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1.
J Nanobiotechnology ; 17(1): 78, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269964

RESUMO

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Dissulfetos/química , Portadores de Fármacos/química , Molibdênio/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes/química , Humanos , Ácido Hialurônico/química , Hipertermia Induzida , Raios Infravermelhos , Camundongos Nus , Transplante de Neoplasias , Oxirredução , Fotoquimioterapia/métodos
2.
Gan To Kagaku Ryoho ; 46(4): 796-798, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164539

RESUMO

A 60-year-old woman underwent intersphincteric resection for lower rectal cancer in 2016. The pathological stage was pT3N1M0, stage Ⅲa and the cancer was curatively resected. Local recurrence was detected 6 months after the surgery. The patient received chemotherapy of 4 courses of FOLFOXIRI plus bevacizumab(Bev). A Grade 4 adverse event(febrile neutropenia) occurred but the treatment was continued after a dose reduction to 80%. The size of the tumor decreased significantly after chemotherapy and posterior pelvic exenteration with sacral resection was performed. Pathological analysis revealed a positive radial margin but there were no remarkable complications after surgery and no obvious recurrence during the 9 months after the operation. Therefore, we concluded that FOLFOXIRI plus Bev chemotherapy is a manageable and useful treatment for locally recurrent rectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Compostos Organoplatínicos/administração & dosagem , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgia
3.
Int J Nanomedicine ; 14: 3799-3817, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213802

RESUMO

Background and aim: We have synthesized a novel lactone-stabilized camptothecin (CPT) analog named CZ48 and demonstrated its potent anticancer effects via bioconversion to the active CPT in earlier studies. Herein, we aimed to develop, optimize and characterize CZ48 nanosuspensions, for a sustained delivery of this drug in humans with an intravenous (i.v.) administration. Methods and materials: A three-factor, five-level central composite design (CCD) was employed to establish the impacts of the critical influencing factors (concentrations (wt%) of CZ48, polysorbate 80 (Tween-80), and Pluronic® F-108 (F-108)) on the responses (particle size and zeta potential). Based on the quantitative influencing factor-response relationships, two optimized CZ48 nanosuspensions of 197.22 ± 7.12 nm (NS-S) and 589.35 ± 23.27 nm (NS-L) were developed with the zeta potential values of -26.5 mV and -27.9 mV, respectively. Results: CZ48 released from the nanosuspensions in a sustained manner in contrast to the rapid release from cosolvent in both PBS and human plasma. Moreover, NS-S exhibited more favored pharmacokinetic properties than NS-L, with a 31-fold prolonged elimination half-life of CPT, and a 2.4-fold enhanced CPT exposure over cosolvent. In efficacy study, NS-S exhibited significant tumor suppression and an improved survival rate with a higher tolerable dose, compared to CZ48 cosolvent. Conclusion: We have successfully developed CZ48 nanosuspensions with significantly favorable pharmacokinetics and improved efficacy using CCD approach. The formulation offers potential merits as a preferred candidate for clinical trials with the prolonged CPT exposure, which is known to correlate with the clinical efficacy.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Nanopartículas/química , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/química , Camptotecina/farmacocinética , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Nus , Nanopartículas/administração & dosagem , Tamanho da Partícula , Suspensões , Distribuição Tecidual/efeitos dos fármacos , Inibidores da Topoisomerase I
4.
Molecules ; 24(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917485

