RESUMO
PURPOSE: Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients. DESIGN/METHODS: We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/m2 of oral VNR on days 1, 8, and 15 during the first 28-day treatment cycle and 80 mg/m2, unless contraindicated, from cycle 2-12. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling within the Monolix® software. Fifty SNPs of pharmacokinetic-related genes were genotyped. The influence of demographic, biological, and pharmacogenetic covariates on pharmacokinetic parameters was investigated using a stepwise multivariate procedure. RESULTS: A three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (Vc/F) and elimination rate constant were 803 L and 0.60 h-1, respectively. Following covariate analysis, BSA, leukocytes count, and drug transport ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Conversely, age and sex had no significant effect on VNR pharmacokinetics. CONCLUSION: Beyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.
Assuntos
Modelos Biológicos , Farmacogenética , Criança , Humanos , Recidiva Local de Neoplasia , Polimorfismo de Nucleotídeo Único , VinorelbinaRESUMO
AIMS: There is a crucial need for pharmacokinetic (PK) data on oral vinorelbine (VNR) in the paediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS: A multicentre, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumours, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS: PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg m-2 dose level, were 472 L h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (P = .004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION: Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among paediatric patients.
Assuntos
Glioma , Recidiva Local de Neoplasia , Adolescente , Criança , Glioma/tratamento farmacológico , Meia-Vida , Humanos , Infusões Intravenosas , Recidiva Local de Neoplasia/tratamento farmacológico , VinorelbinaRESUMO
PURPOSE: The aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancer patients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context. METHODS: A multicenter study including 109 metastatic colorectal cancer patients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters. RESULTS: A seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38. CONCLUSION: To our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00559676.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Irinotecano/farmacocinética , Inibidores da Topoisomerase I/farmacocinética , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Oxaliplatina/uso terapêutico , Inibidores da Topoisomerase I/uso terapêuticoRESUMO
A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 (UGT1A9-rs3832043) and nuclear receptor PXR (NR1I2-rs3814055, NR1I2-rs2472677 and NR1I2-rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting UGT1A9, genetic polymorphisms of NR1I2 have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.
Assuntos
Antineoplásicos/toxicidade , Polimorfismo de Nucleotídeo Único , Sorafenibe/toxicidade , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos/sangue , Área Sob a Curva , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Glucuronosiltransferase/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pessoa de Meia-Idade , Testes Farmacogenômicos , Receptor de Pregnano X/genética , Índice de Gravidade de Doença , Sorafenibe/sangue , Câncer Papilífero da Tireoide/sangue , Neoplasias da Glândula Tireoide/sangue , UDP-Glucuronosiltransferase 1ARESUMO
Glioblastoma multiforme (GBM) is one of the most aggressive cancers, where the aggressiveness of tumor has been associated to its high vascularization rate. Bevacizumab (Avastin®), an anti-angiogenic monoclonal antibody, has been used to decrease the angiogenic profile. To circumvent the blood-brain barrier (BBB) and decrease off-target organ toxicity, bevacizumab-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NP) were developed and intranasally administrated in CD-1 mice to study their pharmacokinetic and pharmacodynamic profile. After 7â¯days of administration, PLGA NP showed a higher brain bioavailability of bevacizumab when compared to intranasally administrated free bevacizumab. On the other hand, bevacizumab-loaded PLGA NP were able to increase the penetration (higher Cmáx) and the residence time of bevacizumab into the brain (higher Clast). Furthermore, PLGA NP formulation totally prevented bevacizumab systemic exposure. The efficacy of this nanosystem was next evaluated in a validated orthotopic GBM nude mice model, studying the tumor growth over time by bioluminescence and the anti-angiogenic effects. After 14â¯days, bevacizumab-loaded PLGA NP demonstrated a reduction in the tumor growth accompanied by a higher anti-angiogenic effect compared to the free bevacizumab. These results can be explained by the fact that bevacizumab was found in the brain just for bevacizumab-loaded PLGA NP group, after 14â¯days of formulation administration. Therefore, we believe that our strategy would be an efficient alternative to improve GBM treatment with high impact for patient life quality and survival.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/química , Glioblastoma/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Administração Intranasal , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Animais , Bevacizumab/farmacocinética , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Camundongos Endogâmicos C57BL , Camundongos Nus , Nanopartículas/química , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/químicaRESUMO
