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Chronic Kidney Disease (CKD) and cancer constitute two major public health burdens and are on the rise. Moreover, the number of patients affected simultaneously by both conditions is growing. Potential nephrotoxic effect of cancer therapies is particularly important for patients with CKD, as they are also affected by several comorbidities. Therefore, administering the right therapy at the right dose for patients with decreased kidney function can represent a daunting challenge. We review in detail the renal toxicities of anti-cancer therapies i.e. conventional chemotherapy, targeted therapy, immune checkpoint inhibitors, and radioligand therapies, issue recommendations for patient monitoring along with guidance on when to withdraw treatment and suggest dosage guidelines for select agents in advanced stage CKD. Various electrolytes disturbances can occur as the result of the administration of anti-cancer agents in the patient with decreased kidney function. These patients are prone to developing hyponatremia, hyperkalemia, and other metabolic abnormalities because of a decreased GFR. Therefore, all electrolytes, minerals and acid base status should be checked at baseline and before each administration of chemotherapeutic agents. Moreover, studies on patients on kidney replacement therapy (KRT) are very limited and only single cases or small case series are published. Therefore, clinical therapeutical decisions in cancer patients with decreased function should be made by multidisciplinary teams constituted of medical oncologists, nephrologists, and other specialists. Onconephrology is an evolving and expanding subspecialty. It is crucial to consider anticancer drug treatment in these patients and offer them a chance to be treated effectively.
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Cancer is still one of the most challenging diseases to treat, making the pursuit for novel molecules with potential anticancer activity an important research topic. Herein, we have performed a comparative investigation into the anticancer activity of analogs of marine coelenterazine and coelenteramine. The former is a well-known bioluminescent substrate, while the latter is a metabolic product of the resulting bioluminescent reaction. While both types of analogs showed anticancer activity toward lung and gastric cancer cell lines, we have obtained data that highlight relevant differences between the activity of these two types of compounds. More specifically, we observed relevant differences in structure-activity relationships between these types of compounds. Also, coelenteramine analogs showed time-dependent activity, while coelenterazine-based compounds usually present time-independent activity. Coelenterazine analogs also appear to be relatively safer toward noncancer cells than coelenteramine analogs. There was also seen a correlation between the activity of the coelenterazine-based compounds and their light-emission properties. Thus, these results further indicate the potential of the marine coelenterazine chemi-/bioluminescent system as a source of new molecules with anticancer activity, while providing more insight into their modes of action.
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Imidazoles , Pirazinas , Imidazoles/química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
The development of antitumor drugs and therapy requires new approaches and molecules, and products of natural origin provide intriguing alternatives for antitumor research. Gastropodan hemocyanins-multimeric copper-containing glycoproteins have been used in therapeutic vaccines and antitumor agents in many cancer models. MATERIALS AND METHODS: We established a murine model of melanoma by challenging C57BL/6 mice with a B16F10 cell line for solid tumor formation in experimental animals. The anticancer properties of hemocyanins isolated from the marine snail Rapana thomasiana (RtH) and the terrestrial snail Helix aspersa (HaH) were evaluated in this melanoma model using various schemes of therapy. Flow cytometry, ELISA, proliferation, and cytotoxicity assays, as well as histology investigations, were also performed. RESULTS: Beneficial effects on tumor growth, tumor incidence, and survival of tumor-bearing C57BL/6 mice after administration of the RtH or HaH were observed. The generation of high titers of melanoma-specific IgM antibodies, pro-inflammatory cytokines, and tumor-specific CTLs, and high levels of tumor-infiltrated M1 macrophages enhanced the immune reaction and tumor suppression. DISCUSSION: Both RtH and HaH exhibited promising properties for applications as antitumor therapeutic agents and future experiments with humans.