RESUMO

Camptothecin (CPT) shows potent anticancer activity through inhibition of topoisomerase I. However, its water insolubility and severe toxicity limit its clinical application. Coupling with bile acid moieties is a promising method for liver-targeted drug delivery, which takes advantage of the bile acid receptors on hepatocytes. In this study, we evaluated the potential liver targeting and stability of a deoxycholic acid-CPT conjugate (G2). The competitive inhibition of antitumor activity experiment based on bile acid transporters was performed using the MTT method. The effects of deoxycholic acid on uptake of G2 and CPT were assessed in 2D and 3D HepG2 cell models. The stability of G2 and CPT was evaluated in vitro (in simulated gastric fluid, simulated intestinal fluid, and fresh rat plasma). Finally, biodistribution of G2 and CPT was investigated in Kunming mice following oral administration. The results showed that deoxycholic acid pretreatment could significantly reduce the antitumor activity and cellular uptake of G2 in HepG2 cells, but had no distinct effects on CPT. Meanwhile, G2 exhibited better stability compared with CPT. More importantly, biodistribution study in mice demonstrated that the liver targeting index of G2 increased 1.67-fold than that of CPT. Overall, the study suggests that conjugation with deoxycholic acid is a feasible method to achieve liver targeting delivery of CPT.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/administração & dosagem , Ácido Desoxicólico/química , Fígado/química , Administração Oral , Animais , Camptotecina/química , Camptotecina/farmacocinética , Proliferação de Células/efeitos dos fármacos , Ácido Desoxicólico/administração & dosagem , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Camundongos , Modelos Biológicos , Ratos , Solubilidade , Distribuição Tecidual
5.
Dis Markers ; 2019: 6812045, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30805037

RESUMO

Background: Previously, it was demonstrated that serum levels of tumor markers, CEA and CA19-9, correlated with chemotherapy. Consequently, it has been hypothesized that dynamic monitoring of changes in these markers may predict the shrinkage or growth of colorectal cancers. To test this hypothesis, we analyzed CEA and CA19-9 serum levels in patients with advanced colorectal cancer who received cetuximab in combination with chemotherapy. These levels were evaluated at various time points to identify their potential to serve as early efficacy predictors during treatment and early predictors of disease progression. Patients and Methods: Measurements of tumor markers, CEA and CA 19-9, in patients with metastatic colorectal cancer (n = 73) who received cetuximab plus folinic acid, fluorouracil, and oxaliplatin or irinotecan (FOLFOX4/FOLFIRI) as a first-line treatment at our center were retrospectively analyzed. These levels were also compared with objective responses according to the World Health Organization criteria. Initially, 65 patients had elevated CEA levels (>5 ng/ml), and 59 patients had elevated levels of CA19-9 (>37 U/ml). A total of 172 cycles and 165 cycles of computed tomography/magnetic resonance imaging observations were available for review from these two patient groups. Results: After completing three cycles of treatment, the best diagnosis of cetuximab resistance was achieved when CEA increased by 35% (efficacy, 83.33%; sensitivity, 75.41%) and when CA19-9 increased by 28% (efficacy, 80.00%; sensitivity, 84.31%). Next, the efficacy of cetuximab at the time of diagnosis (at the first imaging examination/after three cycles of treatment) was evaluated after the first cycle of chemotherapy. When CEA decreased by 60% from its baseline level, the best effective rate and sensitivity were observed (63.64% and 80.95%, respectively). Similarly, when CA19-9 was 45% lower than its baseline level, the best effective rate and sensitivity were observed (84.21% and 93.18%, respectively). To evaluate progression-free survival (PFS), levels of both CEA and CA19-9 were evaluated after the third cycle of chemotherapy. Increases of 35% and 28%, respectively, resulted in a shorter PFS period compared with the other patients (3.15 months vs. 9.10 months, respectively; P < 0.0001). Conversely, when the evaluation was performed after the first cycle of chemotherapy, patients exhibiting a 60% decrease in CEA and a 45% decrease in CA19-9 had a longer PFS period (11.13 months vs. 8.10 months, respectively; P = 0.0395). Conclusions: CEA and CA19-9 are useful indicators of therapeutic curative effect from cetuximab combined with first-line chemotherapy. These markers also helped assess cetuximab resistance and served as early predictors of initial treatment effectiveness. Furthermore, a simultaneous increase or decrease in the levels of both indicators was consistent with the observed differences in PFS.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Ca-125/sangue , Antígeno CA-19-9/sangue , Camptotecina/análogos & derivados , Cetuximab/uso terapêutico , Neoplasias Colorretais/sangue , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Intervalo Livre de Progressão
6.
Cell Mol Life Sci ; 76(8): 1595-1604, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30778617

