RESUMO
Purpose: A vaccine composition based on the extracellular domain of the human epidermal growth factor receptor 1 (HER1-ECD) and the combination of VSSP (very small size proteoliposomes) and Montanide ISA 51 adjuvants when used by intramuscular route, demonstrated promising results in preclinical studies. However, in order to avoid potential adverse events due to the use of Montanide, it is proposed to modify the vaccine formulation by using VSSP (very small size proteoliposomes) adjuvant alone, and to evaluate the quality of subcutaneously induced immune response. This study aimed to assess the immunotoxicological effects of HER1 vaccine in Cercopithecus aethiops.Materials and methods: Fifteen monkeys were randomized into four groups: Negative Control (Tris/NaCl, s.c.), Positive Control (200 µg HER1-ECD/VSSP/Montanide ISA-51 VG, i.m), Low Dose (200 µg HER1-ECD/VSSP/Tris NaCl, s.c.) and High Dose (800 µg HER1-ECD/VSSP/Tris NaCl, s.c). All monkeys received 7 doses and were daily inspected for clinical signs. Body weight, rectal temperature, cardiac and respiratory rates were measured during the study, and electrocardiographical and ophthalmological studies were performed. Humoral and cellular immune response and clinical pathology parameters were analyzed.Results: Animal's survival in the study was 100% (n = 15). Administration site reactions were observed in the Positive Control animals (n = 4). HER1 vaccine administered subcutaneously (High Dose Group) achieved good IgG antibody titers although lower than the Positive Control group, but with higher ability to inhibit HER1 phosphorylation. Conclusions: This suggests that the alternative of eliminating the use of Montanide in the HER1 vaccine preparation and the using subcutaneous route is feasible.
Assuntos
Vacinas Anticâncer/farmacologia , Animais , Vacinas Anticâncer/efeitos adversos , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Receptores ErbB/efeitos adversos , Receptores ErbB/farmacologia , Feminino , Injeções Subcutâneas , MasculinoRESUMO
La administración de drogas que bloquean el sistema del factor de crecimiento epidérmico y su receptor ha demostrado efectos beneficiosos en pacientes con tumores sólidos de origen epitelial. Cada día resulta más frecuente el uso de múltiples modalidades terapéuticas para combatir estos tumores, las cuales incluyen la asociación de agentes blanco y cirugía. Los agentes que actúan sobre dicho sistema pudieran causar trastornos de la cicatrización al bloquear vías del sistema que también intervienen en la cicatrización de las heridas. El objetivo de este artículo es revisar y comentar acerca del conocimiento de la relación entre el uso de las drogas anti-EGF/EGFR y los trastornos en la cicatrización de las heridas. La búsqueda bibliográfica se realizó en PubMed y Google (solo en español e inglés) y se tuvo en cuenta cualquier publicación encontrada hasta enero del 2014. Se incluyeron los anticuerpos monoclonales cetuximab, panitumumab y nimotuzumab; las pequeñas moléculas erlotinib y gefitinib y las vacunas terapéuticas contra el cáncer CIMAvax EGF y HER-1. Se hace especial énfasis en los biofarmacéuticos nimotuzumab, CIMAvax EGF y HER-1; producidos en el Centro de Inmunología Molecular, La Habana, Cuba, debido a su amplio uso en Cuba y otros países de América Latina. No se encontraron evidencias de relación entre el uso de estos productos y la aparición de trastornos en la cicatrización de las heridas. Dado que los tratamientos anti-EGF/EGFR también inhiben la proliferación celular que induce el drenaje de las heridas y la migración celular inducida por las radiaciones, se sugiere que el tratamiento anti-EGF/EGFR no debe suspenderse, ni antes ni después de la cirugía y sus posibles efectos deben ser vigilados. Obviamente, se necesitan ulteriores investigaciones por parte de los farmacólogos no clínicos y clínicos, oncólogos clínicos y cirujanos oncológicos para entender mejor los procesos fisiopatológicos de cicatrización en los cánceres de origen epitelial(AU)
