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1.
BMC Cancer ; 22(1): 349, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361149

RESUMO

BACKGROUND: The prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma. METHODS: PubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities. RESULTS: Six retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31-58) for objective response and 66% (55-77) for disease control. Grade 3-4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3-16), 7% (3-11), and 8% (5-10) of chemotherapeutic cycles, respectively. 18% (7-32) and 6% (2-11) of patients suffered grade 3-4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment. CONCLUSION: Irinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results.


Assuntos
Neutropenia , Sarcoma de Ewing , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina , Dacarbazina/efeitos adversos , Humanos , Irinotecano/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Sarcoma de Ewing/tratamento farmacológico , Temozolomida/uso terapêutico
2.
PLoS One ; 17(5): e0267027, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35503762

RESUMO

ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.


Assuntos
Neoplasias da Mama , Imunoconjugados , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/uso terapêutico , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Trastuzumab/genética , Trastuzumab/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
6.
Bioengineered ; 13(4): 9754-9765, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35411835

RESUMO

In the recent study, we have developed novel tumor targetable and pH-sensitive PLGA nanoparticles co-loaded with camptothecin (CPT) and metformin (Metf) to simultaneously improve the Type 2 Diabetes Mellitus (T2DM) and malignant breast cancer. To improve the drug loading efficiency, the hydrophobic CPT was conjugated with PLGA polymer by the pH-sensitive hydrazone bonds (hyd). Then, the Metf was physically loaded into the hydrophobicity inner core of CPT-conjugated PLGA nanocomplex to form the dual drugs-loaded nanoparticles (NP/CPT-Metf). Furthermore, on the surface of NP/CPT-Metf was modified with tumor-homing CGKRK peptides to obtain the tumor targetable and pH-sensitive polymer nanoparticles (CNP/CPT-Metf). It was demonstrated that the developed CNP/CPT-Metf displayed sufficient sensitivity to the weak acidic tumor microenvironment. Besides, excellent ability of CNP/CPT-Metf to mediate accumulation of drugs in cells and tumor tissues finally in turn resulted in a signal enhanced anti-tumor effect. Furthermore, it was demonstrated as well that CNP/CPT-Metf was able of significantly alleviating the type 2 diabetes mellitus in diabetic mice. In summary, the developed multifunctional polymer nanoparticles might represent a promising strategy for simultaneously improve the T2DM and treat malignant breast cancer.


Assuntos
Neoplasias da Mama , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Nanopartículas , Animais , Neoplasias da Mama/tratamento farmacológico , Camptotecina/química , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/química , Polímeros , Microambiente Tumoral
7.
Oncologist ; 27(4): 292-298, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35380713

RESUMO

BACKGROUND: Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. PATIENTS AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). CONCLUSION: In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted.Clinical Trial Registration: NCT02292758.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Camptotecina/efeitos adversos , Cetuximab/efeitos adversos , Neoplasias Colorretais/patologia , Fluoruracila , Humanos , Irinotecano/uso terapêutico
8.
Int J Nanomedicine ; 17: 1381-1395, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35369034

RESUMO

Background: Hepatocellular carcinoma (HCC), arising from hepatocytes, is the most common primary liver cancer. It is urgent to develop novel therapeutic approaches to improve the grim prognosis of advanced HCC. 10-hydroxycamptothecin (HCPT) has good antitumor activity in cells; however, its hydrophobicity limits its application in the chemotherapy of HCC. Recently, nanoscale porphyrin metal-organic frameworks have been used as drug carriers due to their low biotoxicity and photodynamic properties. Methods: Nanoscale zirconium porphyrin metal-organic frameworks (NMOFs) were coated with arginine-glycine-aspartic acid (RGD) peptide to prepare NMOFs-RGD first. The HepG2 cell line, zebrafish embryos and larvae were used to test the biotoxicity and fluorescence imaging capability of NMOFs-RGD both in vitro and in vivo. Then, NMOFs were used as the skeleton, HCPT was assembled into the pores of NMOFs, while RGD peptide was wrapped around to synthesize a novel kind of nanocomposites, HCPT@NMOFs-RGD. The tissue distribution and chemo- and photodynamic therapeutic effects of HCPT@NMOFs-RGD were evaluated in a doxycycline-induced zebrafish HCC model and xenograft mouse model. Results: NMOFs-RGD had low biotoxicity, good biocompatibility and excellent imaging capability. In HCC-bearing zebrafish, HCPT@NMOFs-RGD were specifically enriched in the tumor by binding specifically to integrin αvß3 and led to a reduction in tumor volume. Moreover, the xenografts in mice were eliminated remarkably following HCPT@NMOFs-RGD treatment with laser irradiation, while little morphological change was found in other main organs. Conclusion: The nanocomposites HCPT@NMOFs-RGD accomplish tumor targeting and play synergistic chemo- and photodynamic therapeutic effects on HCC, offering a novel imaging-guided drug delivery and theranostic platform.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanocompostos , Fotoquimioterapia , Animais , Camptotecina/análogos & derivados , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Oligopeptídeos , Peixe-Zebra
9.
BMC Genomics ; 23(1): 256, 2022 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-35366818