RESUMO

Tetraspanin protein CD151 has typically been studied as binding partner and functional regulator of laminin-binding integrins. However, we show here that CD151 supports anti-cancer drug resistance independent of integrins. CD151 ablation sensitized multiple tumor cell types to several anti-cancer drugs (e.g., gefitinib and camptothecin), thus increasing apoptosis, as seen using cleaved caspase-3, cleaved PARP (poly (ADP-ribose) polymerase), annexin V, and propidium iodide staining assays. Drug sensitization due to CD151 ablation is integrin-independent, because, (1) effects occurred in cells when integrins were unengaged with ligand, (2) integrin ablation (α3 and α6 subunits) did not mimic effects of CD151 ablation, (3) the CD151QRD mutant, with diminished integrin association, and CD151WT (unmutated CD151) similarly reconstituted drug protection, and (4) treatment with anti-cancer drugs selectively upregulated intracellular nonintegrin-associated CD151 (NIA-CD151), consistent with its role in drug resistance. Together, these results suggest that upregulated CD151 expression may support not only typical integrin-dependent functions, but also integrin-independent survival of circulating (and possibly metastatic) cancer cells during anti-cancer drug therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Integrinas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tetraspanina 24/metabolismo , Células A549 , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Camptotecina/administração & dosagem , Linhagem Celular Tumoral , Gefitinibe/administração & dosagem , Humanos , Laminina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tetraspanina 24/genética
7.
Expert Rev Pharmacoecon Outcomes Res ; 19(5): 601-608, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30739558

RESUMO

Objectives: This study compared the cost and quality of life (QoL) of 407 advanced colorectal cancer patients, randomly assigned to receive LV5FU2 followed by FOLFOX6 (sequential strategy) or FOLFOX6 followed by FOLFIRI (combination strategy). Methods: Costs were compared from the French health insurance perspective, until the end of the second line of treatment. Consumed resources, collected during the trial, included medicines, hospitalizations, examinations, and transportation. Valuations were made using 2009 and 2016 tariffs. QoL was assessed using the QLQ-C30 questionnaire and clinically significant variations were searched. Results: In 2009, the mean cost per patient was significantly lower for the sequential strategy compared to the combination strategy (18,061€ and 23,119€, p = 0.001). In 2016, the difference was no longer significant (16,876€ and 18,090€, p = 0.41) because oxaliplatin and irinotecan became generics. The QoL analysis (292 patients) showed that there was significantly less improvement of global health status in the sequential strategy than in the combination strategy (29% and 42%; p = 0.02) during first-line therapy. No significant differences were observed for emotional functioning (p = 0.45) and physical functioning (p = 0.07) or during second-line therapy. Conclusion: The choice to treat patients with advanced colorectal cancer using one or the other strategy cannot be based on costs or QoL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/economia , Neoplasias Colorretais/economia , Neoplasias Colorretais/patologia , Custos de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/economia , França , Nível de Saúde , Humanos , Leucovorina/administração & dosagem , Leucovorina/economia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/economia , Estudos Prospectivos , Inquéritos e Questionários
8.
Eur J Pharm Biopharm ; 136: 174-183, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30654016

RESUMO

Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis(hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48 h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity.


