RESUMEN

Chemotherapy-induced diarrhea (CID) is a potentially serious side effect that often occurs during anticancer therapy and is caused by the toxic effects of chemotherapeutic drugs on the gastrointestinal tract, resulting in increased frequency of bowel movements and fluid contents. Among these agents, irinotecan (CPT-11) is most commonly associated with CID. Hesperidin (HPD), a flavonoid glycoside found predominantly in citrus fruits, has anti-oxidation properties and anti-inflammation properties that may benefit CID management. Nevertheless, its potential mechanism is still uncertain. In this study, we firstly evaluated the pharmacodynamics of HPD for the treatment of CID in a mouse model, then used network pharmacology and molecular docking methods to excavate the mechanism of HPD in relieving CID, and finally further proved the predicted mechanism through molecular biology experiments. The results demonstrate that HPD significantly alleviated diarrhea, weight loss, colonic pathological damage, oxidative stress, and inflammation in CID mice. In addition, 74 potential targets for HPD intervention in CID were verified by network pharmacology, with the top 10 key targets being AKT1, CASP3, ALB, EGFR, HSP90AA1, MMP9, ESR1, ANXA5, PPARG, and IGF1. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the PI3K-Akt pathway, FoxO pathway, MAPK pathway, TNF pathway, and Ras pathway were most relevant to the HPD potential treatment of CID genes. The molecular docking results showed that HPD had good binding to seven apoptosis-related targets, including AKT1, ANXA5, CASP3, HSP90AA1, IGF1, MMP9, and PPARG. Moreover, we verified apoptosis by TdT-mediated dUTP nick-end labeling (TUNEL) staining and immunohistochemistry, and the hypothesis about the proteins above was further verified by Western blotting in vivo experiments. Overall, this study elucidates the potential and underlying mechanisms of HPD in alleviating CID.

Asunto(s)

Diarrea , Hesperidina , Irinotecán , Simulación del Acoplamiento Molecular , Farmacología en Red , Hesperidina/farmacología , Hesperidina/química , Hesperidina/uso terapéutico , Animales , Diarrea/tratamiento farmacológico , Diarrea/inducido químicamente , Ratones , Irinotecán/efectos adversos , Irinotecán/farmacología , Modelos Animales de Enfermedad , Masculino , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Introduction: In recent years, the development of drug-eluting embolization beads that can be imaged has become a hot research topic in regard to meeting clinical needs. In our previous study, we successfully developed nano-assembled microspheres (NAMs) for multimodal imaging purposes. NAMs can not only be visualized under CT/MR/Raman imaging but can also load clinically required doses of doxorubicin. It is important to systematically compare the pharmacokinetics of NAMs with those of commercially available DC Beads and CalliSpheres to evaluate the clinical application potential of NAMs. Methods: In our study, we compared NAMs with two types of drug-eluting beads (DEBs) in terms of irinotecan, drug-loading capacity, release profiles, microsphere diameter variation, and morphological characteristics. Results: Our results indicate that NAMs had an irinotecan loading capacity similar to those of DC Beads and CalliSpheres but exhibited better sustained release in vitro. Conclusion: NAMs have great potential for application in transcatheter arterial chemoembolization for the treatment of colorectal cancer liver metastases.

Asunto(s)

Irinotecán , Microesferas , Imagen Multimodal , Irinotecán/administración & dosificación , Irinotecán/farmacología , Humanos , Imagen Multimodal/métodos , Portadores de Fármacos/química , Liberación de Fármacos , Quimioembolización Terapéutica/métodos , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/farmacología

RESUMEN

An anticancer nanodrug with few side effects that does not require the use of a nanocarrier, polyethylene glycol, or other additives has been developed. We have fabricated nano-prodrugs (NPDs) composed only of homodimeric prodrugs of the anticancer agent SN-38, which contains a disulfide bond. The prodrugs are stable against hydrolysis but selectively release SN-38 when the disulfide bond is cleaved by glutathione, which is present in high concentrations in cancer cells. The best-performing NPDs showed good dispersion stability in nanoparticle form, and animal experiments revealed that they possess much higher antitumor activity than irinotecan, a clinically applied prodrug of SN-38. This performance was achieved by improving tumor accumulation due to the size effect and targeted drug release mechanism. The present study provides an insight into the development of non-invasive NPDs with high pharmacological activity, and also offers new possibilities for designing prodrug molecules that can release drugs in response to various kinds of triggers.

