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Exogenous enzyme-activated prodrug therapy (EPT) is a potential cancer treatment strategy that delivers non-human enzymes into or on the surface of the cell and subsequently converts a non-toxic prodrug into an active cytotoxic substance at a specific location and time. The development of several pharmacological pairs based on EPT has been the focus of anticancer research for more than three decades. Numerous of these pharmacological pairs have progressed to clinical trials, and a few have achieved application in specific cancer therapies. The current review highlights the potential of enzyme-activated prodrug therapy as a promising anticancer treatment. Different microbial, plant, or viral enzymes and their corresponding prodrugs that advanced to clinical trials have been listed. Additionally, we discuss new trends in the field of enzyme-activated prodrug nanocarriers, including nanobubbles combined with ultrasound (NB/US), mesoscopic-sized polyion complex vesicles (PICsomes), nanoparticles, and extracellular vesicles (EVs), with special emphasis on smart stimuli-triggered drug release, hybrid nanocarriers, and the main application of nanotechnology in improving prodrugs.
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Short-term outcome of myeloablative (MAC) and reduced intensity (RIC) conditioning in the prospective randomized international EBMT RICMAC study in patients with myelodyplastic syndrome (MDS) was comparable but longer follow up is lacking. Patients with MDS aged 18-65 years were randomized to receive MAC (N = 64) with busulfan/cyclophosphamide or RIC (n = 65) with busulfan/fludarabine followed by stem cell transplantation -(HCT) from HLA matched or mismatched donor. After a median follow-up of 6.2 (0.4-12.5) years, 10-year OS and RFS were 54.0% and 43.9% for RIC and 44.4% and 44.2% for MAC (p = 0.15 and p = 0.78), respectively. Since the first report, 6 patients died on NRM, 4 after RIC, and 2 after MAC. Similarly, 8 patients relapsed (4 in each arm), increasing the number of relapsed patients to 28. The second HCT was performed in 18 pts, 8 in the MAC, and 10 in the RIC arm. In a multivariate analysis, ECOG status and chemotherapy prior to HCT were independent risk factors for OS and RFS, ECOG and low cytogenetic risk for NRM and chemotherapy prior to HCT for RI. Patients with low cytogenetic risk had better OS [p = 0.002], RFS [p = 0.02], and NRM (p = 0.015) after RIC as compared to MAC.
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Síndromes Mielodisplásicas , Condicionamento Pré-Transplante , Humanos , Condicionamento Pré-Transplante/métodos , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/mortalidade , Pessoa de Meia-Idade , Adulto , Masculino , Feminino , Idoso , Bussulfano/uso terapêutico , Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vidarabina/administração & dosagem , Ciclofosfamida/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Adulto Jovem , Seguimentos , Estudos ProspectivosRESUMO
Allogeneic haematopoietic cell transplantation (allo-HCT) remains an option for tyrosine kinase inhibitor-resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high-risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry-based study of 1686 CML patients undergoing first allo-HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo-HCT was 46 years (IQR 36-55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse-free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non-relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft-versus-host disease (GvHD)-free/relapse-free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Adulto , Masculino , Feminino , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/etiologia , Transplante Homólogo , Sistema de Registros , Doadores de Tecidos , Doadores não RelacionadosRESUMO
Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.
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Crise Blástica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Sistema de Registros , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Crise Blástica/patologia , Gerenciamento Clínico , Europa (Continente) , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Prognóstico , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Idoso de 80 Anos ou maisRESUMO
Benzophenone-3 (also referred to as oxybenzone) is a putative endocrine disrupting chemical and common ingredient in sunscreens and other personal care products. We previously showed that benzophenone-3 was promotional for epithelial tumorigenesis in mice fed adult high-fat diet, while protective against the incidence of more aggressive spindle cell tumors in the same treatment group. In this study, we show that benzophenone-3 reduces epithelial to mesenchymal transition in the epithelial tumors of these mice. This reduction in epithelial to mesenchymal transition is associated with altered expression of several genes involved in regulation of angiogenesis and epithelial to mesenchymal transition. Among the genes altered in expression, Timp1 is of particular interest because benzophenone-3 suppressed both migration and Timp1 expression in a mammary tumor cell line that displays epithelial to mesenchymal transition characteristics. These alterations in gene expression plausibly stabilize the vasculature of epithelial carcinomas and contribute to benzophenone-3 promotion of epithelial tumors, while at the same time suppress epithelial to mesenchymal transition and suppress incidence of spindle cell tumors.