RESUMO

BACKGROUND: Ophiorrhiza pumila (Rubiaceae) is capable of producing camptothecin (CPT), one monoterpene indole alkaloid extensively employed in the treatment of multiple cancers. Transcription factors (TFs) GATA are a group of transcription regulators involved in plant development and metabolism, and show the feature of binding to the GATA motif within the promoters of target genes. However, GATA TFs have not been characterized in O. pumila. RESULT: In this study, a total of 18 GATA genes classified into four subfamilies were identified, which randomly distributed on 11 chromosomes of O. pumila. Synteny analysis of GATA genes between O. pumila and other plant species such as Arabidopsis thaliana, Oryza sativa, Glycine max, Solanum lycopersicum, Vitis vinifera, and Catharanthus roseus genomes were analyzed. Tissue expression pattern revealed that OpGATA1 and OpGATA18 were found to be correlated with ASA, MK, CPR and GPPS, which were highly expressed in leaves. OpGATA7, showed high expression in roots as most of the CPT biosynthetic pathway genes did, suggesting that these OpGATAs may be potential candidates regulating CPT biosynthesis in O. pumila. CONCLUSIONS: In this study, we systematically analyzed the OpGATA TFs, and provided insights into the involvement of OpGATA TFs from O. pumila in CPT biosynthesis.


Assuntos
Camptotecina , Rubiaceae , Vias Biossintéticas , Raízes de Plantas/genética , Rubiaceae/genética , Rubiaceae/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Cancer Treat Rev ; 106: 102378, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35430509

RESUMO

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd-related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd-related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms. SEARCH STRATEGY AND SELECTION CRITERIA: References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors' own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.


Assuntos
Imunoconjugados , Doenças Pulmonares Intersticiais , Pneumonia , Camptotecina/análogos & derivados , Humanos , Imunoconjugados/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Trastuzumab/efeitos adversos
11.
Expert Opin Drug Discov ; 17(5): 427-436, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35426752

RESUMO

INTRODUCTION: Gastric cancer is common worldwide, and while multiple therapeutic options exist, the prognosis remains poor. Tumors may overexpress HER2. While targeting HER2 with trastuzumab provides a survival benefit, options following progression are limited. Subsequent trials of HER2-targeted agents failed to improve outcomes. Recently, DESTINY-Gastric01 demonstrated a survival benefit utilizing the antibody-drug conjugate (ADC) trastuzumab deruxtecan in gastric cancer patients that progressed on trastuzumab. AREAS COVERED: /The authors give background to gastric cancer/HER2 and discuss prognostic implications of HER2 overexpression. They also describe initial trials of anti-HER2 therapy, resistance mechanisms, and ADC development/optimization. Finally, the authors review DESTINY-Gastric01 and provide future perspectives. EXPERT OPINION: While the 2010 ToGA trial demonstrated efficacy of trastuzumab in HER2 positive gastric cancer, subsequent trials of HER2-directed therapy have disappointed. Downregulation of HER2 after trastuzumab may play a role; however, trastuzumab deruxtecan maintains some efficacy in low-level HER2 expressing tumors. The DESTINY-Gastric01 cohort was from South Korea/Japan; authors have reported differences in gastric cancer risk factors/physiology between Eastern and Western populations. DESTINY-Gastric02 will evaluate trastuzumab deruxtecan in Western patients to confirm generalizability. Pulmonary side effects are notable;physicians must be cognizant of overlapping toxicities with combination therapy.