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Hemocianinas , Melanoma Experimental , Ratones Endogámicos C57BL , Animales , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Ratones , Hemocianinas/farmacología , Hemocianinas/química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Moluscos/química , Modelos Animales de Enfermedad , Citocinas/metabolismo , Caracoles , Proliferación Celular/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/inmunologíaRESUMEN
Investigating combined treatment methodologies is crucial for addressing the complex nature of cancer. As an emerging strategy, nano-biotechnology encourages the design of unique nanocarriers possessing simultaneous therapeutic application properties. This study aims to explore the combined effects of photodynamic and anticancer treatments using a multifunctional nanocarrier system co-administering the photosensitizer IR780 and the anticancer agent curcumin (Cur) on lung cancer cells. Nanocarriers were prepared by encapsulation IR780 and Cur inside polyethylene glycol-capped mesoporous silica nanoparticles (Cur&IR780@MSN). Various concentrations of nanocarriers were evaluated on A549 cells following 5 min NIR laser light (continuous wave, 785 nm, 500 mW/cm2) irradiation. The internalization of nanocarriers was observed through the fluorescence of Cur. Changes in cell viability were determined using the MTT assay and AO/PI staining. A scratch assay analysis was also performed to examine the impact of combined treatments on cell migration. Characterization of the nanocarriers revealed adequate hydrophobic drug loading, temperature-inhibited feature, enhanced reactive oxygen species generation, a pH-dependent curcumin release profile, and high biocompatibility. Cur&IR780@MSN, which enabled the observation of synergistic treatment efficacy, successfully reduced cell viability by up to 78%. In contrast, monotherapies with curcumin-loaded nanocarriers (Cur@MSN) and IR780-loaded nanocarriers (IR780@MSN) resulted in a 38% and 56% decrease in cell viability, respectively. The constructed Cur&IR780@MSN nanocarrier has demonstrated remarkable performance in the application of combination therapies for lung cancer cells. These nanocarriers have the potential to inspire future studies in tumor treatment methods.
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Antineoplásicos , Curcumina , Neoplasias Pulmonares , Nanopartículas , Fotoquimioterapia , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Curcumina/farmacología , Curcumina/uso terapéutico , Dióxido de Silicio/química , Portadores de Fármacos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Nanopartículas/químicaRESUMEN
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives: tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer.
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Benzofuranos , Carcinoma , Topotecan , Animales , Ratones , Topotecan/farmacología , Topotecan/uso terapéutico , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , EsterasasRESUMEN
According to data from the World Health Organization (WHO), cancer is considered to be one of the leading causes of death worldwide, and new therapeutic approaches, especially improved novel cancer treatment regimens, are in high demand. Considering that many chemotherapeutic drugs tend to have poor pharmacokinetic profiles, including rapid clearance and limited on-site accumulation, a combined approach with tumor-homing peptide (THP)-functionalized magnetic nanoparticles could lead to remarkable improvements. This is confirmed by an increasing number of papers in this field, showing that the on-target peptide functionalization of magnetic nanoparticles improves their penetration properties and ensures tumor-specific binding, which results in an increased clinical response. This review aims to highlight the potential applications of THPs in combination with magnetic carriers across various fields, including a pharmacoeconomic perspective.
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Antineoplásicos , Neoplasias , Péptidos , Humanos , Neoplasias/tratamiento farmacológico , Péptidos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Animales , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapéutico , Economía Farmacéutica , Portadores de Fármacos/químicaRESUMEN
A 76-year-old female patient presented with an iodine-refractory papillary thyroid carcinoma (PTC), diagnosed eight years earlier, with several lymph node recurrences requiring successive surgeries. Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging revealed a new unresectable loco-regional recurrence. The patient was diagnosed with a somatic BRAF V600E mutation. Therefore, dabrafenib and trametinib combination therapy was introduced and closely monitored by a dedicated multidisciplinary team, involving pharmaceutical consultations. As early as six weeks after treatment initiation, the patient reported multiple adverse events (AEs) to the clinical pharmacy team, who provided advice on resolving AEs or improving tolerance. Close interprofessional collaboration among healthcare workers involved in the care pathway allowed for the identification of the most opportune times for temporary suspension of treatment (four suspensions over seven months) or dose reduction (two reductions over 3.5 months). This resulted in a total treatment duration (one year) longer than the average times reported in the literature. The patient showed a rapid and excellent response to treatment immediately after initiation, culminating in a complete metabolic response assessed by [18F]FDG PET/CT imaging at nine months. Twenty-five months after treatment discontinuation, the disease remained controlled. Overall, dabrafenib and trametinib combination could offer excellent outcomes in selected patients with refractory BRAF-mutated PTC, with additional clinical pharmacy initiatives allowing for the optimized management of AEs and prolonged treatment periods.
