title: Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma.
abstract: BACKGROUND
  3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed.
  
  
  METHODS
  Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT).
  
  
  RESULTS
  3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%.
  
  
  CONCLUSIONS
  Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect.
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Robert T
authors: RT
authors: Wicks
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Javad
authors: J
authors: Azadi
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Antonella
authors: A
authors: Mangraviti
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Irma
authors: I
authors: Zhang
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Lee
authors: L
authors: Hwang
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Avadhut
authors: A
authors: Joshi
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Hansen
authors: H
authors: Bow
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Marianne
authors: M
authors: Hutt-Cabezas
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Kristin L
authors: KL
authors: Martin
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Michelle A
authors: MA
authors: Rudek
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Ming
authors: M
authors: Zhao
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Henry
authors: H
authors: Brem
authors: Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
authors: Betty M
authors: BM
authors: Tyler
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity; D001932:Brain Neoplasms / Q000378:metabolism* / Q000517:prevention & control / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D003999:Dichloroacetic Acid / Q000008:administration & dosage* / Q000633:toxicity; D004333:Drug Administration Routes; D004338:Drug Combinations; D016503:Drug Delivery Systems; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000517:prevention & control / Q000532:radiotherapy; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D053208:Kaplan-Meier Estimate; D011108:Polymers; D011773:Pyruvates / Q000008:administration & dosage* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004338:Drug Combinations; D011108:Polymers; D011773:Pyruvates; C017092:bromopyruvate; D003606:Dacarbazine; D003999:Dichloroacetic Acid; D000077204:Temozolomide
keywords: 3-bromopyruvate; dichloroacetate; glioma; glycolytic inhibitor; pCPP:SA