PURPOSE: FOLFIRINOX regimen is commonly used in colorectal and more recently pancreatic cancer. However, FOLFIRINOX induces significant and dose-limiting toxic effects leading to empirical dose reduction and sometimes treatment discontinuation. Model-based FOLFIRINOX regimen optimization might help improving patients' outcome. As a first step, the current review aims at bringing together all published population pharmacokinetics models for FOLFIRINOX anticancer drugs. METHODS: A literature search was conducted in the PubMed database from inception to February 2018, using the following terms: population pharmacokinetic(s), irinotecan, oxaliplatin, fluorouracil, FOLFIRI, FOLFOX, FOLFIRINOX. Only articles displaying nonlinear mixed effect models were included. Study description, pharmacokinetic parameter values and influential covariates are reported. For each model, the typical pharmacokinetic profile was simulated for the standard FOLFIRINOX protocol. RESULTS: The FOLFIRINOX compounds have been studied only separately so far. A total of six articles were retained for 5-fluorouracil, 6 for oxaliplatin and 5 for irinotecan (also including metabolites). Either one- or two-compartment models have been described for 5-fluorouracil, while two- or three-compartment models were reported for oxaliplatin and irinotecan pharmacokinetics. Non-linear elimination was sometimes reported for 5-fluorouracil. Sex and body size were found as influential covariates for all molecules in some publications. Despite some differences in model structures and parameter values, the simulated profiles and subsequent exposure were consistent between studies. CONCLUSIONS: The current review allows for a global understanding of FOLFIRINOX pharmacokinetics, and will provide a basis for further development of pharmacokinetics-pharmacodynamics-toxicity models for model-driven FOLFIRINOX protocol optimization to reach the best benefit-to-risk ratio.
Assuntos
Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ensaios Clínicos como Assunto , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Humanos , Irinotecano/farmacocinética , Irinotecano/farmacologia , Leucovorina/farmacocinética , Leucovorina/farmacologia , Neoplasias/metabolismo , Oxaliplatina/farmacocinética , Oxaliplatina/farmacologia , Distribuição TecidualRESUMO
Displaying a strong antiproliferative activity on a wide variety of cancer cells, EAPB0203 and EAPB0503 belong to the imidazo[1,2-a]quinoxalines family of imiquimod structural analogues. EAPB0503 has been shown to inhibit tubulin polymerization. The aim of the present study is to characterize the interaction of EAPB0203 and EAPB0503 with tubulin. We combine experimental approaches at the cellular and the molecular level both in vitro and in silico in order to evaluate the interaction of EAPB0203 and EAPB0503 with tubulin. We examine the influence of EAPB0203 and EAPB0503 on the cell cycle and fate, explore the binding interaction with purified tubulin, and use a computational molecular docking model to determine the binding modes to the microtubule. We then use a drug combination study with other anti-microtubule agents to compare the binding site of EAPB0203 and EAPB0503 to known potent tubulin inhibitors. We demonstrate that EAPB0203 and EAPB0503 are capable of blocking human melanoma cells in G2 and M phases and inducing cell death and apoptosis. Second, we show that EAPB0203 and EAPB0503, but also unexpectedly imiquimod, bind directly to purified tubulin and inhibit tubulin polymerization. As suggested by molecular docking and binding competition studies, we identify the colchicine binding site on ß-tubulin as the interaction pocket. Furthermore, we find that EAPB0203, EAPB0503 and imiquimod display antagonistic cytotoxic effect when combined with colchicine, and disrupt tubulin network in human melanoma cells. We conclude that EAPB0203, EAPB0503, as well as imiquimod, interact with tubulin through the colchicine binding site, and that the cytotoxic activity of EAPB0203, EAPB0503 and imiquimod is correlated to their tubulin inhibiting effect. These compounds appear as interesting anticancer drug candidates as suggested by their activity and mechanism of action, and deserve further investigation for their use in the clinic.
