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Myxoid liposarcoma (MLPS) is a rare soft-tissue sarcoma characterised by the expression of FUS-DDIT3 chimera. Trabectedin has shown significant clinical anti-tumour activity against MLPS. To characterise the molecular mechanism of trabectedin sensitivity and of resistance against it, we integrated genomic and transcriptomic data from treated mice bearing ML017 or ML017/ET, two patient-derived MLPS xenograft models, sensitive to and resistant against trabectedin, respectively. Longitudinal RNA-Seq analysis of ML017 showed that trabectedin acts mainly as a transcriptional regulator: 15 days after the third dose trabectedin modulates the transcription of 4883 genes involved in processes that sustain adipocyte differentiation. No such differences were observed in ML017/ET. Genomic analysis showed that prolonged treatment causes losses in 4p15.2, 4p16.3 and 17q21.3 cytobands leading to acquired-resistance against the drug. The results dissect the complex mechanism of action of trabectedin and provide the basis for novel combinatorial approaches for the treatment of MLPS that could overcome drug-resistance.
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Liposarcoma Mixoide , Adulto , Animales , Modelos Animales de Enfermedad , Humanos , Liposarcoma Mixoide/tratamiento farmacológico , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/patología , Ratones , Trabectedina/uso terapéuticoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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BACKGROUND: Myxoid liposarcoma is a histological subtype of liposarcoma particularly sensitive to trabectedin. In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. No other effective therapies are available for trabectedin-resistant patients. METHODS: Through repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin. RESULTS: At basal level, the morphology of the resistant and sensitive models did not differ, in keeping with the finding that the transcriptional profiles of the resistant and sensitive tumours were very similar. After trabectedin treatment adipogenesis was induced in the parental xenograft but not in the resistant one, as assessed by pathological and molecular analysis. A defective transcription-coupled-nucleotide excision repair in the resistant tumour due to mutation of the UVSSA gene may be implicated in the mechanism of resistance. CONCLUSIONS: This is the first in vivo model of myxoid liposarcoma with acquired resistance to trabectedin. Although further studies are necessary to characterise the resistance mechanisms, this is a useful tool for studying new therapeutic strategies to overcome trabectedin resistance in patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas Portadoras/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Liposarcoma Mixoide/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptosis , Carbolinas/administración & dosificación , Proliferación Celular , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos/genética , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/patología , Ratones , Ratones Desnudos , Trabectedina/administración & dosificación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
It has recently been reported that a large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c-MYC oncogene. This gene drives several tumorigenic processes and is overexpressed in many cancers. Although c-MYC is a strategic target to restrain cancer processes, no drugs acting as c-MYC inhibitors are available. The novel thienotriazolodiazepine small-molecule bromodomain inhibitor OTX015/MK-8628 has shown potent antiproliferative activity accompanied by c-MYC downregulation in several tumor types. This study was designed to evaluate the growth inhibitory effect of OTX015 on patient-derived MPM473, MPM487 and MPM60 mesothelioma cell lines and its antitumor activity in three patient-derived xenograft models, MPM473, MPM487 and MPM484, comparing it with cisplatin, gemcitabine and pemetrexed, three agents which are currently used to treat MPM in the clinic. OTX015 caused a significant delay in cell growth both in vitro and in vivo. It was the most effective drug in MPM473 xenografts and showed a similar level of activity as the most efficient treatment in the other two MPM models (gemcitabine in MPM487 and cisplatin in MPM484). In vitro studies showed that OTX015 downregulated c-MYC protein levels in both MPM473 and MPM487 cell lines. Our findings represent the first evidence of promising therapeutic activity of OTX015 in mesothelioma.
