title: Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival and ablates both tumor-initiating cells and recruited glial progenitors.
abstract: 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 (platelet-derived growth factor)-IRES (internal ribosome entry site)-GFP (green fluorescent protein)-expressing retrovirus, treated the tumors by convection-enhanced delivery (CED) of topotecan (136 μmol/L) 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 about 10-fold and recruited progenitors by about 80-fold while providing a significant survival advantage that improved with greater treatment duration. Regions of glial progenitor ablation occurred corresponding to the anatomic 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.
authors.affiliation: Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Lopez
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Tannenbaum
authors.forename: Marcela C
authors.initials: MC
authors.lastname: Assanah
authors.forename: Katy
authors.initials: K
authors.lastname: Linskey
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yun
authors.forename: Alayar
authors.initials: A
authors.lastname: Kangarlu
authors.forename: Orlando D
authors.initials: OD
authors.lastname: Gil
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage; D051381:Rats; D019772:Topotecan / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010982:Platelet-Derived Growth Factor; D019772:Topotecan