Assuntos
Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Colchicina/farmacologia , Quinoxalinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação ProteicaRESUMO
BACKGROUND: Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols. METHODS: Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. RESULTS: A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. CONCLUSIONS: Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Citidina Desaminase/metabolismo , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Monitoramento de Medicamentos/métodos , Humanos , Neoplasias Pancreáticas/metabolismo , GencitabinaRESUMO
BACKGROUND: The present study focuses on biodistribution profile and pharmacokinetic parameters of EGFR-targeted chitosan nanoparticles (TG CS nanoparticles) for siRNA/cisplatin combination therapy of lung cancer. MATERIAL & METHODS: Mad2 siRNA was encapsulated in EGFR targeted and nontargeted (NTG) CS nanoparticles by electrostatic interaction. The biodistribution of the nanoparticles was assessed qualitatively and quantitatively in cisplatin (DDP) sensitive and resistant lung cancer xenograft model. RESULTS: TG nanoparticles showed a consistent and preferential tumor targeting ability with rapid clearance from the plasma to infiltrate and sustain within the tumor up to 96 h. They exhibit a sixfold higher tumor targeting efficiency compared with the NTG nanoparticles. CONCLUSION: TG nanoparticles present as an attractive drug delivery platform for RNAi therapeutics against NSCLC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quitosana/química , Cisplatino/farmacologia , Neoplasias Pulmonares/terapia , Proteínas Mad2/genética , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quitosana/metabolismo , Cisplatino/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Nanopartículas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos , Distribuição TecidualRESUMO
The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague-Dawley rats using an oil-in-water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood-brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity.
Assuntos
Encéfalo/metabolismo , Ciclosporina/farmacocinética , Administração Intranasal , Administração Intravenosa , Animais , Ciclosporina/administração & dosagem , Feminino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
The primary objective of this study was to compare the biodistribution and pharmacokinetic profile of 17-ß-estradiol (17-ßE) on systemic delivery using either the cationic or the CREKA-peptide-modified (Cysteine-Arginine-Glutamic-acid-Lysine-Alanine) omega-3-fatty acid oil containing nanoemulsion system in vivo in the wild type C57BL/6 mice. Higher blood concentrations of 17-ßE, higher accumulation in the tissues of interest - heart and aorta, and higher accumulation within the other tissues - liver and kidney was observed on delivering 17-ßE using the CREKA-peptide-modified nanoemulsion system (AUClast in plasma - 263.89±21.81min*%/injected dose/ml) as compared to the cationic nanoemulsion (AUClast in plasma - 20.2±1.86min*%/injected dose/ml) and solution form (AUClast in plasma - 44.9±1.24min*%/injected dose/ml) respectively. Both, the cationic nanoemulsion and the CREKA-peptide-modified nanoemulsion showed a higher relative targeting efficiency of 4.57 and 4.86 respectively for 17-ßE than the relative targeting efficiency of 1.78 observed with the solution form. In conclusion, since the maximum exposure (highest AUClast for plasma and tissues) for 17-ßE was observed with the CREKA-peptide-modified nanoemulsion system, the study shows that CREKA-peptide-modified nanoemulsion system was the most suitable vehicle for systemic delivery of 17-ßE in the wild type C57BL/6 mice.
Assuntos
Portadores de Fármacos/química , Emulsões/química , Estradiol/administração & dosagem , Estradiol/farmacocinética , Ácidos Graxos Ômega-3/química , Oligopeptídeos/química , Animais , Aterosclerose/tratamento farmacológico , Cátions/química , Estradiol/sangue , Estradiol/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição TecidualRESUMO
PURPOSE: Although neuro-active peptides are highly potent as central nervous system (CNS) therapeutics, their systemic delivery across the blood-brain barrier (BBB) is limited due to lack of permeability in the brain and rapid systemic metabolism. In this study, we aimed at enhancing the brain delivery and stability of chemically modified [D-Arg(2), Lys(4)]-dermorphin-(1-4)-amide)] (DALDA) peptide to achieve prolonged analgesic effects. METHODS: The C8-DALDA peptide analog was encapsulated in an oil-in-water nanoemulsion formulation made specifically with oils rich in omega-3 rich polyunsaturated fatty acid (PUFA) to enhance CNS availability. The nanoemulsion formulation was administered systemically in CD-1 mice and qualitative and quantitative biodistribution was evaluated. We have also examined the effect of curcumin, which is known to down-regulate efflux transporters and inhibit systemic metabolism, on the pharmacokinetic properties of the peptide. RESULTS: Qualitative and quantitative biodistribution and pharmacokinetic studies in mice clearly demonstrated improved plasma and brain exposure of modified DALDA when administered in nanoemulsion, thereby providing an exciting opportunity towards improved efficacy and/or lowered dose of the peptide. The various dosing regimens tested for modified DALDA solution and curcumin nanoemulsion directed towards a novel combination strategy for improved systemic delivery of peptides across the BBB. CONCLUSIONS: Encapsulation of the drug in PUFA nanoemulsion is an effective strategy for delivery of peptides. This work provides a novel combination strategy for improved delivery of peptides to the brain.