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Imidazoles , Oximas , Piridonas , Pirimidinonas , Neoplasias de la Tiroides , Humanos , Femenino , Oximas/uso terapéutico , Oximas/administración & dosificación , Imidazoles/uso terapéutico , Imidazoles/administración & dosificación , Piridonas/uso terapéutico , Piridonas/administración & dosificación , Anciano , Pirimidinonas/uso terapéutico , Pirimidinonas/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radioisótopos de Yodo/uso terapéutico , Radioisótopos de Yodo/administración & dosificación , Cáncer Papilar Tiroideo/tratamiento farmacológico , Resultado del Tratamiento , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and is responsible for approximately one million deaths each year. The current standard of care is surgical resection of the lesion and chemotherapy with 5-fluorouracil (5-FU). However, of concern is the increasing incidence in an increasingly younger patient population and the ability of CRC cells to develop resistance to 5-FU. In this review, we discuss the effects of thymoquinone (TQ), one of the main bioactive components of Nigella sativa seeds, on CRC, with a particular focus on the use of TQ in combination therapy with other chemotherapeutic agents. TQ exhibits anti-CRC activity by inducing a proapoptotic effect and inhibiting proliferation, primarily through its effect on the regulation of signaling pathways crucial for tumor progression and oxidative stress. TQ can be used synergistically with chemotherapeutic agents to enhance their anticancer effects and to influence the expression of signaling pathways and other genes important in cancer development. These data appear to be most relevant for co-treatment with 5-FU. We believe that TQ is a suitable candidate for consideration in the chemoprevention and adjuvant therapy for CRC, but further studies, including clinical trials, are needed to confirm its safety and efficacy in the treatment of cancer.
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A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.
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Enfermedades Cardiovasculares , Cardiopatías , Neoplasias , Humanos , Neoplasias/complicaciones , Carcinogénesis , MitocondriasRESUMEN
Three new dinuclear gold(I) complexes (1-3) containing a carbene (1,3-Bis(2,6-di-isopropylphenyl)imidazol-2-ylidene (IPr)) and diphosphane ligands [bis(1,2-diphenylphosphano)ethane (Dppe), bis(1,3-diphenylphosphano)propane (Dppp) and bis[2-(dicyclohexylphosphano)ethyl]amine (DCyPA)], were synthesized and characterized by elemental analysis and, ESI-MS, mid FT-IR and NMR spectroscopic methods. The structures of complexes 2 and 3 were determined by X-ray crystallography, which revealed that the complexes are dinuclear having gold(I) ions linearly coordinated. The anticancer activities of the complexes (1-3) were evaluated in lung (A549), breast (MC-F7), prostate (PC-3), osteosarcoma (MG-63) and ovarian (A2780 and A2780cis) cancer models. Growth inhibition by the new complexes was higher than cisplatin in all cell lines tested. The mechanism of action of complex 3 was investigated in A549 cells using 2-dimensional (2D) models and 3D-multicellular tumor spheroids. Treatment of A549 cells with complex 3 caused: the induction of apoptosis and the generation of reactive oxygen species; the cell cycle arrest in the G0/G1 phase; the inhibition of both the proteasome and the NF-kB activity; the down-regulation of lung cancer stem cell markers (NOTCH1, CD133, ALDH1 and CD44). Complex 3 was more active than cisplatin also in 3D models of A549 lung cancer cells.