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Acetanilidas/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Pemetrexed/administración & dosificación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Acetanilidas/farmacología , Anciano , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Mesotelioma/metabolismo , Mesotelioma Maligno , Ratones , Persona de Mediana Edad , Pemetrexed/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
BACKGROUND: Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells. METHODS: In this study we investigated whether lurbinectedin has the ability to modulate the inflammatory microenvironment and the viability of myeloid cells in tumour-bearing mice. RESULTS: Administration of lurbinectedin significantly and selectively decreased the number of circulating monocytes and, in tumour tissues, that of macrophages and vessels. Similar findings were observed when a lurbinectedin-resistant tumour variant was used, indicating a direct effect of lurbinectedin on the tumour microenviroment. In vitro, lurbinectedin induced caspase-8-dependent apoptosis of human purified monocytes, whereas at low doses it significantly inhibited the production of inflammatory/growth factors (CCL2, CXCL8 and VEGF) and dramatically impaired monocyte adhesion and migration ability. These findings were supported by the strong inhibition of genes of the Rho-GTPase family in lurbinectedin-treated monocytes. CONCLUSIONS: The results illustrate that lurbinectedin affects at multiple levels the inflammatory microenvironment by acting on the viability and functional activity of mononuclear phagocytes. These peculiar effects, combined with its intrinsic activity against cancer cells, make lurbinectedin a compound of particular interest in oncology.
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Antineoplásicos Alquilantes/farmacología , Carbolinas/farmacología , Fibrosarcoma/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Macrófagos , Monocitos/efectos de los fármacos , Monocitos/fisiología , Neoplasias Ováricas/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos Alquilantes/uso terapéutico , Apoptosis/efectos de los fármacos , Carbolinas/uso terapéutico , Caspasa 8/metabolismo , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/biosíntesis , Dioxoles/farmacología , Regulación hacia Abajo , Femenino , Fibrosarcoma/inmunología , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Células HL-60 , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Interleucina-8/biosíntesis , Recuento de Leucocitos , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo , Neovascularización Patológica/prevención & control , Tetrahidroisoquinolinas/farmacología , Trabectedina , Microambiente Tumoral/inmunología , Células U937 , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas de Unión al GTP rho/genéticaRESUMEN
BACKGROUND: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. METHODS: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. RESULTS: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. CONCLUSIONS: Trabectedin could be good candidate for clinical studies in JMML/CMML patients.
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Antineoplásicos Alquilantes/uso terapéutico , Dioxoles/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Tetrahidroisoquinolinas/uso terapéutico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patología , Ratones , Ratones Desnudos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Trabectedina , Ensayo de Tumor de Célula MadreRESUMEN
Polymer nanoparticles (NPs) represent a promising way to deliver poorly water-soluble anticancer drugs without the use of unwanted excipients, whose presence can be the cause of severe side effects. In this work, a Cremophor-free formulation for paclitaxel (PTX) has been developed by employing PEGylated polymer nanoparticles (NPs) as drug delivery carriers based on modified poly(ε-caprolactone) macromonomers and synthesized through free radical emulsion polymerization. Paclitaxel was loaded in the NPs in a postsynthesis process which allowed to obtain a drug concentration suitable for in vivo use. In vivo experiments on drug biodistribution and therapeutic efficacy show comparable behavior between the NPs and the Cremophor formulation, also showing good tolerability of the new formulation proposed.
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Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Paclitaxel/química , Polietilenglicoles/química , Polímeros/química , PolimerizacionRESUMEN
PURPOSE: Thrombospondin-1 (TSP-1), a major regulator of cell interaction with the environment, is often deregulated in cancers, including ovarian carcinoma. Both the tumor and the host cells can release TSP-1 in the tumor microenvironment. The relative contribution of the two sources in determining TSP-1 levels in ovarian cancer remains to be elucidated. This study was designed to investigate the expression of tumor TSP-1 in a panel of 29 patient-derived ovarian adenocarcinoma xenografts (PDX), using analytical tools specific for human (tumor-derived) rather than murine (host-derived) TSP-1. METHODOLOGY: Human-specific microarray and ELISA were used to measure tumor TSP-1 expression and plasma levels. RESULTS: Tumor-derived TSP-1 was heterogeneously expressed in PDX. Expression was higher in the corresponding original patient's tumor, where stroma-derived TSP-1 is also analyzed, indicating that both the tumor and the host contribute to TSP-1 production. TSP-1 was differentially expressed according to tumor grade, but not affected by p53 expression or mutational status. Findings were confirmed in an external gene expression dataset (101 patients). In a functional enrichment analysis, TSP-1 correlated with genes related to angiogenesis, cell motility, communication and shape. Plasma TSP-1, detectable in 10/11 PDX, was not associated to its expression in the tumor. The possible association of plasma TSP-1 with p53 mutations and response to chemotherapy warrants further investigation. CONCLUSIONS: Ovarian carcinoma PDX are a useful tool to investigate the relative contribution of stroma and tumor cells in the production of tumor associated factors, in relation to the tumor behavior, molecular properties and response to therapy.