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Benzofenonas , Carcinoma , Transição Epitelial-Mesenquimal , Camundongos , Animais , Transformação Celular Neoplásica , Carcinogênese/genética , Neovascularização Patológica , Linhagem Celular TumoralRESUMO
Candida albicans and non-albicans Candida species are a common cause of human mucosal infections, as well as bloodstream infections and deep mycoses. The emergence of resistance of Candida spp. to antifungal drugs used in practice requires the search for new antimycotics. The present study unravels the antifungal potential of the synthetic dialk(en)ylthiosulfinates in comparison with an enzymatic in situ methionine γ-lyase-based thiosulfinate generation system (TGS). The kinetics of the TGS reaction, namely, the methionine γ-lyase-catalyzed ß-elimination of S-alk(en)yl-L-cysteine sulfoxides, was investigated via 1H NMR spectroscopy for the first time, revealing fast conversion rates and the efficient production of anticandidal dialk(en)ylthiosulfinates. The anticandidal potential of this system vs. synthetic thiosulfinates was investigated through an in vitro assay. TGS proved to be more effective (MIC range 0.36-1.1 µg/mL) than individual substances (MIC range 0.69-3.31 µg/mL). The tested preparations had an additive effect with the commercial antimycotics fluconazole, amphotericin B and 5-flucytosine demonstrating a fractional inhibitory coefficient index in the range of 0.5-2 µg/mL. TGS can be regarded as an attractive candidate for the targeted delivery of antimycotic thiosulfinates and for further implementation onto medically implanted devices.
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In this single-center analysis, we evaluated the trends in 5185 hematopoietic cell transplantations performed between 1990 and 2022. The study group comprised 3237 allogeneic (alloHCT) and 1948 autologous (autoHCT) hematopoietic cell transplantations. In the multivariate analysis, there was an improvement in event-free-survival (EFS) after autoHCT (HR 0.6, 95% CI 0.4-0.7, p < 0.0001) due to reduced cumulative incidence of relapse in the last five years (56% in 2010-2014 vs. 38% in 2015-2022). An improvement in EFS after alloHCT over time was observed (HR 0.33, 95% CI 0.23-0.48, p < 0.0001), which was due to reduced non-relapse mortality. No difference in cumulative relapse incidence was observed over the last decade for allografted patients. Survival after autoHCT improved in Hodgkin's disease (HR 0.1, 95% CI 0.1-0.3), multiple myeloma (HR 0.4, 95% CI 0.2-0.7) and solid tumors (HR 0.2, 95% CI 0.2-0.4), while after alloHCT, improvement was observed in acute myeloid leukemia (HR 0.3, 95% CI 0.1-0.5), acute lymphoblastic leukemia (HR 0.2, 95% CI 0.1-0.5), Hodgkin's disease (HR 0.1, 95% CI 0.0-0.4), non-Hodgkin's lymphomas and chronic lymphocytic leukemia (HR 0.2, 95% CI 0.0-0.6), inborn diseases (HR 0.2, 95% CI 0.2-0.4) and acquired aplastic anemia with matched related donors and matched unrelated donors (HR 0.3, 95% CI 0.2-0.8).