Asunto(s)

Camptotecina , Irinotecán , Profármacos , Profármacos/química , Profármacos/farmacología , Animales , Irinotecán/química , Irinotecán/farmacología , Humanos , Ratones , Camptotecina/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Línea Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Nanopartículas/química , Liberación de Fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ratones Endogámicos BALB C , Ratones Desnudos

RESUMEN

[Gd(OH)]2+[(SN-38)0.5(FdUMP)0.5]2- inorganic-organic hybrid nanoparticles (IOH-NPs) with a chemotherapeutic cocktail of ethyl-10-hydroxycamptothecin (SN-38, active form of irinotecan) and 5-fluoro-2'-deoxyuridine-5'-phosphate (FdUMP, active form of 5'-fluoruracil), 40 nm in size, are prepared in water. The IOH-NPs contain a total drug load of 63 wt% with 33 wt% of SN-38 and 30 wt% of FdUMP. Cell-based assays show efficient cellular uptake and promising anti-tumour activity on two pancreatic cancer cell lines of murine origin (KPC, Panc02). Beside the high-load drug cocktail, especially the option to use SN-38, which - although 100- to 1000-times more potent than irinotecan - is usually unsuitable for systemic administration due to poor solubility, low stability, and high toxicity upon non-selective delivery. The [Gd(OH)]2+[(SN-38)0.5(FdUMP)0.5]2- IOH-NPs are a new concept to deliver a drug cocktail with SN-38 and FdUMP directly to the tumour, shielded in a nanoparticle, to reduce side effects.

Asunto(s)

Camptotecina , Irinotecán , Nanopartículas , Irinotecán/química , Irinotecán/farmacología , Camptotecina/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Ratones , Línea Celular Tumoral , Animales , Nanopartículas/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Portadores de Fármacos/química , Floxuridina/química , Floxuridina/farmacología

RESUMEN

Traditional antibody-drug conjugates (ADCs) mainly suppress tumor growth through either chemotherapy with cytotoxic payloads or immunotherapy with immuno-modulators. However, a single therapeutic modality may limit their exploration. Herein, we developed a new type of drug conjugate termed CAR-EDC (CAR-M-derived exosome-drug conjugate) by using CAR-exosomes from CAR-M cells as the targeting drug carrier that contains a high level of CXCL10. CAR-exosomes could significantly enhance the immunological activation and migratory capacity of T lymphocytes and promote their differentiation into CD8+ T cells. It also increased the proportion of M1 macrophages. The CAR-EDC, covalently loaded with SN-38, was internalized into Raji cells through endocytosis mediated by the CAR molecules. It exerted excellent antitumor activity in vivo by virtue of not only chemotherapy by SN38 but also immunotherapy by CXCL10-mediated antitumor immunity. Generally, this study provides an exosome-drug conjugate system with enhanced antitumor effects over traditional ADCs through the synergism of chemotherapy and immunotherapy.

Asunto(s)

Exosomas , Inmunoterapia , Exosomas/metabolismo , Humanos , Animales , Inmunoterapia/métodos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Quimiocina CXCL10/metabolismo , Línea Celular Tumoral , Inmunoconjugados/química , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Irinotecán/farmacología , Irinotecán/uso terapéutico , Irinotecán/química , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Ratones Endogámicos BALB C

RESUMEN

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Asunto(s)

Antineoplásicos , Sistemas CRISPR-Cas , Resistencia a Antineoplásicos , Irinotecán , Oxaliplatino , Proteínas Serina-Treonina Quinasas , Resistencia a Antineoplásicos/genética , Humanos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Oxaliplatino/farmacología , Irinotecán/farmacología , Sistemas CRISPR-Cas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Animales , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Ratones , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos

RESUMEN

Introduction: Glioblastoma multiforme (GBM), a highly invasive and prognostically challenging brain cancer, poses a significant hurdle for current treatments due to the existence of the blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Methods: We present a biomimetic nanoplatform with angiopep-2-modified macrophage membrane, loaded with indocyanine green (ICG) templated self-assembly of SN38 (AM-NP), facilitating active tumor targeting and effective blood-brain barrier penetration through specific ligand-receptor interaction. Results: Upon accumulation at tumor sites, these nanoparticles achieved high drug concentrations. Subsequent combination of laser irradiation and release of chemotherapy agent SN38 induced a synergistic chemo-photothermal therapy. Compared to bare nanoparticles (NPs) lacking cell membrane encapsulation, AM-NPs significantly suppressed tumor growth, markedly enhanced survival rates, and exhibited excellent biocompatibility with minimal side effects. Conclusion: This NIR-activatable biomimetic camouflaging macrophage membrane-based nanoparticles enhanced drug delivery targeting ability through modifications of macrophage membranes and specific ligands. It simultaneously achieved synergistic chemo-photothermal therapy, enhancing treatment effectiveness. Compared to traditional treatment modalities, it provided a precise, efficient, and synergistic method that might have contributed to advancements in glioblastoma therapy.

Asunto(s)

Barrera Hematoencefálica , Neoplasias Encefálicas , Liberación de Fármacos , Glioblastoma , Verde de Indocianina , Nanopartículas , Terapia Fototérmica , Glioblastoma/terapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Animales , Verde de Indocianina/química , Verde de Indocianina/farmacocinética , Verde de Indocianina/farmacología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Humanos , Línea Celular Tumoral , Ratones , Nanopartículas/química , Terapia Fototérmica/métodos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Irinotecán/farmacocinética , Irinotecán/química , Irinotecán/farmacología , Péptidos/química , Péptidos/farmacología , Péptidos/farmacocinética , Rayos Infrarrojos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacocinética , Materiales Biomiméticos/farmacología , Sistemas de Liberación de Medicamentos/métodos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Desnudos , Terapia Combinada/métodos

RESUMEN

OBJECTIVE: Colorectal cancer, one of the most frequently diagnosed cancers worldwide, has a high mortality rate. Thus, our research aims to examine the preventive effects of diosmin (DIO) alone and in conjunction with the anti-cancer drug irinotecan (camptothecin-11, CPT-11), on 1,2-dimethylhydrazine (DMH)-induced colon cancer (CC) in male Wistar rats. MATERIALS AND METHODS: Fifty adult male Wistar rats were categorized into five groups. Group I (Normal) received saline 0.9 orally % as a vehicle once a week for 14 weeks. Group II (DMH) received DMH (20 mg/kg/week) orally dissolved in 0.9% saline for 14 weeks and 1% carboxymethylcellulose (CMC) every other day for the final 10 weeks. Group III (DMH+DIO) received DMH orally for 14 weeks and DIO (10 mg/kg, suspended in 1% CMC) every other day for the final 10 weeks. Group IV (DMH+CPT-11) received DMH orally for 14 weeks and intraperitoneal injection of CPT-11 (3 mg/kg) twice a week for the final 10 weeks. Group V (DMH+DIO+CPT-11) orally received DMH for 14 weeks and both DIO and CPT-11. RESULTS: All treated groups showed a significant reduction (p<0.05) in their elevated serum malondialdehyde levels and significant amelioration (p<0.05) of their lowered activities of colon glutathione-S-transferase (GST) and glutathione reductase (GR) as well as serum glutathione level (GSH). In addition, simultaneous treatment with DIO and CPT-11 led to a significant decrease (p<0.05) in the elevated serum levels of carcinoembryonic antigen (CEA) in rats administered with DMH, as well as a reduction in the colon expression levels of the inflammatory mediator (NF-κB), cell proliferator protein (Ki-67), and proapoptotic protein (p53). CONCLUSIONS: These findings suggest DIO, CPT-11, and their combination have anticarcinogenic effects against DMH-induced CC by suppressing oxidative stress, simulating the antioxidant defense system, attenuating the inflammatory effects, and reducing cell proliferation.