Assuntos
Camptotecina/administração & dosagem , Quitosana/administração & dosagem , Reagentes para Ligações Cruzadas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Compostos Organofosforados/administração & dosagem , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Células CACO-2 , Camptotecina/química , Camptotecina/farmacocinética , Quitosana/química , Quitosana/farmacocinética , Reagentes para Ligações Cruzadas/química , Reagentes para Ligações Cruzadas/farmacocinética , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacocinética , Masculino , Compostos Organofosforados/química , Compostos Organofosforados/farmacocinética , Ratos , Ratos Wistar
9.
J Colloid Interface Sci ; 541: 163-174, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30685611

RESUMO

MIL-100(Fe) and MIL-101(Fe) metal-organic frameworks (MOFs) are excellent vehicles for drug delivery systems (DDSs) due to their high biocompatibility and stability in physiological fluids, as well as their pore diameter in the mesoporous range. Although they are appropriate for the internal diffusion of 20-(S)-camptothecin (CPT), a strongly cytotoxic molecule with excellent antitumor activity, no stable delivery system has been proposed so far for this drug based in MOFs. We here present novel DDSs based in amine functionalized MIL-100(Fe) and MIL-101(Fe) nanoMOFs with covalently bonded CPT. These CPT nanoplatforms are able to incorporate almost 20% of this molecule and show high stability at physiological pH, with no non-specific release. Based on their surface charge, some of these CPT loaded nanoMOFs present improved cell internalization in in vitro experiments. Moreover, a strong response to acid pH is observed, with up to four fold drug discharge at pH 5, which boost intracellular release by endosomolytic activity. These novel DDSs will help to achieve safe delivery of the very cytotoxic CPT, allowing to reduce the therapeutic dose and minimizing drug secondary effects.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Sobrevivência Celular , Sistemas de Liberação de Medicamentos , Nanopartículas Metálicas/administração & dosagem , Estruturas Metalorgânicas/química , Antineoplásicos Fitogênicos/química , Camptotecina/química , Células Cultivadas , Liberação Controlada de Fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas Metálicas/química , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia
10.
Int J Clin Oncol ; 24(5): 508-515, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30604155

RESUMO

BACKGROUND: Dose modification of chemotherapy for metastatic colorectal cancer (MCRC) is often needed, especially in second-line and later-line treatments due to adverse events of previous treatment and poor patient condition. No study has focused on ramucirumab plus modified dose of FOLFIRI for MCRC, and whether low relative dose intensity (RDI) affects treatment efficacy has not been clarified. METHODS: MCRC patients who received ramucirumab plus FOLFIRI, which consisted of 150 mg/m2 of irinotecan, at six institutions were retrospectively analyzed. RESULTS: A total of 43 patients were assessed. Median age was 63 years, and 22 patients (51%) were women. Twenty-six patients (60%) were given ramucirumab plus FOLFIRI as second-line therapy, and 17 (40%) as third or later-line. The median relative dose intensity (RDI) of irinotecan was 60.6%, which is lower than that in the pivotal phase 3 study (RAISE), and other agents showed the same trend. Median progression-free survival was 4.8 [95% confidence interval (CI) 3.2-5.7] months for all patients, 5.4 (95% CI 3.5-7.2) months for second-line patients, and 2.8 (95% CI 1.6-5.8) months for third or later-line patients. Median overall survival was 17.3 (95% CI 11.5-22.4) months for all patients. Patients with irinotecan RDI less than 60% showed similar treatment efficacy. Hematological toxicities of grade 3 or worse were observed in 21 patients, but all were manageable. CONCLUSION: Low RDI did not compromise the treatment efficacy of ramucirumab plus modified FOLFIRI for MCRC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Doenças Hematológicas/induzido quimicamente , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
11.
Cancer Sci ; 110(3): 1032-1043, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30657223

RESUMO

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 µg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/metabolismo , Intervalo Livre de Doença , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Estudos Prospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Eur J Pharm Biopharm ; 134: 178-184, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30529294

