RESUMO
The simultaneous targeting of both endothelial cells and pericytes via inhibition of VEGF receptor (VEGFR) and PDGFbeta receptor (PDGFRbeta) signaling, respectively, has been proposed to enhance the efficacy of antiangiogenic tumor therapy. Clinical and preclinical modeling of combined VEGFR and PDGFRbeta signaling inhibition, however, has used small molecule kinase inhibitors with inherently broad substrate specificities, precluding detailed examination of this hypothesis. Here, adenoviral expression of a soluble VEGFR2/Flk1 ectodomain (Ad Flk1-Fc) in combination with a soluble ectodomain of PDGFRbeta (Ad sPDGFRbeta) allowed highly selective inhibition of these pathways. The activity of Ad sPDGFRbeta was validated in vitro against PDGF-BB and in vivo with near-complete blockade of pericyte recruitment in the angiogenic corpus luteum, resulting in prominent hemorrhage, thus demonstrating an essential function for PDGF signaling during ovarian angiogenesis. Combination therapy with Ad PDGFRbeta and submaximal doses of Ad Flk1-Fc produced modest additive antitumor effects; however, no additivity was observed with maximal VEGF inhibition in numerous s.c. models. Notably, VEGF inhibition via Ad Flk1-Fc was sufficient to strongly suppress tumor endothelial and pericyte content as well as intratumoral PDGF-B mRNA, obscuring additive Ad sPDGFRbeta effects on pericytes or tumor volume. These studies using highly specific soluble receptors suggest that additivity between VEGFR and PDGFRbeta inhibition depends on the strength of VEGF blockade and appears minimal under conditions of maximal VEGF antagonism.
Assuntos
Neovascularização Patológica , Neovascularização Fisiológica , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adenoviridae/genética , Animais , Corpo Lúteo/irrigação sanguínea , Corpo Lúteo/citologia , Feminino , Terapia Genética , Hemorragia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/genética , Neoplasias Experimentais/terapia , Pericitos/citologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/fisiologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Solubilidade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Botulinum toxin has emerged as an important therapeutic intervention within the realm of movement disorders, especially for focal and generalized dystonias. Botulinum toxin has additionally been used for a variety of symptoms associated with parkinsonism. In this review, we will specifically evaluate use of botulinum toxin in idiopathic Parkinson's disease. We will discuss symptoms including sialorrhea, limb, dystonia, tremor, dyskinesias, freezing of gait, camptocormia, pisa syndrome, urinary dysfunction, constipation, dysphagia, eyelid opening apraxia, and blepharospasm.