Asunto(s)

1,2-Dimetilhidrazina , Neoplasias del Colon , Diosmina , Irinotecán , Ratas Wistar , Animales , Masculino , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Neoplasias del Colon/metabolismo , Ratas , Diosmina/farmacología , Diosmina/administración & dosificación , Irinotecán/farmacología , Irinotecán/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacología , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function. We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis. Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 µM) or the pro-inflammatory cytokines TNFα and IL-1ß (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 µM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 µM). Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation. These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.

Asunto(s)

Cannabidiol , Cannabinoides , Mucosa Intestinal , Irinotecán , Especies Reactivas de Oxígeno , Humanos , Células CACO-2 , Cannabidiol/farmacología , Cannabinoides/farmacología , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Funcion de la Barrera Intestinal , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Irinotecán/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

AIMS: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer. MAIN METHODS: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan. KEY FINDINGS: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan. SIGNIFICANCE: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.

Asunto(s)

Neoplasias Colorrectales , Quinasa Activadora de Quinasas Ciclina-Dependientes , Quinasas Ciclina-Dependientes , Resistencia a Antineoplásicos , Irinotecán , Irinotecán/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Humanos , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Células HT29 , Quinasas Ciclina-Dependientes/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos BALB C , Femenino , Proliferación Celular/efectos de los fármacos

RESUMEN

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Irinotecán , Oxaliplatino , Neoplasias Pancreáticas , Medicina de Precisión , Transcriptoma , Humanos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Quimioterapia Adyuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Oxaliplatino/farmacología , Masculino , Medicina de Precisión/métodos , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Irinotecán/farmacología , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Persona de Mediana Edad , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Gemcitabina , Anciano , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Inteligencia Artificial , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos

RESUMEN

BACKGROUND: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Camptotecina , Neoplasias Colorrectales , Fluorouracilo , Genotipo , Glucuronosiltransferasa , Leucovorina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Bevacizumab/administración & dosificación , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Bevacizumab/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Masculino , Femenino , Glucuronosiltransferasa/genética , Persona de Mediana Edad , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Leucovorina/efectos adversos , Anciano , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacología , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Adulto , Anciano de 80 o más Años , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Irinotecán/efectos adversos , Irinotecán/farmacología

RESUMEN

FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou-Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Fluorouracilo , Leucovorina , MicroARNs , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/tratamiento farmacológico , Línea Celular Tumoral , Fluorouracilo/farmacología , Viroterapia Oncolítica/métodos , MicroARNs/genética , Virus Oncolíticos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucovorina/farmacología , Leucovorina/uso terapéutico , Compuestos Organoplatinos/farmacología , Oxaliplatino/farmacología , Enterovirus Humano B/efectos de los fármacos , Terapia Combinada , Irinotecán/farmacología

RESUMEN

Supramolecular polymers (SPs) are an emerging class of drug transporters employed to improve drug therapy. Through the rational design of self-assembling monomers, one can optimize the properties of the resulting supramolecular nanostructures, such as size, shape, surface chemistry, release, and, therefore, biological fates. This study highlights the design of isomeric SN38 prodrugs through the conjugation of hydrophilic oligo(ethylene glycol) (OEG) with hydroxyls at positions 10 and 20 on hydrophobic SN-38. Self-assembling prodrug (SAPD) isomers 10-OEG-SN38 and 20-OEG-SN38 can self-assemble into giant nanotubes and filamentous assemblies, respectively, via aromatic associations that dominate self-assembly. Our study reveales the influence of modification sites on the assembly behavior and ability of the SN38 SAPDs, as well as drug release and subsequent in vitro and in vivo antitumor effects. The SAPD modified at position 20 exhibits stronger π-π interactions among SN38 units, leading to more compact packing and enhanced assembly capability, whereas OEG at position 10 poses steric hindrance for aromatic associations. Importantly, owing to its higher chemical and supramolecular stability, 20-OEG-SN38 outperforms 10-OEG-SN38 and irinotecan, a clinically used prodrug of SN38, in a CT26 tumor model, demonstrating enhanced tumor growth inhibition and prolonged animal survival. This study presents a new strategy of using interactions among drug molecules as dominating features to create supramolecular assemblies. It also brings some insights into creating effective supramolecular drug assemblies via the engineering of self-assembling building blocks, which could contribute to the optimization of design principles for supramolecular drug delivery systems.

