ABSTRACT
El neuroblastoma (NB) es el tumor sólido más común en niños y adolescentes y representa hasta un 15% de la muerte infantil asociada al cáncer. Tiene su origen en el sistema nervioso simpático y su comportamiento puede llegar a ser muy agresivo y no responder a los tratamientos actuales. En esta revisión se recogen nuevas alternativas terapéuticas basadas en la epigenética, es decir, en moduladores de la expresión génica como los microRNAs y su potencial aplicación clínica en NB
Neuroblastoma (NB) is the most common solid tumour in children and adolescents, and accounts for up to 15% of all cancer deaths in this group. It originates in the sympathetic nervous system, and its behaviour can be very aggressive and become resistant to current treatments. A review is presented, summarising the new alternative therapies based on epigenetics, i.e., modulators of gene expression, such as microRNAs and their potential application in the clinical practice of NB treatment
Subject(s)
Humans , Male , Female , Child , Adolescent , Neuroblastoma/genetics , Neuroblastoma , Neuroblastoma/drug therapy , RNAi Therapeutics/instrumentation , RNAi Therapeutics , Tumor Suppressor Protein p53/analysis , MicroRNAs/analysis , MicroRNAs/therapeutic use , Epigenetic Repression/radiation effects , Response Evaluation Criteria in Solid Tumors , Sympathetic Nervous System/pathology , Sympathetic Nervous System , Immune System , Immune System/pathology , RNA Polymerase II/therapeutic use , RNA Polymerase III/therapeutic use , RNAi Therapeutics/methods , RNAi Therapeutics/standardsABSTRACT
Today, lentiviral vectors are favorable vectors for RNA interference delivery in anti-HIV therapeutic approaches. Nevertheless, problems such as the specific recognition of target cells and uncontrolled expression of the transgene can restrict their use in vivo. Herein we present a new HIV-inducible promoter to express anti-HIV short hairpin RNA (shRNA) by RNA Pol II in mammalian cells. We likewise showed a novel third-generation lentiviral vector system with more safety and a specific tropism to the target cells. The new promoter, CkRhsp, was constructed from the chicken ß-actin core promoter with the R region of HIV-1 long terminal repeat fused upstream of minimal hsp70 promoter. This system was induced by HIV-1 Tat, and activates transcription of two shRNAs against two conserved regions of HIV-1 transcripts produced in two steps of the virus life cycle. We also mimicked HIV-1 cell tropism by using the HIV-1 envelope in structure of third-generation lentiviral vector. The new fusion promoter efficiently expressed shRNA in a Tat-inducible manner. HIV-1 replication was inhibited in transient transfection and stable transduction assays. The new viral vector infected only CD4+cells. CkRhsp promoter may be safer than other inducible promoters for shRNA-mediated gene therapies against HIV. The use of the wild envelope in the vector packaging system may provide the specific targeting T lymphocytes and hematopoietic stem cells for anti-HIV-1 therapeutic approaches in vivo.
