RESUMO
Monkey studies were conducted for the preclinical safety assessment of SCH 412499, an adenovirus encoding p21, administered by subconjunctival injection prior to trabeculectomy for postoperative maintenance of the surgical opening. Biodistribution of SCH 412499 was minimal and there was no systemic toxicity. Findings included swollen, partially closed or shut eye(s) and transient congestion in the conjunctiva. A mononuclear cell infiltrate was present in the conjunctiva, choroid and other ocular tissues, but completely or partially resolved over time. Electroretinograms and visual evoked potentials revealed no adverse findings. Thus, the findings are not expected to preclude the clinical investigation of SCH 412499.
Assuntos
Adenoviridae/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Terapia Genética , Implantes para Drenagem de Glaucoma , Anestesia , Animais , Pressão Sanguínea/fisiologia , Túnica Conjuntiva , Conjuntivite/patologia , Eletrorretinografia , Ensaio de Imunoadsorção Enzimática , Potenciais Evocados Visuais/fisiologia , Olho/patologia , Feminino , Frequência Cardíaca/fisiologia , Injeções , Macaca fascicularis , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Distribuição Tecidual , Malha Trabecular , CicatrizaçãoRESUMO
Exposure of cultured glomeruli to benzo[a]pyrene (BaP), a carcinogenic hydrocarbon, modulates mesangial and visceral epithelial cell proliferation in vivo and in vitro. The present studies were conducted to characterize mitogenic signaling profiles of cultured glomeruli following repeated cycles of BaP challenge. Enhanced rates of DNA synthesis were observed by the third passage in randomly cycling cultures after single or repeated carcinogen exposure. This response was characterized by upregulation of mitogenic sensitivity during early cell cycle transit, and increased cell numbers under restrictive growth conditions. The mitogenic response to platelet-derived growth factor (0.5 to 25 ng/mL), acidic fibroblast growth factor (2.5 to 10 ng/mL), basic fibroblast growth factor (0.05 to 5 ng/mL), epidermal growth factor (0.5 to 5 ng/mL), or conditioned medium was not enhanced by hydrocarbon challenge. BaP-treated cultures exhibited anchorage-independent growth and increased expression of hepatocyte growth factor mRNA and E-cadherin protein. Binding of activator protein-1 to DNA was enhanced in BaP-treated cells, but this change did not involve truncation or mutation of the c-jun delta region. Collectively, the data demonstrate that repeated cycles of BaP injury alter mitogenic signaling profiles in cultured glomerular cells. These alterations may contribute to deregulation of proliferative control following carcinogen exposure in vivo.