Asunto(s)

Irinotecán , Profármacos , Profármacos/química , Profármacos/farmacología , Profármacos/síntesis química , Irinotecán/química , Irinotecán/farmacología , Humanos , Animales , Ratones , Isomerismo , Proliferación Celular/efectos de los fármacos , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Ratones Endogámicos BALB C , Tamaño de la Partícula , Sustancias Macromoleculares/química , Sustancias Macromoleculares/síntesis química , Sustancias Macromoleculares/farmacología , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Polietilenglicoles/química , Camptotecina/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Ratones Desnudos

RESUMEN

Purpose: SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan, has been extensively studied in drug delivery systems. However, its impact on neural metabolism remains unclear. This study aims to investigate the toxic effects of SN-38 on mouse brain metabolism. Methods: Male mice were divided into an SN-38 group and a control group. The SN-38 group received SN-38 (20 mg/kg/day) via intraperitoneal injection, while the control group was given an equal volume of a blank solvent mixture (DMSO and saline, ratio 1:9). Gas chromatography-mass spectrometry (GC-MS) was employed to analyze differential metabolites in the cortical and hippocampal regions of the SN-38-treated mice. Results: SN-38 induced metabolic disturbances in the central nervous system. Eighteen differential metabolites were identified in the hippocampus and twenty-four in the cortex, with six common to both regions. KEGG pathway enrichment analysis revealed statistically significant alterations in six metabolic pathways in the hippocampus and ten in the cortex (P<0.05). Conclusion: This study is the first to demonstrate the neurotoxicity of SN-38 in male mice through metabolomics. Differential metabolites in the hippocampal and cortical regions were closely linked to purine metabolism, pyrimidine metabolism, amino acid metabolism, and glyceride metabolism, indicating disruptions in the blood-brain barrier, energy metabolism, and central signaling pathways.

Asunto(s)

Encéfalo , Irinotecán , Metabolómica , Animales , Masculino , Irinotecán/farmacología , Ratones , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Inyecciones Intraperitoneales

RESUMEN

To improve the biodistribution of the drug in the tumor, a supramolecular prodrug of SN38 was fabricated in situ between endogenous albumin and SN38 prodrug modified with semaglutide side chain. Firstly, SN38 was conjugated with semaglutide side chain and octadecanedioic acid via glycine linkers to obtain SI-Gly-SN38 and OA-Gly-SN38 prodrugs, respectively. Both SI-Gly-SN38 and OA-Gly-SN38 exhibited excellent stability in PBS for over 24 h. Due to the strong binding affinity of the semaglutide side chain with albumin, the plasma half-life of SI-Gly-SN38 was 2.7 times higher than that of OA-Gly-SN38. Furthermore, with addition of HSA, the fluorescence intensity of SI-Gly-SN38 was 4 times higher than that of OA-Gly-SN38, confirming its strong binding capability with HSA. MTT assay showed that the cytotoxicity of SI-Gly-SN38 and OA-Gly-SN38 was higher than that of Irinotecan. Even incubated with HSA, the SI-Gly-SN38 and OA-Gly-SN38 still maintained high cytotoxicity, indicating minimal influence of HSA on their cytotoxicity. In vivo pharmacokinetic studies demonstrated that the circulation half-life of SI-Gly-SN38 was twice that of OA-Gly-SN38. SI-Gly-SN38 exhibited significantly reduced accumulation in the lungs, being only 0.23 times that of OA-Gly-SN38. The release of free SN38 in the lungs from SI-Gly-SN38 was only 0.4 times that from OA-Gly-SN38 and Irinotecan. The SI-Gly-SN38 showed the highest accumulation in tumors. The tumor inhibition rate of SI-Gly-SN38 was 6.42% higher than that of OA-Gly-SN38, and 8.67% higher than that of Irinotecan, respectively. These results indicate that the supramolecular prodrug delivery system can be constructed between SI-Gly-SN38 and endogenous albumin, which improves drug biodistribution in vivo, enhances tumor accumulation, and plays a crucial role in tumor growth inhibition.