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Pharmacological value of some natural compounds makes them attractive for use in oncology. The sulfur-containing thiosulfinates found in plants of the genus Allium have long been known as compounds with various therapeutic properties, including antitumor. Over the last few years, the effect of thiosulfinates on various stages of carcinogenesis has been actively investigated. In vitro and in vivo studies have shown that thiosulfinates inhibit proliferation of cancer cells, as well as they induce apoptosis. The purpose of this review is to summarize current data on the use of natural and synthetic thiosulfinates in cancer therapy. Antitumor mechanisms and molecular targets of these promising compounds are discussed. A significant part of the review is devoted to consideration of a new strategy for treatment of oncological diseases - use of the directed enzyme prodrug therapy approach aiming to obtain antitumor thiosulfinates in situ.
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O-acetylhomoserine sulfhydrylase is one of the key enzymes in biosynthesis of methionine in Clostridioides difficile. The mechanism of γ-substitution reaction of O-acetyl-L-homoserine catalyzed by this enzyme is the least studied among the pyridoxal-5'-phosphate-dependent enzymes involved in metabolism of cysteine and methionine. To clarify the role of active site residues Tyr52 and Tyr107, four mutant forms of the enzyme with replacements of these residues with phenylalanine and alanine were generated. Catalytic and spectral properties of the mutant forms were investigated. The rate of γ-substitution reaction catalyzed by the mutant forms with replaced Tyr52 residue decreased by more than three orders of magnitude compared to the wild-type enzyme. The Tyr107Phe and Tyr107Ala mutant forms practically did not catalyze this reaction. Replacements of the Tyr52 and Tyr107 residues led to the decrease in affinity of apoenzyme to coenzyme by three orders of magnitude and changes in the ionic state of the internal aldimine of the enzyme. The obtained results allowed us to assume that Tyr52 is involved in ensuring optimal position of the catalytic coenzyme-binding lysine residue at the stages of C-α-proton elimination and elimination of the side group of the substrate. Tyr107 could act as a general acid catalyst at the stage of acetate elimination.
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Clostridioides difficile , Clostridioides difficile/metabolismo , Cisteína Sintase/química , Cisteína Sintase/metabolismo , Domínio Catalítico , Clostridioides/metabolismo , Tirosina , Fosfato de Piridoxal/química , Fosfato de Piridoxal/metabolismo , Metionina , CinéticaRESUMO
Introduction: Tyrosine kinase inhibitor (TKI) therapy has greatly improved the prognosis of patients with chronic myeloid leukemia (CML), improving the survival expectancy of patients with chronic phase (CP) CML to that of the general population. However, despite these advances, nearly 50% of patients with CP CML experience failure to respond to frontline therapy, and most fail to respond to the subsequent second-line TKI. Treatment guidelines for patients failing second-line therapy are lacking. This study aimed to determine the efficacy of TKIs as third-line therapy in a "real-world" clinical practice setting and identify factors favorably influencing the long-term outcomes of therapy. Methods: We have retrospectively analyzed the medical records of 100 patients with CP CML. Results: The median age of the patients was 51 (range, 21-88) years, and 36% of the patients were men. The median duration of the third-line TKI therapy was 22 (range, 1- 147) months. Overall, the rate of achieving complete cytogenetic response (CCyR) was 35%. Among the four patient groups with different levels of responses at baseline, the best results were achieved in the groups with any CyR at the baseline of third-line therapy. Thus, СCyR was reached in all 15 and 8/ 16 (50%) patients with partial cytogenetic response (PCyR) or minimal or minor CyR (mmCyR), respectively, whereas CCyR was detected only in 12/69 (17%) patients without any CyR at baseline (p < 0.001). Univariate regression analysis revealed that the factors negatively associated with CCyR achievement in thirdline TKI therapy were the absence of any CyR on first- or second-line TKI therapy (p < 0.001), absence of CHR prior to third-line TKI (p = 0.003), and absence of any CyR prior to third-line TKI (p < 0.001). During the median observation time from treatment initiation to the last visit [56 (4-180) months], 27% of cases progressed into accelerated phase or blast phase CML, and 32% of patients died. Discussion: Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with CCyR on third-line than in the group without CCyR on third-line therapy. At the last visit, third-line TKI therapy was ongoing in 18% of patients, with a median time of treatment exposure of 58 (range, 6-140) months; 83% of these patients had stable and durable CCyR, suggesting that patients without CHR at baseline and without CCyR at least by 12 months on third-line TKI should be candidates for allogeneic stem cell transplantation, third-generation TKIs, or experimental therapies.