The use of blocking drugs for epidermal growth factor and its receptor system has shown beneficial effects in patients with solid tumors of epithelial origin. It is increasingly common to use a multi-modal treatment approach towards solid tumors, often including the association of target agents and surgical resection. Some target agents can impair wound healing or cause increasing risk of perioperative complications if they block system pathways that may intervene in wound healing. The objective of this paper was to review and comment on the existing knowledge about the relationship between the use of anti-EGF/EGFR drugs and the disorders in wound healing. Citations from PubMed and Google (English and Spanish languages only) regardless of the date of publication were reviewed to identify potentially useful articles until January 2014. Monoclonal antibodies cetuximab, panitumumab, nimotuzumab; the small molecules erlotinib and gefitinib, and the therapeutic cancer vaccines called CIMAvax EGF and HER-1. Special emphasis was made on biopharmaceuticals nimotuzumab, CIMAvax EGF and HER-1, all of them produced at the Center of Molecular Immunology, Havana, Cuba, because of their extensive use in Cuba and many Latin-American countries. No evidence of association between the use of these products and the occurrence of complications in wound healing was found. Given that the anti-EGF/EGFR treatments also inhibit the tumor cell proliferation that wound drainage induces and the radiation-induced cell migration, it is suggested that that the administration of this kind of drugs should be kept before and after the surgery and consequently, its possible effects must be under surveillance. Obviously, non-clinical and clinical pharmacologists, clinical oncologists and surgeons need further researches for better understanding the pathophysiological wound healing processes in epithelial cancers(AU)
Assuntos
Humanos , Masculino , Feminino , Cicatrização , Vacinas Anticâncer/uso terapêutico , Anticorpos Monoclonais/imunologia , Neoplasias/cirurgia , CubaRESUMO
BACKGROUND: The epidermal growth factor receptor (EGFR) signaling system is frequently unbalanced in human malignancies due to increased ligand production, receptor overexpression, receptor mutations, and/or cross-talk with other receptor systems. For this reason, the EGFR is an attractive target for anticancer therapy. The epidermal growth factor also plays an important role in regulating multiple facets of cutaneous wound healing, including inflammation, wound contraction, proliferation, migration, and angiogenesis. In the Center of Molecular Immunology, a cancer vaccine is produced (CIMAvax® EGF) that blocks the binding of EGF to its receptor. This blockade causes a significant inverse association between the anti-EGF antibody titers and EGF concentration. Around 1,500 patients with non-small cell lung cancer have been treated, showing that this vaccine is safe, immunogenic, increases survival and improves quality of life. Taking into account the therapeutic benefits of CIMAvax® EGF vaccination and the role of EGF-EGFR system in the wound healing process, we decided to conduct a retrospective research with the aim of determining the effect to the CIMAvax® EGF vaccine on the wound healing process in patients undergoing surgical treatment. METHODS: Medical records of 452 vaccinated patients were reviewed and only six patients receiving surgical treatment were identified. Further information about these six patients was obtained from source documents, including medical records and operative reports using an observational list that included different variables. Post-surgical wound healing complications were identified using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTC) version 3.0. RESULTS: None of the six patients operated on presented adverse events related to the wound healing, that is to say, no wound dehiscence, wound infection, delayed wound healing, fistula formation, abscess formation or hemorrhage/bleeding associated with surgery during treatment with CIMAvax® EGF occurred. CONCLUSIONS: These results suggest that the use of CIMAvax® EGF does not produce a deleterious effect in the wound healing process.
Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fator de Crescimento Epidérmico/antagonistas & inibidores , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Fator de Crescimento Epidérmico/imunologia , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacosRESUMO
En el mes de octubre de 2005 un pequeño grupo de investigadores de diferentes nacionalidades se reunieron en Viena, Austria, bajo los auspicios del Organismo Internacional de Energía Atómica con el objetivo de preparar un documento sencillo y útil para el personal involucrado en la preparación de productos biológicos radiomarcados como péptidos, proteínas y anticuerpos. Este documento debe incluir los aspectos prácticos, metodológicos y éticos relacionados con los productos radiomarcados anteriormente mencionados y debe esclarecer la ruta crítica que se debe seguir en esa área. Ese documento no cubre el uso de oligonucleótidos, células y otros productos antólogos radiomarcados y no ofrece protocolos técnicos sobre metodologías. En el trabajo presento recomendaciones farmacodinámicas y toxicológicas para los estudios preclínicos in vivo que deben seguir estos productos. Esta guía sólo representa mi forma actual de pensar sobre este tema.