Asunto(s)

Irinotecán , Profármacos , Irinotecán/química , Irinotecán/farmacología , Profármacos/química , Profármacos/farmacología , Profármacos/síntesis química , Animales , Humanos , Ratones , Distribución Tisular , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Ratones Desnudos , Albúminas/química , Masculino , Relación Estructura-Actividad , Albúmina Sérica Humana/química , Péptidos Similares al Glucagón

RESUMEN

Liposomes and nanofibers have been implemented as efficacious vehicles for delivering anticancer drugs. With this view, this study explores the antiproliferative efficacy and apoptosis induction in leukemia cancer cells utilizing irinotecan-loaded liposome-embedded nanofibers fabricated from chitosan, a biological source. Specifically, we investigate the effectiveness of poly(ε-caprolactone) (PCL)/chitosan (CS) (core)/irinotecan (CPT)nanofibers (termed PCL-CS10 CPT), PCL/chitosan/irinotecan (core)/PCL/chitosan (shell) nanofibers (termed CS/CPT/PCL/CS), and irinotecan-coloaded liposome-incorporated PCL/chitosan-chitosan nanofibers (termed CPT@Lipo/CS/PCL/CS) in releasing irinotecan in a controlled manner and treating leukemia cancer. The fabricated formulations were characterized utilizing Fourier transform infrared analysis, transmission electron microscopy, scanning electron microscopy, dynamic light scattering, zeta potential, and polydispersity index. Irinotecan was released in a controlled manner from nanofibers filled with liposomes over 30 days. The cell viability of the fabricated nanofibrous materials toward Human umbilical vein endothelial cells (HUVECs) non-cancerous cells after 168 h was >98 % ± 1 %. The CPT@Lipo/CS/PCL/CS nanofibers achieved maximal cytotoxicity of 85 % ± 2.5 % against K562 leukemia cancer cells. The CPT@Lipo/CS/PCL/CS NFs exhibit a three-stage drug release pattern and demonstrate significant in vitro cytotoxicity. These findings indicate the potential of these liposome-incorporated core-shell nanofibers for future cancer therapy.

Asunto(s)

Apoptosis , Proliferación Celular , Quitosano , Irinotecán , Leucemia , Liposomas , Nanofibras , Quitosano/química , Humanos , Liposomas/química , Irinotecán/farmacología , Irinotecán/química , Irinotecán/administración & dosificación , Nanofibras/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Leucemia/tratamiento farmacológico , Leucemia/patología , Células Endoteliales de la Vena Umbilical Humana , Liberación de Fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Poliésteres/química , Antineoplásicos/farmacología , Antineoplásicos/química

RESUMEN

The activity of known modulators of the Nrf2 signaling pathway (bardoxolone and brusatol) was studied on cultures of tumor organoids of metastatic colorectal cancer previously obtained from three patients. The effect of modulators was studied both as monotherapy and in combination with standard chemotherapy drugs used to treat colorectal cancer. The Nrf2 inhibitor brusatol and the Nrf2 activator bardoxolone have antitumor activity. Moreover, bardoxolone and brusatol also significantly enhance the effect of the chemotherapy drugs 5-fluorouracil, oxaliplatin, and irinotecan metabolite SN-38. Thus, bardoxolone and brusatol can be considered promising candidates for further preclinical and clinical studies in the treatment of colorectal cancer.

