Enhanced expression of Vastatin inhibits angiogenesis and prolongs survival in murine orthotopic glioblastoma model.

BACKGROUND: Antiangiogenic therapies are considered promising for the treatment of glioblastoma (GB). The non-collagenous C-terminal globular NC1 domain of type VIII collagen a1 chain, Vastatin, is an endogenous antiangiogenic polypeptide. Sustained enhanced expression of Vastatin was shown to inhibit tumour growth and metastasis in murine hepatocellular carcinoma models. In this study, we further explored the efficacy of Vastatin in the treatment of GB xenografts. METHOD: Treatment of Vastatin was carried out using a nanopolymer gene vector PEI600-CyD-Folate (H1). Antiangiogenic effect of Vastatin was tested in vitro by using co-culture system and conditioned medium. An orthotopic GB murine model was established to examine the in vivo therapeutic effect of Vastatin alone treatment and its combination with temozolomide. RESULTS: Vastatin gene transfection mediated by H1 could target tumour cells specifically and suppress the proliferation of microvessel endothelial cells (MECs) through a paracrine inhibition manner. Enhancing Vastatin expression by intracerebral injection of H1-Vastatin significantly prolonged animal survival from 48 to 75 days in GB murine model, which was comparable to the effect of Endostatin, the most studied endogenous antiangiogenic polypeptide. The diminished presence of CD34 positive cells in the GB xenografts suggested that Vastatin induced significant antiangiogenesis. Moreover, a synergistic effect in extending survival was detected when H1-Vastatin was administered with temozolomide (TMZ) in GB chemoresistant murine models. CONCLUSION: Our results suggest, for the first time, that Vastatin is an antiangiogenic polypeptide with significant potential therapeutic benefit for GB. H1-Vastatin gene therapy may have important implications in re-sensitizing recurrent GB to standard chemotherapeutic agents.

Vastatin (the NC1 domain of human type VIII collagen a1 chain) is linked to stromal reactivity and elevated in serum from patients with colorectal cancer.

Vastatin, a fragment derived from type VIII collagen, is one of the least studied collagen-derived matrikines. Vastatin can be detected in serum but little is known regarding the relevance of serum vastatin in colorectal cancer (CRC). In this study, serum vastatin was measured (ELISA) in 67 healthy controls and 48 CRC patients prior to resection and compared to clinicopathological parameters and serum biomarkers of stromal reactivity (C3M, VICM). Impact of resection and chemotherapy were evaluated by comparing baseline values with a 3-month follow-up sample (n = 23). Serum vastatin was detectable in 114 of 115 subjects. At baseline vastatin was elevated in CRC compared to controls (P < 0.001) with a diagnostic accuracy (AUROC) of 0.865, p < 0.0001. Vastatin correlated with age in controls but not in patients with CRC; no association was seen with clinicopathological parameters. Vastatin was independently associated with C3M (stepwise linear regression coefficient 0.25, p = 0.046). Overall, no difference was seen in vastatin levels between baseline and follow-up. In conclusion, vastatin is elevated in serum from patients with CRC and correlate with interstitial matrix degradation (C3M). This indicates that vastatin is linked to stromal reactivity and suggests that vastatin has biomarker potential in CRC. The association with clinicopathological parameters and treatment effect needs further evaluation.

Estudo comparativo duplo-cego, randomizado entre pravastatina e lovastatina: análise da eficácia e segurança / Randomized, Double-blind Comparative Study Between Pravastatin and Lovastatin. Efficacy and Safety Evaluation

Objetivo - Verificar eventuais diferenças na eficácia e segurança da lovastatina (L) em relaçäo à provastatina (P), considerando doses crescentes, até as consideradas máximas e recomendáveis na prática clínica. Métodos - Estudo de 48 hipercolesterolêmicos (LDL-C > 160mg/dl após 7 semanas de placebo), randomizado, constituído de 2 grupos em 24 pacientes (GLe GP). Por esquema duplo-cego, GL recebeu 20mg/dia de L e GP 10mg/dia de P. As doses foram duplicadas após 6 e 12 semanas. Ao final do período placebo e na 6ª, 12ª e 18ª semanas foram avaliados em relaçäo aos dados clínicos e aspectos laboratoriais, compreendendo perfil lipídico (CT, TG, HDL-C e LDL-C); enzimas (AST, ALT, CPK, gama-GT, fosfatase alcalina); dados bioquímicos (uréia, creatinina, bilirrubinas, ácido úrico, glicose); hematológico completo e urina tipo I. Resultados - As duas drogas determinaram reduçöes significativas de CT e LDL-C com as menores doses de uso clínico (L 20mg/dia; P 10mg/dia), acentuadas com aumento progressivo das doses. Essas respostas contudo foram sempre significativamente maiores para L, para todas as doses utilizadas. Näo foram observados efeitos adversos que exigissem interrupçäo de tratamento para ambas as drogas. Conclusäo - L teve efeito redutor sobre CT e LDL-C superior ao obtido com a P, quando confrontadas doses recomendadas pelos respectivos laboratórios farmacêuticos