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Antineoplásicos , Complejos de Coordinación , Neoplasias Pulmonares , Neoplasias Ováricas , Femenino , Masculino , Humanos , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Cisplatino/farmacología , Complejo de la Endopetidasa Proteasomal/farmacología , Oro/farmacología , Oro/química , Antineoplásicos/farmacología , Antineoplásicos/química , Espectroscopía Infrarroja por Transformada de Fourier , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Pulmón , Células Madre , Ligandos , Proliferación CelularRESUMEN
The mode of action toward gastric cancer cells of brominated Coelenteramine, an analogue of a metabolic product of a marine bioluminescent reaction, was investigated by synchrotron radiation-based Fourier Transform Infrared spectrocopy (FTIR). This method revealed that the anticancer activity of brominated Coelenteramine is closely connected with cellular lipids, by affecting their organization and composition. More specifically, there is an increasing extent of oxidative stress, which results in changes in membrane polarity, lipid chain packing and lipid composition. However, this effect was not observed in a noncancer cell line, helping to explain its selectivity profile. Thus, synchrotron radiation-based FTIR helped to identify the potential of this Coelenteramine analogue in targeting membrane lipids, while proving to be a powerful technique to probe the mechanism of anticancer drugs.
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Neoplasias , Sincrotrones , Humanos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Estrés Oxidativo , LípidosRESUMEN
Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, therapy resistance, and poor prognosis in many cancers. Although both DUBs are involved in the regulation of similar genes and signaling pathways, such as histone H2B monoubiquitination (H2Bub1), c-Myc, FOXP3, and p53, the interdependence of USP22 and USP7 expression has never been described. In the study, we found that targeting USP7 via either siRNA-mediated knockdown or pharmaceutical inhibitors dramatically upregulates USP22 in cancer cells. Mechanistically, the elevated USP22 occurs through a transcriptional pathway, possibly due to desuppression of the transcriptional activity of SP1 via promoting its degradation upon USP7 inhibition. Importantly, increased USP22 expression leads to significant activation of downstream signal pathways including H2Bub1 and c-Myc, which may potentially enhance cancer malignancy and counteract the anticancer efficacy of USP7 inhibition. Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of p53 tumor suppressor signaling pathway. In addition, USP22-Ko cancer cells are more sensitive to a combination of cisplatin and USP7 inhibitor. USP7 inhibitor treatment further suppresses in vivo angiogenesis and tumor growth and induced more apoptosis in USP22-Ko cancer xenografts. Taken together, our findings demonstrate that USP7 inhibition can dramatically upregulate USP22 in cancer cells; and targeting USP7 and USP22 may represent a more effective approach for targeted cancer therapy, which warrants further study. Video Abstract.
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Neoplasias Pulmonares , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Peptidasa Específica de Ubiquitina 7/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Neoplasias Pulmonares/patología , Histonas/metabolismo , Transducción de Señal , Línea Celular TumoralRESUMEN
PURPOSE: In response to the COVID-19 pandemic, virtual consultations were introduced rapidly across cancer services. This created a particular set of challenges for systemic anticancer therapy services, where patients have frequent, regular appointments to support decision-making regarding treatment. This study explores the experiences of staff who provide these consultations to understand the implications for patients, staff, and services. METHODS: A mixed-methods approach was utilized using electronic surveys containing open text and structured responses and a focus group. The survey was sent to all staff in a regional cancer center who carried out consultations with patients receiving Systemic Anticancer Therapy. Data collection took place between October 2020 and January 2021. Open text responses were analyzed using framework techniques. RESULTS: Thirty-three medical, nursing, and pharmacy staff completed the survey, and 21 attended the focus group. Staff experiences were described within a framework of risk, loss, and gain. Virtual consultations had clinical consequences for the accuracy of assessments and communication with patients. Criteria for using virtual or in-person appointments were identified along with organizational systems and processes that influenced effectiveness and safety. Concerns were raised regarding role satisfaction and use of clinical skills. CONCLUSION: The study provides new insights into the experiences and concerns of staff associated with virtual appointments. The primary purpose of consultation in systemic anticancer therapy services is to support decision-making regarding treatment, and the study identified obstacles to achieving this alongside possible criteria for determining when in-person or virtual consultations may be appropriate.