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Estudio de Asociación del Genoma Completo , Neovascularización Patológica/patología , Neoplasias Ováricas/patología , Trombospondina 1/metabolismo , Microambiente Tumoral/fisiología , Animales , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Estudio de Asociación del Genoma Completo/métodos , Xenoinjertos , Ratones , Neoplasias Ováricas/genética , Trombospondina 1/genéticaRESUMEN
We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise and highly accurate for the measurement of the drug and the main metabolites. The lower limit of quantification resulted in 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate, respectively, was appropriate for the analysis, as demonstrated by the accuracy of between 96.8% and 102.4% for plasma and 96.6 to 102.3% for the tumor. The interdays precision and accuracy determined on quality controls at three different levels were in the ranges of 6.9 to 7.5% and 99.3 to 101.0%, and 0.96 to 1.91% and 102.3 to 105.8% for plasma and tumor, respectively. With the application of the novel assay in explorative pharmacokinetic studies, following acute and chronic oral administration of the nanoformulation, fenretinide was detected in plasma and tumor tissue at a concentration higher than the IC50 value necessary for in vitro inhibitory activity (i.e., 1-5 µM) in different cancer cells lines. We were also able to detect the presence in plasma and tumor of active and inactive metabolites of fenretinide.
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This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non-homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects.
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Carbolinas/farmacología , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Dioxoles/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias/tratamiento farmacológico , Tetrahidroisoquinolinas/farmacología , Alcaloides/farmacología , Animales , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Pollos , Citometría de Flujo , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Estructura Molecular , Neoplasias/patología , Trabectedina , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Platinum-based chemotherapy is the first-line treatment for different cancer types, and in particular, for malignant pleural mesothelioma patients (a tumor histotype with urgent medical needs). Herein, a strategy is presented to stabilize, transport, and intracellularly release a platinumIV (PtIV ) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as an anticancer drug, is promoted by the presence of glutathione in neoplastic cells that also causes the destruction of the carrier. The nanocage presents a single internal cavity in which the hydrophobic complex (Pt(dach)Cl2 (OH)2 ), (dach = R,R-diaminocyclohexane) is encapsulated. The in vitro uptake and the internalization kinetics in cancer model cells are evaluated and, using flow cytometry analysis, the successful release and activation of the Pt-based drug inside cancer cells are demonstrated. The in vitro findings are confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patient-derived malignant pleural mesothelioma. MPM487 confirms the well-known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth is observed when mice are treated with the PtIV , entrapped in the nanocages, at an equivalent dose of the platinum complex.