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In the early randomized trials the efficacy of calcineurin inhibitors (CNI) in the treatment of graft-versus-host disease (GVHD) was comparable to corticosteroids (CS), but these results became obsolete with the introduction of CNIs in prophylaxis. Recently several effective CNI-free GVHD prophylaxis regimens were introduced based on posttransplantation cyclophosphamide (PTCY) and αß ex vivo T-cell depletion (αß-TCD). Among patients treated under these protocols 34 patients with grade II-IV acute (aGVHD) and 40 with moderate and severe chronic (cGVHD) disease were treated with CNIs or other CS-free regimens as the first line. Overall response rate (ORR) was significantly higher in cGVHD than in aGVHD: 80% (95% CI 68-92) vs 47% (95% CI 30-64%), p = 0.0031. In aGVHD it was almost completely restricted to isolated stage III skin GVHD. In cGVHD patients with moderate disease ORR was higher than in severe: 96% (95% CI 88-100%) vs 56% (95%CI 32-81%), p = 0.0022. Two-year overall survival was 76% (95% CI 58-87%) in aGVHD and 95% (95% CI 81-99%) in cGVHD. Failure-free survival was 21% (95% CI 9-37%) in aGVHD and 81% (95% CI 64-91%) in cGVHD. Patients responding to steroid-free regimens had lower use of systemic antibiotics (p = 0.0095), antifungals (p = 0.0319) and antivirals (p < 0.0001).
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Medula Óssea/efeitos adversos , Inibidores de Calcineurina/uso terapêutico , Corticosteroides/uso terapêutico , Doença AgudaRESUMO
Amino acid deprivation therapy (AADT) is a promising strategy for developing novel anticancer treatments, based on variations in metabolism of healthy and malignant cells. L-asparaginase was the first amino acid-degrading enzyme that received FDA approval for the treatment of acute lymphoblastic leukemia (ALL). Arginase and arginine deiminase were effective in clinical trials for the treatment of metastatic melanomas and hepatocellular carcinomas. Essential dependence of certain cancer cells on methionine explains the anticancer efficacy of methionine-g-lyase. Along with significant progress in identification of metabolic vulnerabilities of cancer cells, new amino acid-cleaving enzymes appear as promising agents for cancer treatment: lysine oxidase, tyrosine phenol-lyase, cysteinase, and phenylalanine ammonia-lyase. However, sensitivity of specific cancer cell types to these enzymes differs. Hence, search for prognostic and predictive markers for AADT and introduction of the markers into clinical practice are of great importance for translational medicine. As specific metabolic pathways in cancer cells are determined by the enzyme expression, some of these enzymes may define the sensitivity to AADT. This review considers the known predictors for efficiency of AADT, emphasizing the importance of knowledge on cancer-specific amino acid significance for such predictions.