Assuntos
Imunoconjugados , Neoplasias Gástricas , Camptotecina/análogos & derivados , Quimioterapia Combinada/efeitos adversos , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêutico
12.
Eur J Cancer ; 167: 23-31, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35366570

RESUMO

BACKGROUND: We performed a pooled analysis of TRIBE and TRIBE2 studies to assess the efficacy and safety of the intensification of upfront chemotherapy backbone - from doublets to the triplet FOLFOXIRI - in combination with bevacizumab (bev) in patients with early-onset metastatic colorectal cancer (EO-mCRC; aged <50 years) and to explore whether EO-mCRCs have a peculiar tumour genomic profiling. MATERIALS AND METHODS: Subgroup analyses according to age (<50 versus ≥50 years) and treatment (FOLFOXIRI/bev versus doublets/bev) were carried out for rates of any grade and grade ≥3 (≥G3) overall and singular adverse events, progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Tumour genomic profiling was obtained using a DNA-based next-generation sequencing platform. RESULTS: Of 1187 patients included, 194 (16%) patients were aged <50 years. Females were more frequently diagnosed with EO-mCRC (P = 0.04). Patients aged <50 years showed a lower risk of ≥G3 neutropenia (P = 0.07), diarrhoea (P = 0.04), asthenia (P = 0.008) and a higher risk of any grade nausea (P < 0.01) and vomiting (P < 0.01). Patients receiving FOLFOXIRI/bev more frequently experienced ≥G3 chemotherapy-related adverse events respect to doublets/bev, regardless of age (Pinteraction = 0.60). FOLFOXIRI/bev was associated to a lower incidence of neutropenia (P = 0.04) and asthenia (P = 0.01) in patients <50 years old, than those aged ≥50 years. PFS, OS and ORR did not differ according to age (PFS P = 0.81, OS P = 0.44, ORR P = 0.50) and no interaction between age and the benefit from the intensification of upfront chemotherapy was observed (PFS Pinteraction = 0.72, OS Pinteraction = 0.54, ORR Pinteraction = 0.65). Genomic profiling was assessed in 296 patients, showing an enrichment of FBXW7 and POLE mutations in EO-mCRC. CONCLUSIONS: Upfront FOLFOXIRI/bev shows a favourable efficacy/safety balance in EO-mCRC. TRIAL REGISTRATION: Clinicaltrials.gov Identifiers NCT00719797, NCT0233-9116.


Assuntos
Neoplasias Colorretais , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Astenia/induzido quimicamente , Bevacizumab/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Fluoruracila/efeitos adversos , Humanos , Leucovorina/efeitos adversos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Compostos Organoplatínicos
13.
J Med Chem ; 65(7): 5850-5865, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35380045

RESUMO

Novel enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers with a camptothecin (CPT) warhead were designed and synthesized based on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT (a high-generation dendrimer) exhibited the highest activity with IC50s in the nanomolar range (31-747 nM) against a panel of cancer cells, which is 3-10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrix metalloproteinase-2/9 and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy.


Assuntos
Camptotecina , Peptídeos Penetradores de Células , Dendrímeros , Sistemas de Liberação de Medicamentos , Neoplasias , Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/farmacologia , Desenho de Fármacos , Humanos , Metaloproteinase 2 da Matriz , Neoplasias/tratamento farmacológico
14.
J Med Chem ; 65(8): 6056-6069, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35427109

RESUMO

The controlled release of a molecule of interest (MOI) is useful in probe design, prodrug construction, and drug delivery. We report herein a versatile thiol-triggered fluorogenic release system using the Baylis-Hillman (BH) adducts as a module. Common functional groups (e.g., amino, hydroxyl, carboxylic, and sulfhydryl groups) in a MOI are readily integrated into the module. The MOI release is fast (∼10 min) with a nearly quantitative yield and a >250-fold fluorescence increment. We further prepared two prodrugs to release camptothecin and nitric oxide (NO) using the two-photon excitable template, and the activation of prodrugs was visualized in live cells and mouse tissues. The therapeutic potential of the NO prodrug was also validated in a stroke model. This BH adduct-based fluorogenic release features multiple advantages, such as easy preparation, compatibility of various functional groups, fast response, high release yield, and tunable emission spectra, and is expected to have broad applications.