RESUMO

Nanoparticles decorated with hydrophilic PEG chains had been emerged as effective drug delivery system due to their biocompatibility and biodegradability, while, the influence of their architecture on antitumor efficacy remained challenging. In this study, the linear poly(ethylene glycol) (PEG45), brush oligo(triethylene glycol) (TEG10), and oligo(ethylene glycol) dendron (G2), which showed the similar molar mass but different architecture, were utilized as nanocarriers to prepare 10-hydroxycamptothecin (HCPT) nanoparticles. It was found that all of three HCPT NPs (PEG45 NPs, TEG10 NPs, and G2 NPs) presented similar DLCs (∼60%), zeta potentials (-13 to -16 mv), and stabilities, meanwhile, the particle sizes, morphologies, release profiles, and anticancer efficacies were affected by the architecture of nanocarriers. Changing the architecture from linear, brush to dendron, the mean particles diameter was decreased from 240 to 170 nm, the sustained releases were elongated from 5 to 9 days. More importantly, the cytotoxicity of G2 NPs based on OEG dendron was enhanced significant comparing with linear PEG45 NPs, the IC50 was decreased almost 10.1-fold (p < 0.01). Besides, the tumor inhibition rate of G2 NPs was 1.7-fold higher than PEG45 NPs, showing significantly optimized antitumor efficacy in vivo. These results suggested the architecture of nanocarriers could affect the antitumor activity, due to the steric hindrance of nanocarriers influence the morphologies of HCPT-loaded nanoparticles.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/análogos & derivados , Portadores de Fármacos/química , Etilenoglicol/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Nanopartículas/química , Tamanho da Partícula , Ratos , Distribuição Tecidual
13.
Anticancer Res ; 39(1): 245-252, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591465

RESUMO

BACKGROUND: Based on our pre-clinical data, we hypothesized that sequencing chemotherapy with erlotinib would increase the tumor response rate in patients with metastatic colorectal cancer. PATIENTS AND METHODS: A phase II trial (planned n=58) using second-line therapy for metastatic colorectal cancer with either oxaliplatin-based (mFOLFOX6) or irinotecan-based (FOLFIRI) combination chemotherapy and 100 mg erlotinib daily on days 3-8 after each infusion (days 1 and 2) every 14 days. The primary endpoint was the response rate compared to the historical response rate. RESULTS: The FOLFIRI/erlotinib arm met the pre-specified response rate criteria of at least 10% to expand accrual to the intended sample size. The trial was halted after an interim safety analysis (n=11) due to excess grade 3 neutropenia, dose reductions and treatment delays. Grade 3 or 4 neutropenia was observed in 64% of patients. The response rate was 18%. CONCLUSION: In second-line treatment for metastatic colorectal cancer, mFOLFOX6 or FOLFIRI with erlotinib in a sequence-dependent fashion is not feasible despite potential promising activity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Cloridrato de Erlotinib/administração & dosagem , Adulto , Idoso , Camptotecina/administração & dosagem , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem
14.
Anticancer Res ; 39(1): 313-318, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591474

RESUMO

AIM: To prospectively correlate clinical responses to second-line chemotherapy for recurrent epithelial ovarian cancer (EOC) with in vitro integrative tumor-response assay (ITRA) results. PATIENTS AND METHODS: Forty-four patients with advanced EOC were enrolled from 2015-2017 at the Asan Medical Center, Seoul, Korea. ITRA comprised of two sequential histoculture drug response assays (HDRAs) of the tumor tissues. The first stage was HDRA with paclitaxel-carboplatin, paclitaxel, and carboplatin chemotherapy. The second stage was performed with surviving tumor cells from the first stage using topotecan, belotecan, gemcitabine, doxorubicin, ifosfamide, vinorelbine, and etoposide. RESULTS: The median follow-up period was 23.35 (range=4-35.35) months. Eighteen patients (40.9%) completed the second-line chemotherapy, based on the ITRA results. The objective response rate was 38.9%. The clinical response rate was 50%; two patients (11.1%) had stable disease. The sensitivity of ITRA for predicting response was 85.7% (specificity=18.2%; accuracy=44.44%). CONCLUSION: ITRAs had acceptable applicability and may help choose second-line chemotherapy for patients with advanced EOC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Epitelial do Ovário/epidemiologia , Carcinoma Epitelial do Ovário/patologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , República da Coreia , Topotecan/administração & dosagem , Topotecan/efeitos adversos
15.
Br J Cancer ; 120(2): 183-189, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30531832

