Convection-Enhanced Delivery of Topotecan into a PDGF-Driven Model of Glioblastoma Prolongs Survival and Ablates Both Tumor-Initiating Cells and Recruited Glial Progenitors

The contribution of microenvironment to tumor growth has important implications for optimizing chemotherapeutic response and understanding the biology of recurrent tumors. In this study, we tested the effects of locally administered topotecan on a rat model of glioblastoma that is induced by intracerebral injection of PDGF-IRES-GFP-expressing retrovirus, we treated the tumors by convection-enhanced delivery (CED) of topotecan (136 μM) for 1, 4, or 7 days and then characterized the effects on both the retrovirus-transformed tumor cells (GFP+ cells) as well as the uninfected glial progenitor cells (GFP- cells) that are recruited to the tumor. Topotecan treatment reduced GFP+ cells ~10-fold and recruited progenitors by ~80-fold while providing a significant survival advantage that improved with greater treatment duration. Regions of glial progenitor ablation occurred corresponding to the anatomical distribution of topotecan as predicted by MRI of a surrogate tracer. Histopathologic changes in recurrent tumors point to a decrease in recruitment, most likely due to the chemotherapeutic ablation of the recruitable progenitor pool.