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The emergence of novel immunotherapies for myelodysplastic syndrome (MDS) calls for a profound characterization of the "immunome" in the bone marrow (BM) and evaluation of prognostic impact of immunological changes. We performed a prospective study of 87 MDS patients who were referred to a tertiary hematological center and of 11 bone marrow donors who were not related to the study cohort. A flow cytometry panel with 48 markers including checkpoint ligands and receptors was used to study lymphoid and myeloid subpopulations in the bone marrow aspirates. The study found that both the healthy donors and the MDS patients have a high proportion of lymphocytes with PD-1 expression (41±18% and 58±25% respectively) and a high proportion of myeloid cells with PD-1L expression (31±23% and 12±7% respectively), indicating a potential physiological role of checkpoint systems in BM. At the same time, complex alterations including PD-1, CTLA-4, LAG-3 and TIM3 pathways accompanied by an increased level of T-reg and myeloid derived suppressor cell populations were identified in the BM of MDS patients. Cluster analysis showed independent prognostic significance of the checkpoint profile for overall survival (HR 1.90, 95%CI 1.01-3.56, p = 0.0471). TIM3-postive NK and CD8 effector cells along with the blast count were the key subpopulations for prognosis. An elevation of blasts in the bone marrow was associated with simultaneous expression of multiple checkpoints on myeloid cells.
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Receptor Celular 2 do Vírus da Hepatite A , Síndromes Mielodisplásicas , Humanos , Antígeno CTLA-4 , Estudos Prospectivos , Receptor de Morte Celular Programada 1/genética , Síndromes Mielodisplásicas/metabolismo , PrognósticoRESUMO
The purpose of this study was to determine the anticancer effect of dipropyl thiosulfinate produced in situ by the pharmacological pair: (1) conjugated with daidzein C115H methionine γ-lyase (EC 4.4.1.11, C115H MGL-Dz) and (2) the substrate, S-propyl-L-cysteine sulfoxide (propiin) against various solid tumor types in vitro and in vivo. The MTT test was used to calculate IC50 values for HT29, COLO205 and HCT116 (colon cancer); Panc1 and MIA-PaCa2 (pancreatic cancer); and 22Rv1, DU-145 and PC3 (prostate cancer). The most promising effect for colon cancer cells in vitro was observed in HT29 (IC50 = 6.9 µM). The IC50 values for MIA-PaCa2 and Panc1 were 3.4 and 3.8 µM, respectively. Among prostate cancer cells, 22Rv1 was the most sensitive (IC50 = 5.4 µM). In vivo antitumor activity of the pharmacological pair was studied in HT29, SW620, Panc1, MIA-PaCa2 and 22Rv1 subcutaneous xenografts in BALB/c nude mice. The application of C115H MGL-Dz /propiin demonstrated a significant reduction in the tumor volume of Panc1 (TGI 67%; p = 0.004), MIA-PaCa2 (TGI 50%; p = 0.011), HT29 (TGI 51%; p = 0.04) and 22Rv1 (TGI 70%; p = 0.043) xenografts. The results suggest that the combination of C115H MGL-Dz/propiin is able to suppress tumor growth in vitro and in vivo and the use of this pharmacological pair can be considered as a new strategy for the treatment of solid tumors.
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Neoplasias do Colo , Neoplasias Pancreáticas , Pró-Fármacos , Neoplasias da Próstata , Animais , Liases de Carbono-Enxofre , Linhagem Celular Tumoral , Cisteína/análogos & derivados , Xenoenxertos , Humanos , Isoflavonas , Masculino , Metionina , Camundongos , Camundongos Nus , Neoplasias da Próstata/tratamento farmacológico , SulfóxidosRESUMO
Laser soldering is a current biophotonic technique for the surgical recovery of the integrity of soft tissues. This technology involves the use of a device providing laser exposure to the cut edges of the wound with a solder applied. The proposed solder consisted of an aqueous dispersion of biopolymer albumin (25 wt.%), single-walled carbon nanotubes (0.1 wt.%) and exogenous indocyanine green chromophore (0.1 wt.%). Under laser exposure, the dispersion transforms into a nanocomposite due to the absorption of radiation and its conversion into heat. The nanocomposite is a frame structure of carbon nanotubes in a biopolymer matrix, which provides adhesion of the wound edges and the formation of a strong laser weld. A new laser device based on a diode laser (808 nm) has been developed to implement the method. The device has a temperature feedback system based on a bolometric infrared matrix sensor. The system determines the hottest area of the laser weld and adjusts the current supplied to the diode laser to maintain the preset laser heating temperature. The laser soldering technology made it possible to heal linear defects (cuts) in the skin of laboratory animals (rabbits) without the formation of a fibrotic scar compared to the control (suture material). The combined use of a biopolymer nanocomposite solder and a laser device made it possible to achieve a tensile strength of the laser welds of 4 ± 0.4 MPa. The results of the experiment demonstrated that the addition of single-walled carbon nanotubes to the solder composition leads to an increase in the ultimate tensile strength of the laser welds by 80%. The analysis of regenerative and morphological features in the early stages (1-3 days) after surgery revealed small wound gaps, a decrease in inflammation, the absence of microcirculatory disorders and an earlier epithelization of laser welds compared to the control. On the 10th day after the surgical operation, the laser weld was characterized by a thin cosmetic scar and a continuous epidermis covering the defect. An immunohistochemical analysis proved the absence of myofibroblasts in the area of the laser welds.
