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150-180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. DISCUSSION: FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. TRIAL REGISTRATION: EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Estudos Multicêntricos como Assunto , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Piridinas/efeitos adversos , Adulto Jovem , Proteínas ras/genética
16.
J Ethnopharmacol ; 276: 114200, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-33989737

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine suggests the use of natural extracts and compounds is a promising strategy to prevent irinotecan (CPT-11)-induced gut toxicity and resulting diarrhea. Previous work from our lab indicated the protective effect of Gegen Qinlian decoction; given this, we further speculated that Gegen Qinlian Pill (GQP) would exhibit similar therapeutic effects. The effective material basis as well as potential mechanisms underlying the effect of GQP for the treatment of CPT-11-induced diarrhea have not been fully elucidated. AIM OF THE STUDY: The application of natural extracts or compounds derived from Chinese medicine is deemed to a promising strategy to prevent irinotecan (CPT-11)-induced gut toxicity. The aim of this study was to investigated the beneficial effects of GQP on CPT-11-induced gut toxicity and further explored its anti-diarrheal mechanism. METHODS: First, the beneficial effect of GQP in alleviating diarrhea in mice following CPT-11 administration was investigated. We also obtained the effective ingredients in GQP from murine serum samples using HPLC-Q-TOF-MS analysis. Based on these active components, we next established an interaction network linking "compound-target-pathway". Finally, a predicted mechanism of action was obtained using in vivo GQP validation based on Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: A total of 19, GQP-derived chemical compounds were identified in murine serum samples. An interaction network linking "compound-target-pathway" was then established to illuminate the interaction between the components present in serum and their targets that mitigated diarrhea. These results indicated GQP exerted a curative effect on diarrhea and diarrhea-related diseases through different targets, which cumulatively regulated inflammation, oxidative stress, and proliferation processes. CONCLUSION: Taken together, this study provides a feasible strategy to elucidate the effective constituents in traditional Chinese medicine formulations. More specifically, this work detailed the basic pharmacological effects and underlying mechanism behind GQP's effects in the treatment of CPT-11-induced gut toxicity.


Assuntos
Diarreia/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Diarreia/sangue , Diarreia/induzido quimicamente , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Gastroenteropatias/sangue , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Irinotecano/efeitos adversos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas de Membrana/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/uso terapêutico , Comprimidos
17.
Oncol Res ; 28(7): 801-809, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34030768

RESUMO

Irinotecan, a topoisomerase inhibitor, is a common cytotoxic agent prescribed for metastatic colorectal cancer (mCRC) patients. Diarrhea is the most common adverse event (AE). The underlying mechanism of irinotecan-induced diarrhea is intestinal mucosal damage caused by SN-38 (active metabolite of irinotecan) hydrolyzed from SN-38G (inactive metabolite) by bacterial -glucuronidase (G). According to an animal study, silymarin reduces the activity of bacterial G without impairing antitumor efficacy. We conducted a prospective open-label pilot study to evaluate the effect of silymarin as supplementation in reducing toxicities of mCRC patients undergoing irinotecan-based chemotherapy. We enrolled and randomized 70 mCRC patients receiving first-line FOLFIRI (5-fluorouracil/leucovorin/irinotecan) plus bevacizumab. In each treatment cycle, the study group was administered silymarin capsules (150 mg) three times daily for 7 days. The study group experienced less AEs in diarrhea (5.7% vs. 14.6%, p=0.002) and nausea (27.0% vs. 40.2%, p=0.005) in comparison with the control group, but no significant differences in hepatic toxicities were observed. In conclusion, simultaneous administration of silymarin is a potential effective supplementation for reducing toxicities in mCRC patients undergoing first-line FOLFIRI plus bevacizumab, especially in diarrhea and nausea.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Silimarina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Diarreia/etiologia , Suplementos Nutricionais , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
18.
Cancer Chemother Pharmacol ; 88(3): 403-414, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34031756

RESUMO

PURPOSE: This phase I trial was performed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), preliminary efficacy, and pharmacokinetics (PK) of LY01610, a novel liposome-encapsulated irinotecan, in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: This trial was conducted in two stages. In the dose-escalation stage, patients with advanced ESCC refractory or intolerant to previous chemotherapy received escalating doses of LY01610. A recommended dose based on patient tolerance was then expanded in the second stage. LY01610 was administered intravenously every 2 weeks, except that the first cycle in dose escalation was 3 weeks to allow observation of DLTs. RESULTS: Twenty-four patients were enrolled across 4 dose levels (30, 60, 90 and 120 mg/m2). The DLTs included vomiting and febrile neutropenia, and the MTD was 90 mg/m2. The most common grade 3/4 adverse events were leukopenia in six patients (25.0%), anemia in six patients (25.0%) and neutropenia in five patients (20.8%). One patient achieved complete response, and four had partial response, including one patient receiving LY01610 at the starting dose of 30 mg/m2. Compared with conventional irinotecan, the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma. CONCLUSION: LY01610 demonstrated manageable toxicity and promising anti-tumor activity in patients with advanced ESCC. Future clinical development of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is warranted. TRIAL REGISTRATION: NCT04088604 at ClinicalTrials.gov.


Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Irinotecano/administração & dosagem , Inibidores da Topoisomerase I/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Irinotecano/efeitos adversos , Irinotecano/farmacocinética , Lipossomos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacocinética
19.
Zhongguo Fei Ai Za Zhi ; 24(3): 167-172, 2021 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-33819966

RESUMO

BACKGROUND: Among malignant tumors, lung cancer has the highest mortality rate. Small cell lung cancer (SCLC) is a kind of malignant lung cancer. Its doubling time is very fast. Patients are prone to drug resistance during treatment, and their condition often deteriorates rapidly after recurrence. Except for topotecan, there is a lack of effective second-line single-agent chemotherapy. This study aims to analysis the efficacy and safety of irinotecan (CPT-11) in the second-line treatment of refractory and relapsed SCLC. METHODS: A total of 107 SCLC patients were collected from the Department of Oncology, Jilin Guowen Hospital, who were diagnosed from April 2012 to March 2020, relapsed within 6 months after first-line treatment, and received second-line chemotherapy with single-agent CPT-11. Follow-up until November 2020, calculate the patient's progression free survival (PFS) and overall survival (OS), and summarize the effects and adverse reactions of CPT-11 chemotherapy. RESULTS: The patient's median PFS was 3.8 (3.4-4.4) months, median OS was 8.1 (6.5-10.9) months, objective response rate (ORR) was 16.82% (18/107), and DCR was 55.14% (59/107). The incidence of grade 3-4 adverse reactions in patients was relatively low. Among them, neutropenia was 13.08%, delayed diarrhea was 7.48%, nausea and vomiting was 17.76%, and liver function impairment was 6.54%. The influencing factors of PFS in single-agent CPT-11 second-line chemotherapy were gender (P=0.001), NSE (P=0.029), and effusion (P=0.040). While the influencing factors of OS were NSE level only (P=0.033). CONCLUSIONS: For patients with refractory relapsed SCLC, CPT-11 single-agent second-line chemotherapy has a certain effect, is well tolerated, and is worthy of promotion.
.


Assuntos
Antineoplásicos/administração & dosagem , Irinotecano/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Feminino , Humanos , Irinotecano/efeitos adversos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Recidiva , Carcinoma de Pequenas Células do Pulmão/mortalidade
20.
Biochem Pharmacol ; 190: 114566, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33865833

RESUMO

Bacterial ß-glucuronidase enzymes (BGUSs) are at the interface of host-microbial metabolic symbiosis, playing an important role in health and disease as well as medication outcomes (efficacy or toxicity) by deconjugating a large number of endogenous and exogenous glucuronides. In recent years, BGUSs inhibition has emerged as a new approach to manage diseases and medication therapy and attracted an increasing research interest. However, a growing body of evidence underlines great genetic diversity, functional promiscuity and varied inhibition propensity of BGUSs, which have posed big challenges to identifying BGUSs involved in a specific pathophysiological or pharmacological process and developing effective inhibition. In this article, we offered a general introduction of the function, in particular the physiological, pathological and pharmacological roles, of BGUSs and their taxonomic distribution in human gut microbiota, highlighting the structural features (active sites and adjacent loop structures) that affecting the protein-substrate (inhibitor) interactions. Recent advances in BGUSs-mediated deconjugation of drugs and carcinogens and the discovery and applications of BGUS inhibitors in management of medication therapy, typically, irinotecan-induced diarrhea and non-steroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy, were also reviewed. At the end, we discussed the perspectives and the challenges of tailoring BGUS inhibition towards precision medicine.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/enzimologia , Glucuronidase/antagonistas & inibidores , Glicoproteínas/farmacologia , Medicina de Precisão/métodos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Diarreia/induzido quimicamente , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/efeitos dos fármacos , Glucuronidase/metabolismo , Glicoproteínas/efeitos adversos , Humanos , Irinotecano/efeitos adversos , Irinotecano/farmacologia , Medicina de Precisão/tendências , Estrutura Secundária de Proteína , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacologia
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