Assuntos
Analgésicos/administração & dosagem , Nanoestruturas , Oligopeptídeos/administração & dosagem , Analgésicos/farmacocinética , Animais , Barreira Hematoencefálica , Emulsões , Camundongos , Microscopia Eletrônica de Transmissão , Óleos , Oligopeptídeos/farmacocinética , Receptores Opioides mu/agonistas , ÁguaRESUMO
Multidrug resistance (MDR) is a significant problem in the clinical management of several cancers. Overcoming MDR generally involves multi-modal therapeutic approaches that integrate enhancement of delivery efficiency using targeted nano-platforms as well as strategies that can sensitize cancer cells to drug treatments. We recently demonstrated that tandem delivery of siRNAs that downregulate anti-apoptotic genes overexpressed in cisplatin resistant tumors followed by therapeutic challenge using cisplatin loaded CD44 targeted hyaluronic acid (HA) nanoparticle (NP) induced synergistic antitumor response CD44 expressing tumors that are resistant to cisplatin. In the current study, a near infrared (NIR) dye-loaded HA NP was employed to image the whole body localization of NPs after intravenous (i.v.) injection into live mice bearing human lung tumors that were sensitive and resistant to cisplatin. In addition, we quantified the siRNA duplexes and cisplatin dose distribution in various tissues and organs using an ultra-sensitive quantitative PCR method and inductively coupled plasma-mass spectrometry (ICP-MS), respectively, after i.v. injection of the payload loaded HA NPs in tumor bearing mice. Our findings demonstrate that the distribution pattern of the siRNA and cisplatin using specifically engineered CD44 targeting HA NPs correlated well with the tumor targeting capability as well as the activity and efficacy obtained with combination treatments.
Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cisplatino/farmacocinética , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , RNA Interferente Pequeno/farmacocinética , Distribuição TecidualRESUMO
The extraction and purification of the bioactive extract of Cystodytes violatinctus (Solomon Islands) led to the isolation and identification of six pyridoacridine alkaloids. The structures of four new members of this family, shermilamine F (1), dehydrokuanoniamine F (2), and arnoamines C (3) and D (4), were elucidated on the basis of NMR and MS data and by comparison with data of known compounds isolated from this genus. A general hypothetical biogenetic pathway is then proposed for pyridoacridine alkaloids that contain a fused pyrrole ring. Comparison of the biological properties of the isolated alkaloids is also discussed.
Assuntos
Acridinas/isolamento & purificação , Acridinas/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Fenantrolinas/isolamento & purificação , Fenantrolinas/farmacologia , Urocordados/química , Acridinas/química , Alcaloides/química , Animais , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Melanesia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fenantrolinas/químicaRESUMO
The objective of this study was to evaluate qualitative and quantitative biodistribution of epidermal growth factor receptor (EGFR)-targeted thiolated type B gelatin nanoparticles in vivo in subcutaneous human pancreatic adenocarcinoma (Panc-1) bearing female SCID Beige mice. EGFR-targeted nanoparticles showed preferential and sustained accumulation in the tumor mass, especially at early time points. Higher blood concentrations and higher tumor accumulations were observed with PEG-modified and EGFR-targeted nanoparticles during the study (AUClast: 17.38 and 19.56%ID/mL·h in blood, 187 and 322%ID/g·h in tumor for PEG-modified and EGFR-targeted nanoparticles, respectively), as compared to control, unmodified particles (AUClast: 10.71%ID/mL·h in blood and 138%ID/g·h in tumor). EGFR-targeted nanoparticles displayed almost twice tumor targeting efficiency than either PEG-modified or the unmodified nanoparticles, highlighting the efficacy of the active targeting strategy. In conclusion, this study shows that EGFR-targeted and PEG-modified nanoparticles were suitable vehicles for specific systemic delivery in subcutaneous Panc-1 tumor xenograft models.
Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos/administração & dosagem , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Gelatina/administração & dosagem , Gelatina/química , Humanos , Radioisótopos de Índio , Camundongos , Camundongos SCID , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Neoplasias Pancreáticas/metabolismo , Peptídeos/farmacocinética , Polietilenoglicóis/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
For several years, our group has been developing quinoxalinic compounds. Two of them, N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine (EAPB0203) and 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503), have emerged as the most promising anticancer drugs. In the present work, we determined metabolism pathways using liver microsomes from four mammalian species including human. We identified the cytochrome P450 isoform(s) involved in the metabolism and then investigated the pharmacokinetics and metabolism of EAPB0203 and EAPB0503 in rat after intravenous and intraperitoneal administration. Biotransformation of the compounds involved demethylation and hydroxylation reactions. Rat and dog metabolized the compounds at a higher rate than mouse and human. In all species, CYP1A1/2 and CYP3A isoforms were the predominant enzymes responsible for the metabolism. From human liver microsomes, unbound intrinsic clearances were approximately 56 ml/(min · g) protein. EAPB0203 and EAPB0503 were extensively bound to human plasma proteins, mainly human serum albumin (HSA) (â¼98-99.5%). Thus, HSA could act as carrier of these compounds in human plasma. Scatchard plots showed patterns in which the plots yielded upwardly convex hyperbolic curves. On the basis of the Hill coefficients, there appears to be interaction between the binding sites of HSA, suggesting positive cooperativity. The main in vitro metabolites were identified in vivo. Total clearances of EAPB0203 and EAPB0503 [3.2 and 2.2 l/(h · kg), respectively] were notably lower than the typical cardiac plasma output in rat. The large volumes of distribution of these compounds (4.3 l/kg for EAPB0203 and 2.5 l/kg for EAPB0503) were consistent with extensive tissue binding. After intraperitoneal administration, bioavailability was 22.7% for EAPB0203 and 35% for EAPB0503 and a significant hepatic first-pass effect occurred.
Assuntos
Antineoplásicos/farmacocinética , Linfoma de Células T/tratamento farmacológico , Melanoma/tratamento farmacológico , Microssomos Hepáticos/metabolismo , Quinoxalinas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Biotransformação , Proteínas Sanguíneas/metabolismo , Cães , Humanos , Linfoma de Células T/metabolismo , Melanoma/metabolismo , Camundongos , Estrutura Molecular , Ligação Proteica , Quinoxalinas/química , Quinoxalinas/metabolismo , Quinoxalinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Espectrometria de Massas por Ionização por Electrospray , Distribuição TecidualRESUMO
In spite of the development of new anticancer drugs by the pharmaceutical industry, melanoma and T lymphomas are diseases for which medical advances remain limited. Thus, there was an urgent need of new therapeutics with an original mechanism of action. Since several years, our group develops quinoxalinic compounds. In this paper, the first preclinical results concerning one lead compound, EAPB0203, are presented. This compound exhibits in vitro cytotoxic activity on A375 and M4Be human melanoma cell lines superior to that of imiquimod and fotemustine. A liquid chromatography-mass spectrometry method was first validated to simultaneously quantify EAPB0203 and its metabolite, EAPB0202, in rat plasma. Thereafter, the pharmacokinetic profiles of EAPB0203 were studied in rat after intravenous and intraperitoneal administrations. After intraperitoneal administration the absolute bioavailability remains limited (22.7%). In xenografted mouse, after intraperitoneal administration of 5 and 20mg/kg, EAPB0203 is more potent than fotemustine. The survival time was increased up to 4 and 2 weeks compared to control mice and mice treated by fotemustine, respectively. The results of this study demonstrate the relationship between the dose of EAPB0203 and its effects on tumor growth. Thus, promising efficacy, tolerance and pharmacokinetic data of EAPB0203 encourage the development towards patient benefit.