Assuntos
Pró-Fármacos , Animais , Camptotecina , Fluorescência , Camundongos , Compostos de Sulfidrila
15.
Cancer Genomics Proteomics ; 19(3): 328-338, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35430566

RESUMO

BACKGROUND/AIM: Schlafen 12 (SLFN12) expression correlates with survival in triple negative breast cancer (TNBC). SLFN12 slows TNBC proliferation and induces TNBC differentiation, but whether SLFN12 affects the tumoral response to chemotherapy or radiation is unknown. MATERIALS AND METHODS: We over-expressed SLFN12 in MDA-MB-231 cells using two different lentiviral vectors. We assessed viable cell numbers via crystal violet assay after treatment with carboplatin, paclitaxel, olaparib, zoledronic acid, camptothecin, or cesium irradiation. CHK1 and CHK2 phosphorylation was assessed by western blot and the effects of inhibiting CHK1/CHK2 by AZD7762 were examined. Key findings were confirmed in Hs578t and BT549 TNBC cells after adenoviral SLFN12 over-expression. RESULTS: SLFN12 over-expression increased TNBC sensitivity to radiation, carboplatin, paclitaxel, zoledronic acid, and camptothecin, but not to olaparib. SLFN12 over-expression decreased CHK1 and CHK2 phosphorylation after treatment with the DNA damaging agent camptothecin (CPT). The CHK1/CHK2 inhibitor diminished the significant cytotoxicity difference between over-expression and baseline SLFN12 levels in response to carboplatin. CONCLUSION: SLFN12 increases TNBC sensitivity to DNA-damaging agents at least in part by reducing CHK1/2 phosphorylation. This may contribute to improved survival in patients whose TNBC over-expresses SLFN12. Therefore, SLFN12 levels may be used to customize or predict radiotherapy and chemotherapy effects in TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Carboplatina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Quinase 1 do Ponto de Checagem/genética , Humanos , Paclitaxel/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Ácido Zoledrônico/farmacologia , Ácido Zoledrônico/uso terapêutico
16.
Chem Biol Interact ; 360: 109946, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35430260

RESUMO

Irinotecan, a first-line chemotherapy for gastrointestinal (GI) cancers has been causing fatal toxicities like bloody diarrhea and steatohepatitis for years. Irinotecan goes through multiple-step drug metabolism after injection and one of its intermediates 7-ethyl-10-hydroxy-camptothecin (SN-38) is responsible for irinotecan side effect. However, it is unclear what is the disposition kinetics of SN-38 in the organs subjected to toxicity. No studies ever quantified the effect of each enzyme or transporter on SN-38 distribution. In current study, we established a new physiologically based pharmacokinetic (PBPK) model to predict the disposition kinetics of irinotecan. The PBPK model was calibrated with in-house mouse pharmacokinetic data and evaluated with external datasets from the literature. We separated the contribution of each parameters in irinotecan pharmacokinetics by calculating the normalized sensitivity coefficient (NSC). The model gave robust prediction of SN-38 distribution in GI tract, the site of injury. We identified that bile excretion and UDP-glucuronosyltransferases (UGT) played more important roles than fecal excretion and renal clearance in SN-38 pharmacokinetics. Our NSC showed that the impact of enzyme and transporter on irinotecan and SN-38 pharmacokinetics evolved when time continued. Additionally, we mapped out the effect of inflammation on irinotecan metabolic pathways with PBPK modelling. We discovered that inflammation significantly increased the blood and liver exposure of irinotecan and SN-38 in the mice receiving bacterial endotoxin. Inflammation suppressed UGT, microbial metabolism but increased fecal excretion. The present PBPK model can serve as an efficacious and versatile tool to quantitively assess the risk of irinotecan toxicity.


Assuntos
Antineoplásicos Fitogênicos , Camptotecina , Animais , Antineoplásicos Fitogênicos/toxicidade , Camptotecina/efeitos adversos , Diarreia/induzido quimicamente , Glucuronosiltransferase/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Irinotecano , Camundongos
17.
Expert Rev Anticancer Ther ; 22(4): 335-341, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35249433

