Epithelial growth factor receptor tyrosine kinase inhibitor prevents infiltration and cerebrospinal fluid dissemination in malignant glioma: an experimental study.

Abstract

BAC1KGROUND: AG1478 is an epithelial growth factor receptor tyrosine kinase inhibitor. Epithelial growth factor receptor regulates the expression of cadherin in cells via its action on β-catenin, and N-cadherin downregulation promotes infiltration and cerebrospinal fluid (CSF) dissemination of glioma cells. To confirm whether AG1478 might have indirect effects on N-cadherin upregulation and whether, in addition to exhibiting an antitumor effect, AG1478 might also exert protective effects against infiltration and CSF dissemination. Green fluorescent protein (GFP) was introduced into C6 cells to obtain C6-GFP, and N-cadherin was introduced into C6-GFP to obtain C6-GFP-NCH. To confirm N-cadherin upregulation and the anti-infiltrative effect of AG1478 in vitro, we conducted Western blotting, aggregation assays, and Matrigel infiltration experiments. To confirm whether AG1478 exerted preventive effects against infiltration and CSF dissemination in vivo, in addition to exerting an antitumor effect, AG1478 was administered via various routes to rat C6-GFP inoculation models. In vitro experiments demonstrated that AG1478 could indirectly upregulate N-cadherin in C6-GFP and reduced infiltration to the level of C6-GFP-NCH. In in vivo experiments, intrathecal administration of AG1478 inhibited CSF dissemination but did not prevent infiltration. Direct administration into the tumor mass demonstrated antitumor and anti-infiltration effects and inhibited CSF dissemination in each cistern, except at the convexity. Direct and intrathecal administration was the best treatment, resulting in significantly reduced numbers of disseminated cells in the CSF smear test. AG1478 was highly effective both when administered intrathecally and when inoculated directly into the tumor mass.