RESUMO

BACKGROUND: Metastatic colorectal cancer (mCRC) has low survival rates. We assessed if addition of veliparib, concurrent to FOLFIRI, improves survival in patients with previously untreated mCRC. METHODS: This study compared veliparib (200 mg BID for 7 days of each 14-day cycle) to placebo, each with FOLFIRI. Bevacizumab was allowed in both arms. The primary endpoint was progression-free survival (PFS). RESULTS: Patients were randomised to receive veliparib (n = 65) or placebo (n = 65) in combination with FOLFIRI. Median PFS was 12 vs 11 months (veliparib vs placebo) [HR = 0.94 (95% CI: 0.60, 1.48)]. Median OS was 25 vs 27 months [HR = 1.26 (95% CI: 0.74, 2.16)]. Response rate was 57% vs 62%. Median DOR was 11 vs 9 months [HR = 0.73 (95% CI: 0.38, 1.40)]. AEs with significantly higher frequency (p < 0.05) in the veliparib group were anaemia (39% vs 19%, p = 0.019) and neutropenia (66% vs 37%, p = 0.001) for common AEs (≥20%); neutropenia (59% vs 22%, p < 0.001) for common Grade 3/4 AEs (≥5%); none in serious AEs. Haematopoietic cytopenias were more common with veliparib (79% vs 52%, p = 0.003). Fourteen percent of patients on veliparib and 15% on placebo discontinued treatment due to AEs. CONCLUSION: Veliparib added to FOLFIRI ± bevacizumab demonstrated similar efficacy as FOLFIRI ± bevacizumab in frontline mCRC patients. No unexpected safety concerns occurred.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão
16.
Br J Cancer ; 120(2): 190-195, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30585257

RESUMO

BACKGROUND: Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. METHODS: Eighty-two patients with the UGT1A1*1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1*28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m2 for UGT1A1*1/*1 and 260 mg/m2 for *1/*28 patients. In the control group, the dose was 180 mg/m2. We analysed the overall response rate (ORR), toxicity, and survival. RESULTS: The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. CONCLUSIONS: Patients with the UGT1A1*1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Glucuronosiltransferase/genética , Irinotecano/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Genótipo , Humanos , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos
17.
Med. clín (Ed. impr.) ; 151(11): 425-430, dic. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-174172

RESUMO

Antecedentes y objetivos: Evaluar la relación entre la presencia de polimorfismos en los genes implicados en la farmacodinamia del irinotecán (UGT1A, SLCO1B1, ABCB1 y ABCC2) y la seguridad asociada al mismo en el tratamiento del cáncer colorrectal metastásico (CCRm). Pacientes y métodos: Estudio prospectivo observacional y unicéntrico de 30 meses de duración, en el que se incluyeron los pacientes diagnosticados de CCRm tratados con el esquema FOLFIRI. La toxicidad fue evaluada en cada ciclo de tratamiento según la Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. La obtención del ADN genómico se realizó mediante una muestra de sangre periférica a partir de un método de extracción basado en lisis alcalina. La caracterización genética se realizó empleando la plataforma LigthCycler®480 y sondas fluorescentes HybProbe® específicas de alelo. Los polimorfismos analizados fueron: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) y ABCB1 (rs1045642). Resultados: Fueron incluidos 34 pacientes (el 73,5% eran hombres, con una edad media de 59,9 años [27-81]). Los polimorfismos: rs8175347, rs17868323, rs3832043, rs11692021 y rs7577677 se relacionaron con una mayor incidencia de efectos adversos. Por otro lado, se observó que aquellos pacientes wild-type, en la serie de genes de la familia UGT analizada, presentan unas menores tasas de toxicidad asociada al tratamiento con irinotecán que aquellos que poseen alguno de los polimorfismos analizados (p=0,010). Conclusiones: Estos resultados sugieren que la presencia de determinados polimorfismos en la familia de genes UGT1A se encuentra relacionada con el desarrollo de toxicidad en el tratamiento con irinotecán en dosis para el esquema FOLFIRI