Asunto(s)

Neoplasias Colorrectales , Fluorouracilo , Irinotecán , Factor 2 Relacionado con NF-E2 , Organoides , Oxaliplatino , Cuassinas , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Cuassinas/farmacología , Cuassinas/uso terapéutico , Organoides/efectos de los fármacos , Organoides/metabolismo , Organoides/patología , Transducción de Señal/efectos de los fármacos , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Irinotecán/farmacología , Irinotecán/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sinergismo Farmacológico , Camptotecina/análogos & derivados , Camptotecina/farmacología , Camptotecina/uso terapéutico

RESUMEN

The clinical application of 7-ethyl hydroxy-camptothecin (SN-38) maintains challenges not only due to its poor solubility and stability but also the lack of effective carriers to actively deliver SN-38 to deep tumor sites. Although SN-38-based nanomedicines could improve the solubility and stability from different aspects, the tumor targeting efficiency remains very low. Leveraging the hypoxic taxis of bifidobacteria bifidum (B. bifi) to the deep tumor area, we report SN-38-based nanomedicines-engineered bifidobacterial complexes for effective tumor-targeted delivery. Firstly, SN-38 was covalently coupled with poly-L-glutamic acid (L-PGA) and obtained soluble polymeric prodrug L-PGA-SN38 to improve its solubility and stability. To prolong the drug release, L-PGA-SN38 was mildly complexed with chitosan to form nanomedicines, and nanomedicines engineered B. bifi were further elaborated via electrostatic interaction of the excess of cationic chitosan shell from nanomedicines and anionic teichoic acid from B. bifi. The engineered B. bifi complexes inherited the bioactivity of native B. bifi and exhibited distinctly enhanced accumulation at the tumor site. More importantly, significantly elevated anti-tumor efficacy was achieved after the treatment of CS-L-PGA-SN38 NPs/B. bifi complexes, with favorable tumor suppression up to 80%. Such a B. bifi-mediated delivery system offers a promising platform for effective drug delivery and enhanced drug accumulation in the hypoxia deep tumor with superior anti-tumor efficacy.

Asunto(s)

Quitosano , Neoplasias Colorrectales , Irinotecán , Nanomedicina , Ácido Poliglutámico , Irinotecán/administración & dosificación , Irinotecán/farmacología , Quitosano/química , Neoplasias Colorrectales/tratamiento farmacológico , Animales , Ácido Poliglutámico/química , Ácido Poliglutámico/análogos & derivados , Humanos , Nanomedicina/métodos , Liberación de Fármacos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , Ratones , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/química , Camptotecina/farmacología , Ratones Endogámicos BALB C , Línea Celular Tumoral , Bifidobacterium bifidum , Ratones Desnudos , Femenino

RESUMEN

BACKGROUND: High-grade neuroendocrine neoplasms (NENs) comprise both well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) nearly always include poorly differentiated NEC as the neuroendocrine component. The efficacy and safety of frontline mFOLFIRINOX chemotherapy has never been investigated in patients with high-grade NENs. PATIENTS AND METHODS: We conducted a multi-institutional retrospective analysis of patients with advanced high-grade NEN of the gastroenteropancreatic tract or of unknown origin seen between February 2016 and April 2023 who received treatment with frontline mFOLFIRINOX. RESULTS: A total of 35 patients were included (G3 NETs: n=2; NECs: n=25; MiNENs: n=8; stage III: n=5; stage IV: n=30). The objective response rate was 77% (complete response: 3%; partial response: 74%). Median progression-free survival was 12 months (95% CI, 9.2-16.2 months) and median overall survival was 20.6 months (95% CI, 17.2-30.6 months). No significant differences in efficacy were seen according to primary site, histopathology, and Ki-67 proliferative index. All 5 patients with stage III disease who received mFOLFIRINOX obtained an objective response and underwent radical surgery or definitive radiotherapy with curative intent, with a recurrence rate of 40%. Grade 3 or 4 adverse events were observed in 43% of patients (mainly neutropenia and diarrhea). Females were at significantly increased risk of developing severe toxicities. CONCLUSIONS: mFOLFIRINOX shows antitumor activity against high-grade NENs. Well-designed, prospective clinical trials are needed to assess the efficacy of mFOLFIRINOX in both the neoadjuvant and metastatic settings.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Irinotecán , Clasificación del Tumor , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Femenino , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Anciano , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Estudios Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Irinotecán/uso terapéutico , Irinotecán/farmacología , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/patología , Neoplasias Intestinales/mortalidad , Oxaliplatino/uso terapéutico , Oxaliplatino/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Resultado del Tratamiento