Assuntos
Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Quinoxalinas/farmacologia , Aminoquinolinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Imidazóis/farmacocinética , Imiquimode , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Camundongos , Camundongos Nus , Compostos de Nitrosoureia/farmacologia , Compostos Organofosforados/farmacologia , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacocinética , Ratos , Neoplasias Cutâneas/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Reactive oxygen species are well-known mediators of various biological responses. Recently, new homologues of the catalytic subunit of NADPH oxidase have been discovered in non-phagocytic cells. These new homologues (Nox1-Nox5) produce low levels of superoxides compared to the phagocytic homologue Nox2/gp91phox. Using Nox1 siRNA, we show that Nox1-dependent superoxide production affects the migration of HT29-D4 colonic adenocarcinoma cells on collagen-I. Nox1 inhibition or down-regulation led to a decrease of superoxide production and alpha 2 beta 1 integrin membrane availability. An addition of arachidonic acid stimulated Nox1-dependent superoxide production and HT29-D4 cell migration. Pharmacological evidences using phospholipase A2, lipoxygenases and protein kinase C inhibitors show that upstream regulation of Nox1 relies on arachidonic acid metabolism. Inhibition of 12-lipoxygenase decreased basal and arachidonic acid induced Nox1-dependent superoxide production and cell migration. Migration and ROS production inhibited by a 12-lipoxygenase inhibitor were restored by the addition of 12(S)-HETE, a downstream product of 12-lipoxygenase. Protein kinase C delta inhibition by rottlerin (and also GO6983) prevented Nox1-dependent superoxide production and inhibited cell migration, while other protein kinase C inhibitors were ineffective. We conclude that Nox1 activation by arachidonic acid metabolism occurs through 12-lipoxygenase and protein kinase C delta, and controls cell migration by affecting integrin alpha 2 subunit turn-over.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Movimento Celular , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , NADPH Oxidases/metabolismo , Superóxidos/metabolismo , Araquidonato 12-Lipoxigenase/metabolismo , Ácidos Araquidônicos/farmacologia , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Células HT29 , Humanos , Integrina alfa2beta1/metabolismo , NADPH Oxidase 1 , Proteína Quinase C-delta/metabolismo , Superóxidos/antagonistas & inibidoresRESUMO
The catalytic subunit of the NADPH oxidase complex, Nox1 (homologue of gp91phox/Nox2), expressed mainly in intestinal epithelial and vascular smooth muscle cells, functions in innate immune defense and cell proliferation. The molecular mechanisms underlying these functions, however, are not completely understood. We measured Nox1-dependent O2- production during cell spreading on Collagen IV (Coll IV) in colon carcinoma cell lines. Knocking down Nox1 by shRNA, we showed that Nox1-dependent O2- production is activated during cell spreading after 4 hr of adhesion on Collagen IV. Nox1 activation during cell spreading relies on Rac1 activation and arachidonic metabolism. Our results showed that manoalide (a secreted phospholipase A2 inhibitor) and cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (a 12-lipoxygenase inhibitor) inhibit O2- production, cell spreading and cell proliferation in these colonic epithelial cells. 12-Lipoxygenase inhibition of ROS production and cell spreading can be reversed by adding 12-HETE, a 12-lipoxygenase product, supporting the specific effect observed with cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. In contrast, Nox1 shRNA and DPI (NADPH oxidase inhibitor) weakly affect cell spreading while inhibiting O2- production and cell proliferation. These results suggest that the 12-lipoxygenase pathway is upstream of Nox1 activation and controls cell spreading and proliferation, while Nox1 specifically affects cell proliferation.
Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Carcinoma/metabolismo , Carcinoma/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/farmacologia , Western Blotting , Ácidos Cafeicos/farmacologia , Carcinoma/enzimologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/enzimologia , Ativação Enzimática , Humanos , Inibidores de Lipoxigenase , NADPH Oxidase 1 , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfolipase A2 , RNA/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Terpenos/farmacologiaRESUMO
Interferon-gamma (IFN-gamma) has been found to be antiproliferative and antitumoral in malignant mesothelioma (MM), but the MM cell response to IFN-gamma has not been fully characterized so far. We investigated gene expression profiles in human MM cell lines (HMCLs) exposed to IFN-gamma. Four HMCLs showing different sensitivities to the antiproliferative effect of IFN-gamma, two of them presenting a defect in the JAK/STAT signaling pathway, were treated with 500 IU/mL of IFN-gamma. Gene expression patterns were studied at 6 and 72 hours after exposure to the IFN-gamma, using a cDNA array technique. Six genes were studied with real-time reverse transcription-polymerase chain reaction. The gene expression profiles in response to IFN-gamma were shown to differ in different HMCLs. Numerous genes involved in cell proliferation and cell adhesion were regulated by IFN-gamma in JAK/STAT-deficient HMCLs. Genes possibly involved in regulation of cell proliferation included CDC2, PLK1, and IGFBP4, as well as several genes involved in cell-cell interactions and cell adhesion. The cDNA array technique revealed differences in expression pathways, especially those involved in cell growth, cell adhesion, and cell proliferation, between IFN-gamma-resistant and -sensitive MM cell lines. We found that the changes in gene expression profiles of HMCLs exposed to IFN-gamma were also related to features other than the antiproliferative response.