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COVID-19 , Humanos , Pandemias , Competencia Clínica , Comunicación , Derivación y ConsultaRESUMEN
BACKGROUND: Autophagy is a lysosome-mediated catabolic process that maintains cell homeostasis and survival. It occurs not only in normal cells such as cardiac muscle cells, neurons, and pancreatic acinar cells but also in various benign and malignant tumors. The abnormal level of intracellular autophagy is closely related to multiple pathophysiological processes, including aging, neurodegeneration, infectious diseases, immune disorders, and cancer. Autophagy mainly plays a dual role in life and death by regulating cell survival, proliferation, and death, thus being involved in the occurrence, development, and treatment of cancer. It is also involved in chemotherapy resistance by a dual role, since it not only promotes the occurrence of drug resistance but also reverses it. Previous findings suggest that the regulation of autophagy can be used as an effective strategy in tumor therapy. SUMMARY: Recent studies found that small molecules from natural products and their derivatives exert anticancer activity by regulating the level of autophagy in tumor cells. KEY MESSAGES: Therefore, this review article describes the mechanism of autophagy, the role of autophagy in normal cells and tumor cells, and the research progress on the anticancer molecular mechanism of targets regulating cell autophagy. The aim is to provide a theoretical basis for developing autophagy inhibitors or activators to improve anticancer efficacy.
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Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Lisosomas , Autofagia , Transducción de Señal/fisiología , Supervivencia CelularRESUMEN
INTRODUCTION: Adherence to anticancer agents is a critical factor in achieving adequate clinical response, and became a major challenge for patients and caregivers since the increased substitution of parenteral cytostatic by oral drugs. One of the factors that influences adherence is how well informed patients are about their therapy. This study assesses the association between patient satisfaction with information about oral anticancer agents and adherence. MATERIALS AND METHODS: This study was conducted among patients (≥18 years) who began oral anticancer therapy. Patients satisfaction with information and adherence were assessed using validated questionnaires. Adherence was also assessed using refill data. Logistic regression was applied to assess the association between overall patient satisfaction with information and both self-reported adherence and adherence based on an MPR value of above 80%. RESULTS: In total, 124 patients were included in the study. The median (IQR) satisfaction with information was 15.0(4) on a scale of 0-17. Eighty-two percent of participants reported adherence, while the refill data demonstrated that 64.5% of patients had an adherence rate of 80% or higher. Overall satisfaction with information was not significantly associated with self-reported adherence (OR adj 0.98 [95% CI 0.85-1.15]) or refill-based adherence (OR adj 1.11 [95% CI 0.99-1.24]). CONCLUSION: The findings indicate no significant relationship between patient satisfaction with information and adherence. The population was highly satisfied with information about the oral anticancer agents, which indicates a high level of satisfaction with usual care. However, the refill data reveals that 35.5% of patients were not adherent.
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Antineoplásicos , Satisfacción del Paciente , Humanos , Cumplimiento de la Medicación , Antineoplásicos/uso terapéutico , Encuestas y Cuestionarios , AutoinformeRESUMEN
Background. Many factors contribute to oral anti-cancer therapy adherence, including counselling and educational support. Objective. We systematically review the literature evaluating the effectiveness of interpersonal communication-, counselling- and education-based interventions on patient adherence to oral anticancer therapy. Methods. Using search terms pertaining to medication adherence, oral anticancer therapy, and communication, education, and counselling, we conducted a systematic search for full-text, original research articles prior to 3/13/20. Two reviewers independently reviewed each paper for inclusion and charted study information. Results. Twenty-four articles were included. All considered the use of oral anticancer therapy between two defined time points. Four studies also considered the length of time a patient persisted on therapy. Half (n = 12) of the studies reported a statistically significant relationship between the intervention and medication adherence, with no consistent pattern among intervention structure/content and effectiveness. Programmes offering in-person counselling and those targeting patients with chronic myeloid leukemia (CML), tended to report positive findings. Most studies faced substantial risk of bias, and only two reported using a behavioural theory to guide interventional content. Conclusions. Findings highlight the infancy of evidence base and need for rigorous and large-scale studies grounded in established behavioural theories to advance patient-targeted educational and counselling practices supporting adherence to oral anti-cancer therapy.