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While mammographic breast density is associated with breast cancer risk in humans, there is no comparable surrogate risk measure in mouse and rat mammary glands following various environmental exposures. In the current study, mammary glands from mice and rats subjected to reproductive factors and exposures to environmental chemicals that have been shown to influence mammary gland development and/or susceptibility to mammary tumors were evaluated for histologic density by manual and automated digital methods. Digital histological density detected changes due to hormonal stimuli/reproductive factors (parity), dietary fat, and exposure to environmental chemicals, such as benzophenone-3 and a combination of perfluorooctanoic acid and zeranol. Thus, digital analysis of mammary gland density offers a high throughput method that can provide a highly reproducible means of comparing a measure of histological density across independent experiments, experimental systems, and laboratories. This methodology holds promise for the detection of environmental impacts on mammary gland structure in mice and rats that may be comparable to human breast density, thus potentially allowing comparisons between rodent models and human breast cancer studies.
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Neoplasias da Mama , Glândulas Mamárias Animais , Animais , Densidade da Mama , Meio Ambiente , Feminino , Humanos , Camundongos , Gravidez , Ratos , RoedoresRESUMO
The main goal of this study was to investigate the cardioprotective properties in terms of effects on cardiodynamics of perfluorocarbon emulsion (PFE) in ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. The first part of the study aimed to determine the dose of 10% perfluoroemulsion (PFE) that would show the best cardioprotective effect in rats on ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. Depending on whether the animals received saline or PFE, the animals were divided into a control or experimental group. They were also grouped depending on the applied dose (8, 12, 16 ml/kg body weight) of saline or PFE. We observed the huge changes in almost all parameters in the PFE groups in comparison with IR group without any pre-treatment. Calculated in percent, dp/dt max was the most changed parameter in group treated with 8 mg/kg, while the dp/dt min, SLVP, DLVP, HR, and CF were the most changed in group treated with 16 mg/kg 10 h before ischemia. The effects of 10% PFE are more pronounced if there is a longer period of time from application to ischemia, i.e., immediate application of PFE before ischemia (1 h) gave the weakest effects on the change of cardiodynamics of isolated rat heart. Therefore, the future of PFE use is in new indications and application methods, and PFE can also be referred to as antihypoxic and antiischemic blood substitute with mild membranotropic effects.