In October of 2005 a small group of researchers from different Countries had a meeting at the International Atomic Energy Agency headquarter in Vienna, Austria; the aim was to prepare a tentative user-friendly document for personnel involved in preparation of radiopharmaceuticals based on peptides, proteins and antibodies for human use. This document should cover all practical, methodological and ethical concerns relating to radiolabelled products mentioned above and should clarify the complicated road-map that one has to follow in this area. This document does not cover the use of radiolabelled oligonucleotides, cells and other autologous products and does not provide technical protocols on actual methodologies. Herein, we will like to present you some pharmacodynamic and toxicological recommendations for in vivo preclinical studies. This guidance only represents my own current thinking in this topic.
RESUMO
The h-R3 is a humanized monoclonal antibody (Mab) that binds to the external domain of the human epidermal growth factor receptor (EGF-R). It has being used for the treatment of head and neck tumors. Since it is known that different animal species have different EGF-R amino acid sequences, it raises the handicap that, a priori, the animal species relevant for the pharmacodynamic, pharmacokinetic, and toxicologic studies of this Mab are unknown. To elucidate relevant laboratory animal species, the authors investigated the immunohistochemical recognition by h-R3 Mab of EGF-R in small skin biopsy samples obtained from NMRI nu/nu, C57Bl/6, and OF-1 mice; Sprague-Dawley rats; Hartley guinea pigs; New Zealand rabbits; and Cercopithecus aethiops and Macaca fascicularis monkeys. Additionally, three human skin biopsies were obtained from trauma victims. The immunolocalization of EGF-R in different tissue sections was performed using the avidin-biotin peroxidase complex (ABC) technique. The skin sections from different tissues were tested with the biotinylated h-R3 Mab or with a biotinylated irrelevant Mab, used as negative control. The staining intensity was qualified as:-, no staining; +, weak staining; ++, moderate staining; +++, strong staining. Macaca fascicularis monkey, New Zealand rabbit, and OF-1 mouse skins had a strong staining intensity; Cercopithecus aethiops monkey and Sprague-Dawley rat skins showed a moderate to strong staining intensity; C57Bl/6 mouse skins showed a moderate staining intensity. No staining was observed in the skins from Hartley guinea pigs and MNRI nu/nu mice. The fact that h-R3 Mab recognizes other animal EGF receptors in addition to the human EGF-R makes it possible to perform relevant pharmacodynamic, pharmacokinetic, and toxicologic studies in some laboratory animals.
Assuntos
Anticorpos Monoclonais/imunologia , Receptores ErbB/análise , Pele/química , Animais , Chlorocebus aethiops , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Cobaias , Humanos , Imuno-Histoquímica , Macaca fascicularis , Camundongos , Camundongos Nus , Coelhos , Ratos , Ratos Sprague-Dawley , Pele/imunologia , Pele/metabolismoRESUMO
El asma bronquial tiene alta prevalencia al nivel mundial y a pesar de los grandes esfuezos que se hacen, la mortalidad por esta causa ha aumentado y su verdadera razón se desconoce. En la presente revisión presentamos evidencias de la participación de las hormonas pancreáticas, insulin y glucagón, en la fisiopatología del asma bronquial. Se plantea la hipótesis de que debido al efecto proinflamatorio de la insulina y antiinflamatorio del glucagón, las alteraciones en las concentraciones plasmáticas de esta hormona podrían ser importantes en la evolución del asma bronquial. Se discute el posible papel deleterio de los tratamientos antiasmáticos clásicos por su influencia sobre estas hormonas y se sugieren investigaciones que pudieran aportar luz a los conocimientos actuales
Assuntos
Asma/fisiopatologia , Glucagon/metabolismo , Insulina/metabolismoRESUMO
Se exponen los resultados obtenidos en los ensayos llevados a cabo para el estudio de las acciones farmacológicas dentro de la fase preclínica experimental del nuevo preparado proveniente de una especie de coral marino extraído del sublitoral de Cuba al que se le ha denominado coralán. Se observó que el coralán tiene acción hipotensora profunda en los 5 primeros minutos después de su administración. Cuando se comienza a disminuir la dosis, este efecto no se observa. Sobre la frecuencia cardíaca tiene acción depresora y se observa un efecto dosisdependiente. En las acciones directas sobre el aparato cardiovascular, el coralán tiene efecto crono e inotropo negativo. No tiene efecto directo sobre la fibra lisa muscular de la aorta ni en el íleon aislado de cobayo