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Consejo , Cumplimiento de la Medicación , Humanos , Comunicación , Administración OralRESUMEN
Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.
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Neoplasias , Fosfatidilinositol 3-Quinasa , Humanos , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasa/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3' end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such adducts. Anticancer drugs such as the TOP1 poisons topotecan and irinotecan are responsible for the stabilization of these complexes. TDP1 neutralizes the effect of these anticancer drugs, eliminating the DNA adducts. Therefore, the inhibition of TDP1 can sensitize tumor cells to the action of TOP1 poisons. This review contains information about methods for determining the TDP1 activity, as well as describing the inhibitors of these enzyme derivatives of natural biologically active substances, such as aminoglycosides, nucleosides, polyphenolic compounds, and terpenoids. Data on the efficiency of combined inhibition of TOP1 and TDP1 in vitro and in vivo are presented.
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Antineoplásicos , Productos Biológicos , Productos Biológicos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Enzimas Reparadoras del ADN/genética , Antineoplásicos/farmacología , Antineoplásicos/química , ADN-Topoisomerasas de Tipo I/metabolismo , Reparación del ADN , ADNRESUMEN
The need for non-invasive therapies capable of conserving drug efficiency and stability while having specific targetability against colorectal cancer (CRC), has made nanoparticles preferable vehicles and principal building blocks for the development of complex and multi-action anti-tumoral approaches. For that purpose, we herein report the production of a combinatory anti-tumoral nanotherapy using the production of a new targeting towards CRC lines. To do so, Magneto-fluorescent NANO3 nanoparticles were used as nanocarriers for a combination of the drugs doxorubicin (DOX) and ofloxacin (OFLO). NANO3 nanoparticles' surface was modified with two different targeting agents, a newly synthesized (anti-CA IX acetazolamide derivative (AZM-SH)) and a commercially available (anti-epidermal growth factor receptor (EGFR), Cetuximab). The cytotoxicity revealed that only DOX-containing nanosystems showed significant and even competitive cytotoxicity when compared to that of free DOX. Interestingly, surface modification with AZM-SH promoted an increased cellular uptake in the HCT116 cell line, surpassing even those functionalized with Cetuximab. The results show that the new target has high potential to be used as a nanotherapy agent for CRC cells, surpassing commercial targets. As a proof-of-concept, an oral administration form of NANO3 systems was successfully combined with Eudragit® enteric coating and studied under extreme conditions.
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Neoplasias Colorrectales , Nanopartículas , Humanos , Cetuximab/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Since their first discovery in the 1960s by Alec Bangham, liposomes have been shown to be effective drug delivery systems for treating various cancers. Several liposome-based formulations received approval by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), with many others in clinical trials. Liposomes have several advantages, including improved pharmacokinetic properties of the encapsulated drug, reduced systemic toxicity, extended circulation time, and targeted disposition in tumor sites due to the enhanced permeability and retention (EPR) mechanism. However, it is worth noting that despite their efficacy in treating various cancers, liposomes still have some potential toxicity and lack specific targeting and disposition. This explains, in part, why their translation into the clinic has progressed only incrementally, which poses the need for more research to focus on addressing such translational limitations. This review summarizes the main properties of liposomes, their current status in cancer therapy, and their limitations and challenges to achieving maximal therapeutic efficacy.