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Substitutos Sanguíneos , Fluorocarbonos , Traumatismo por Reperfusão Miocárdica , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fluorocarbonos/farmacologia , Substitutos Sanguíneos/farmacologia , Substitutos Sanguíneos/uso terapêutico , Fenômenos Fisiológicos CardiovascularesRESUMO
Pyridoxal 5'-phosphate-dependent methionine γ-lyase from Citrobacter freundii (MGL, EC 4.4.1.11) is studied as an antitumor enzyme and in combination with substrates as an antibacterial agent in enzyme pro-drug therapy. For the possibility of in vivo trials, two mutant forms, C115H MGL and V358Y MGL, were encapsulated into polyionic vesicles (PICsomes). Five pairs of polymers with the number of polymer chain units 20, 50, 70, 120, and 160 were synthesized. The effect of polymer length-PEGylated poly-l-aspartic acid and poly-l-lysine-on the degree of MGL incorporation into PICsomes and their size was investigated. Encapsulation of proteins in PICsomes is a rather new technique. Our data demonstrated that the length of the polymers and, therefore, the ratio of the hydrophobic and hydrophilic fragments most likely should be selected individually for each protein to be encapsulated. The efficiency of encapsulation of MGL mutant forms into PICsomes was up to 11%. The hydrodynamic diameter and surface potential of hollow and MGL-loaded PICsomes were evaluated by the dynamic light scattering method. The size and morphology of the PICsomes were determined by atomic force microscopy. The most acceptable for further in vivo studies were PICsomes20 with a size of 57-64 nm, PICsomes70 of 50-90 nm, and PICsomes120 of 100-105 nm. The analysis of the steady-state parameters has demonstrated that both mutant forms retained their catalytic properties inside the nanoparticles. The release study of the enzymes from PICsomes revealed that about 50% of the enzymes remained encapsulated in PICsomes70 and PICsomes120 after 24 h. Based on the data obtained, the most promising for in vivo studies are PICsomes70 and PICsomes120.
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Therapeutic enzymes used for the treatment of a wide range of human disorders often suffer from suboptimal pharmacokinetics and stability. Engineering approaches such as encapsulation in micro- and nanocarriers, and replacements of amino acid residues of the native enzyme provide significant potential for improving the performance of enzyme therapy. Here, we develop a nanodelivery system on the base of polyion complex vesicles (PICsomes) that includes methionine γ-lyase (MGL) as a therapeutic enzyme. We have two strategies for using the enzyme: first, methionine γ-lyase is an anticancer agent removing l-methionine from plasma, second, the binary system methionine γ-lyase/S-alk(en)yl-l-cysteine sulfoxides is effective in enzyme prodrug therapy (EPT). Various lengths polymers were synthesized, and two mutant forms of the enzyme were used. The catalytic and pharmacokinetic parameters of the nanoformulations were investigated. The catalytic efficiencies of encapsulated enzymes were comparable to that of native enzymes. Pharmacokinetic analysis has shown that inclusion into PICsomes increases half-life of the enzymes, and they can be safely administered in vivo. The results suggest the further use of encapsulated MGLs for EPT and anticancer therapy, and this strategy could be leveraged to improve the efficiency of enzyme-based therapies for managing serious human diseases.
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Liases , Liases de Carbono-Enxofre/metabolismo , Cisteína/química , Humanos , Cinética , Liases/metabolismo , Metionina/metabolismo , Sulfóxidos/metabolismoRESUMO
The aim of the study is to describe a case is of clinical interest as the first known occurrence of skin vasculitis during rituximab treatment. The article describes a case of polymorphic dermal angiitis, a combination of hemorrhagic and ulcerative-necrotic forms against the background of rituximab treatment in a 53-year-old woman suffering from chronic lymphocytic leukemia (b-CLL). During four hours after the 5th intravenous administration of rituximab, the appearance of painful rashes on the skin of both shins of a patient was observed. In the following few days, a progression of the pathological skin process was noted. The treatment with prednisolone in the amount of 50 mg/day, amoxicillin and clavulanic acid in the amount of 1000 mg twice per day and Diflucan in a dosage of 50 mg/day for 15 days was prescribed. In a local therapy, wet-drying bandages with antiseptic solutions, combined topic glucocorticosteroid preparations, drugs that improve trophic and tissue regeneration were recommended. After discharge, the patient continued to receive prednisolone in the amount of 50 mg/day for 14 days with a slow decrease in the dosage of the drug until the withdrawal under the supervision of a dermatologist. The described experience of how combined forms of polymorphic dermal angiitis are developing can be considered a result of toxic drug response to rituximab.