RESUMO

INTRODUCTION: Despite rapid advances in the treatment landscape of urothelial cancer, there is a substantial unmet need for safe and effective therapies for patients with locally advanced and metastatic urothelial cancer. Sacituzumab govitecan (SG) is an antibody-drug conjugate, consisting of a Trop-2 directed monoclonal antibody linked to SN-38, the active metabolite of irinotecan. Trop-2 is a glycoprotein overexpressed in various carcinomas, including urothelial carcinomas. AREAS COVERED: We review the available data on SG, including mechanism of action, pharmacology, efficacy, safety, and clinical studies regarding locally advanced or metastatic urothelial cancer. EXPERT OPINION: SG performed well in the TROPHY-U-01 phase II trial with an objective response rate of 27%. The most common adverse effects were diarrhea, nausea, fatigue, alopecia, and neutropenia, with the most common grade ≥ 3 treatment-related AEs being neutropenia, leukopenia, anemia, diarrhea, and febrile neutropenia. However, these effects were managed effectively with supportive care. SG currently has an accelerated approval for patients with locally advanced or metastatic urothelial cancer who have received platinum-based chemotherapy and either programmed cell death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. Several studies are evaluating SG in urothelial cancers as single-agent or in combination with other agents.


Assuntos
Anticorpos Monoclonais Humanizados , Camptotecina , Carcinoma de Células de Transição , Imunoconjugados , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais Humanizados/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Carcinoma de Células de Transição/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Diarreia/induzido quimicamente , Humanos , Imunoconjugados/efeitos adversos , Irinotecano , Neutropenia/induzido quimicamente , Neoplasias da Bexiga Urinária/tratamento farmacológico
18.
Eur J Pharmacol ; 923: 174898, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35305999

RESUMO

9-nitrocamptothecin (9-NC), an active derivative of camptothecin (CPT), demonstrated antitumor effect on experimental tumors in mice by topoisomerase I (Topo I) inhibition. However, under human physiological conditions, the rapid opening of lactone ring of 9-NC resulting in the formation of inactive and high toxic carboxylate limited its clinical efficacy. Therefore, strategies aimed to maintain the active closed-lactone form of 9-NC in the plasma were developed, such as prodrugs. In our study, 9-nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-NC, was designed and synthesized. A preclinical evaluation of the chemotherapeutic potential of NCP4 was performed in vitro and in vivo. In cytotoxicity assay against six human cancer cells, the cytotoxic effect of NCP4 was slightly weaker than 9-NC. In addition, our data showed that 9-NC can be converted from NCP4 in vivo, and that the intracellular conversion of NCP4 to its active metabolites was correlated well with its cytotoxicity, demonstrating that NCP4 could serve as a prodrug of 9-NC. In human hepatoma Bel-7402 xenografts, NCP4 by intravenous injection showed more potent antitumor efficacy than 9-NC. Mechanistically, NCP4 induced cell apoptosis by increasing the expressions of caspase-3 and Bax in tumor tissues. In human hepatoma Hep G2 xenografts, NCP4 by oral administration significantly inhibited tumor growth. Importantly, the toxic effect of NCP4 on mice was much lower than 9-NC, demonstrating improved safety of NCP4. Overall, our study indicated that NCP4 would be a promising anticancer candidate and worthy of further investigation.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Pró-Fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Carbonatos , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Lactonas , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico
19.
Zhongguo Fei Ai Za Zhi ; 25(3): 137-146, 2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35340156

RESUMO

BACKGROUND: The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear. METHODS: A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization. RESULTS: There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not. CONCLUSIONS: In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.


Assuntos
Camptotecina , Glucuronosiltransferase , Neoplasias Pulmonares , Camptotecina/uso terapêutico , Glucuronosiltransferase/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Polimorfismo Genético , Estudos Retrospectivos
20.
J Neurooncol ; 157(2): 355-364, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35239111

RESUMO

INTRODUCTION: At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort. METHODS: We reviewed the files from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination. RESULTS: 72 patients (median age 7.8 years [range 1-19]) received a median of 16 courses (range 3-30). The median duration of treatment was 9 months (range 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range 7.6-75.9 months). Younger patients had a worse PFS (p = 0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan. CONCLUSIONS: Bevacizumab-irinotecan has the potential of disease control clinically and radiographically in children with recurrent LGG whatever their previous characteristics; in many cases however these responses are not sustained, especially in younger children.


Assuntos
Neoplasias Encefálicas , Glioma , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias Encefálicas/patologia , Camptotecina/efeitos adversos , Criança , Pré-Escolar , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Lactente , Irinotecano , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Adulto Jovem
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