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Antineoplásicos , Mesotelioma Maligno , Neoplasias , Animales , Ratones , Compuestos Organoplatinos/química , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Pioglitazone is a Peroxisome Proliferator-Activated Receptor (PPAR) agonist of the thiazolidinedione class of compounds with promising anticancer activity. An innovative quantitative mass spectrometry imaging (MSI) method and a HPLC-UV method were developed and validated to investigate its distribution in tumor and liver tissues. The MSI method is based on stable isotope normalization and resulted highly specific and sensitive (0.2 pmol/spot). The correct identification of the drug ion signal is confirmed by MS/MS analysis on tissue. The method shows an optimal lateral resolution (25 µm) relying on the ionization efficiency and fine laser diameter of the atmospheric pressure MALDI source. The HPLC-UV method is simple and straightforward involving quick protein precipitation and shows good sensitivity (50ng/sample) using a small starting volume of biological sample. Thus, it is applicable to samples obtained from both preclinical models and clinical surgical procedures. MSI and HPLC-UV assays were validated assessing linearity, intra- and inter-day precision and accuracy, limit of quantification, selectivity and recovery. These are the first methods developed and validated for the analysis of pioglitazone in tissues, and they were applied successfully to myxoid liposarcoma xenograft-bearing mice, which received clinically relevant drug doses. Pioglitazone was measured by either method in sections of tumor and liver 2, 6 and 24 h post-treatment. Drug distribution was relatively homogeneous.
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Presión Atmosférica , Espectrometría de Masas en Tándem , Animales , Cromatografía Líquida de Alta Presión , Ratones , Pioglitazona , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Trabectedin (ET743) and lurbinectedin (PM01183) limit the production of inflammatory cytokines that are elevated during cancer cachexia. Mice carrying C26 colon adenocarcinoma display cachexia (i.e., premature death and body wasting with muscle, fat and cardiac tissue depletion), high levels of inflammatory cytokines and subsequent splenomegaly. We tested whether such drugs protected these mice from cachexia. Ten-week-old mice were inoculated with C26 cells and three days later randomized to receive intravenously vehicle or 0.05 mg/kg ET743 or 0.07 mg/kg PM01183, three times a week for three weeks. ET743 or PM01183 extended the lifespan of C26-mice by 30% or 85%, respectively, without affecting tumor growth or food intake. Within 13 days from C26 implant, both drugs did not protect fat, muscle and heart from cachexia. Since PM01183 extended the animal survival more than ET743, we analyzed PM01183 further. In tibialis anterior of C26-mice, but not in atrophying myotubes, PM01183 restrained the NF-κB/PAX7/myogenin axis, possibly reducing the pro-inflammatory milieu, and failed to limit the C/EBPß/atrogin-1 axis. Inflammation-mediated splenomegaly of C26-mice was inhibited by PM01183 for as long as the treatment lasted, without reducing IL-6, M-CSF or IL-1ß in plasma. ET743 and PM01183 extend the survival of C26-bearing mice unchanging tumor growth or cachexia but possibly restrain muscle-related inflammation and C26-induced splenomegaly.
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PURPOSE: This study was aimed at investigating whether the PPARγ agonist pioglitazone-given in combination with trabectedin-is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin. EXPERIMENTAL DESIGN: The antitumor and biological effects of trabectedin, pioglitazone, and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v. administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR, and Western blotting. RESULTS: We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARγ agonist pioglitazone reactivated adipogenesis, assessed by histologic and gene pathway analyses. Pioglitazone was well tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation. CONCLUSIONS: The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.
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Adipocitos/patología , Diferenciación Celular , Resistencia a Antineoplásicos , Liposarcoma Mixoide/tratamiento farmacológico , PPAR gamma/agonistas , Pioglitazona/farmacología , Trabectedina/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Antineoplásicos Alquilantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Femenino , Humanos , Hipoglucemiantes/farmacología , Liposarcoma Mixoide/metabolismo , Liposarcoma Mixoide/patología , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. METHODS: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. RESULTS: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. CONCLUSION: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.
