title: A tumor-targeting p53 nanodelivery system limits chemoresistance to temozolomide prolonging survival in a mouse model of glioblastoma multiforme.
abstract: Development of temozolomide (TMZ) resistance contributes to the poor prognosis for glioblastoma multiforme (GBM) patients. It was previously demonstrated that delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex (SGT-53) which crosses the blood-brain barrier could sensitize highly TMZ-resistant GBM tumors to TMZ. Here we assessed whether SGT-53 could inhibit development of TMZ resistance. SGT-53 significantly chemosensitized TMZ-sensitive human GBM cell lines (U87 and U251), in vitro and in vivo. Furthermore, in an intracranial GBM tumor model, two cycles of concurrent treatment with systemically administered SGT-53 and TMZ inhibited tumor growth, increased apoptosis and most importantly, significantly prolonged median survival. In contrast TMZ alone had no significant effect on median survival compared to a single cycle of TMZ. These results suggest that combining SGT-53 with TMZ appears to limit development of TMZ resistance, prolonging its anti-tumor effect and could be a more effective therapy for GBM.
  
  
  BACKGROUND
  Using human glioblastoma multiforma cell lines, this research team demonstrated that the delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex limited the development of temozolomide resistance and prolonged its anti-tumor effect, which may enable future human application of this or similar techniques.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Antonina
authors.initials: A
authors.lastname: Rait
authors.affiliation: SynerGene Therapeutics, Inc., Potomac, MD, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Pirollo
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Electronic address: change@georgetown.edu.
authors.forename: Esther H
authors.initials: EH
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D018014:Gene Transfer Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Chemosensitization; Glioblastoma multiforme; Limiting TMZ-resistance; Systemic nanodelivery; Temozolomide; p53