Background and objectives: Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). Patients and methods: Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler®480 platform and allele-specific HybProbe® fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). Results: Thirty-four patients were included (73.5% were male, mean age 59.9 years [27-81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (P=.010). Conclusions: These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Camptotecina/toxicidade , Neoplasias Colorretais/tratamento farmacológico , DNA/análise , Polimorfismo Genético , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Estudos Prospectivos , Estudo Observacional , Componentes Genômicos/genética
18.
Recenti Prog Med ; 109(11): 15e-19e, 2018 Nov.
Artigo em Italiano | MEDLINE | ID: mdl-30565582

RESUMO

The inhibition of the antiangiogenic pathway in association with chemotherapy significantly improved disease control and overall survival both in the upfront and in second line treatment of metastatic colorectal cancer patients. The VELOUR study had showed a significant improvement in overall survival with the addition of aflibercept, an antiangiogenic chimeric protein, to FOLFIRI (5-flourouracil, leucovorin, irinotecan) in patients who progressed after an oxaliplatin based chemotherapy (with or without bevacizumab) in first line treatment or within 6 months from the completion of adjuvant chemotherapy. Subgroup analyses from VELOUR trial show that the benefit of aflibercept is independent from previous exposure to bevacizumab in first line. We reported the case of a patient affected by metastatic colorectal adenocarcinoma RAS/ BRAF wild-type, with an initial liver-limited presentation. In this case we used a second line treatment with FOLFIRI aflibercept after a first-line oxaliplatin-based chemotherapy plus an anti-EGFR antibody.


Assuntos
Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Metástase Neoplásica , Oxaliplatina/administração & dosagem
19.
Recenti Prog Med ; 109(11): 20e-23e, 2018 Nov.
Artigo em Italiano | MEDLINE | ID: mdl-30565583

RESUMO

This is the case report of a patient with right-sided, RAS and BRAF wild-type metastatic colorectal cancer, with borderline/potentially resectable liver-limited disease. Following neoadjuvant treatment with FOLFOX plus bevacizumab and radical resection, an early intra-hepatic disease relapse was observed and deemed as potentially resectable. Therefore, treatment with FOLFIRI plus aflibercept was started: a major partial response and radical re-resection were achieved. Following unresectable disease relapse, second-line treatment with FOLFIRI aflibercept was resumed and achieved again a partial response that is still ongoing after more than 9 months. This case report highlights how treatment goals (potentially curative resection vs palliation), molecular status and primary tumor location influence treatment strategies in order to maximize patients' outcomes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Camptotecina/administração & dosagem , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Compostos Organoplatínicos/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Resultado do Tratamento
20.
Recenti Prog Med ; 109(11): 24e-26e, 2018 Nov.
Artigo em Italiano | MEDLINE | ID: mdl-30565584

RESUMO

This is a "best practice" case report of a non-uncommon clinical scenario, referring to an early liver relapse, judged as technically resectable, following adjuvant oxaliplatin-based treatment for left-sided, RAS and BRAF wild-type colon cancer. The choice of aflibercept vs cetuximab/panitumumab relies on the need to counteract an aggressive disease, without loosing the chance of radical surgery, nor loosing treatment options in the third-line setting. Treatment decisions are evidence-based on efficacy data of neoadjuvant anti-angiogenic treatment, as well as on the detrimental effect derived from the addition of cetuximab to perioperative chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Neoplasias Hepáticas/patologia , Inibidores da Angiogênese/administração & dosagem , Camptotecina/administração & dosagem , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Oxaliplatina/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem
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