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Neoplasias del Colon/tratamiento farmacológico , Fenretinida/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Micelas , Células Madre Neoplásicas/efectos de los fármacos , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis , Disponibilidad Biológica , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Fenretinida/química , Fenretinida/farmacocinética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of water-soluble camptothecins obtained by linking a spermidine moiety to the 21-position of the open form through an amidic bond have been tested for their biochemical and biological activities. Growth inhibition assay on the human non-small cell lung cancer carcinoma NCI-H460 cell line revealed that the camptothecin analogues were less potent than topotecan and SN38 after 1 hour of treatment. The potency increased after 72 hours of exposure, being similar to that of reference camptothecins. The analysis of topoisomerase I-mediated DNA cleavage using the purified enzyme indicated that the novel camptothecin analogues retained ability to poison topoisomerase I and displayed the same cleavage pattern of SN38. Persistence of the DNA cleavage was comparable with that of SN38. Stabilization of the cleavable complex was not the result of hydrolysis of the N-C bond between polyamine and the drug because no free camptothecin was recovered at the end of DNA cleavage in presence of IDN5174, the analogue selected for detailed studies. IDN5174 exhibited an antitumor activity comparable with that of topotecan and irinotecan against NCI-H460 tumor xenograft. The pharmacokinetics in mice showed a favorable disposition in tumor tissue with low amount of camptothecin detectable in plasma and tumor (around 5-10%), thus supporting the efficacy of intact IDN5174. In conclusion, we found that IDN5174 maintained the biological and antitumor properties, in spite of lack of the closed E ring. The available results support the interpretation that the polyamine linked at the 21-position may allow a favorable drug interaction in the ternary complex.
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Antineoplásicos Fitogénicos/farmacología , Camptotecina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/farmacocinética , Camptotecina/farmacología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Lactonas/farmacocinética , Lactonas/farmacología , Ratones , Espermidina/análogos & derivados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The advent of nanotechnology in medicine has allowed to eliminate the toxic excipients that are often necessary to formulate lipophilic drugs in clinics. An example is paclitaxel, one of the most important chemotherapeutic drugs developed so far, where the Cremophor EL has been eliminated in the Genexol and Abraxane formulations. However, the complex procedures to synthesize these formulations hamper their cost-effective use and, in turn, their distribution among the patient population. For this reason, a simplified method to formulate this drug directly at the bed of the patient has been adopted. It requires only the use of a syringe and it starts from a native dry amphiphilic biodegradable and biocompatible block-copolymer obtained via the combination of the reversible addition-fragmentation chain transfer polymerization and ring-opening polymerization. In this way, a novel paclitaxel formulation with the same drug pharmacological properties, but without the use of the Cremophor EL, can be produced. In addition, as long as these nanoparticles are engineered to act as solubility enhancers, a lower burden for its approval from the pharmaceutical regulatory agencies is also expected.
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Portadores de Fármacos , Excipientes , Nanopartículas/química , Paclitaxel , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Excipientes/química , Excipientes/farmacocinética , Paclitaxel/química , Paclitaxel/farmacocinética , SolubilidadRESUMEN
The improvement of the pharmacological profile of lipophilic drug formulations is one of the main successes achieved using nanoparticles (NPs) in medicine. However, the complex synthesis procedure and numerous post-processing steps hamper the cost-effective use of these formulations. In this work, an approach which requires only a syringe to produce self-assembling biodegradable and biocompatible poly(caprolactone)-based NPs is developed. The effective synthesis of monodisperse NPs has been made possible by the optimization of the block-copolymer synthesized via a combination of ring opening polymerization and reversible addition-fragmentation chain transfer polymerization. These NPs can be used to formulate lipophilic drugs that are barely soluble in water, such as trabectedin, a potent anticancer therapeutic. Its biodistribution and antitumor activity have been compared with the commercially available formulation Yondelis®. The results indicate that this trabectedin NP formulation performs with the same antitumor activity as Yondelis®, but does not have the drawback of severe local vascular toxicity in the injection site.
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Antineoplásicos Alquilantes , Nanopartículas , Trabectedina , Animales , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacocinética , Femenino , Liposarcoma/tratamiento farmacológico , Ratones Endogámicos C57BL , Ratones Desnudos , Nanopartículas/administración & dosificación , Nanopartículas/química , Polímeros/administración & dosificación , Polímeros/química , Piel/efectos de los fármacos , Piel/patología , Solubilidad , Distribución Tisular , Trabectedina/administración & dosificación , Trabectedina/química , Trabectedina/farmacocinética , Agua/químicaRESUMEN
The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/ß (PDGFRα/ß) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.