Convection-enhanced and local delivery of targeted cytotoxins in the treatment of malignant gliomas.
Despite advances in our knowledge about the genesis, molecular biology, and natural history of malignant gliomas and the use of a multi-disciplinary approach to their treatment, patients harboring this diagnosis continue to face a grim prognosis. At the time of diagnosis, patients typically undergo surgery for the establishment of a histologic diagnosis, the reduction of tumor burden, and the relief of mass effect, with the maintenance of the patient's neurological function in mind. This is followed by the administration of adjuvant therapeutics, including radiation therapy and chemotherapy. Many investigational agents with laboratory evidence of efficacy against malignant gliomas have not met their promise in the clinical setting, largely due to the barriers that they must overcome to reach the tumor at a therapeutically meaningful concentration for a durable period of time. The relevant aspects of the blood-brain barrier, blood-tumor barrier, and blood-cerebrospinal fluid barrier, as they pertain to the delivery of agents to the tumor, will be discussed along with the strategies devised to circumvent them. This discussion will be followed by a description of agents currently in preclinical and clinical development, many of which are the result of intense ongoing research into the molecular biology of gliomas.
Muro
Kenji
K
Department of Neurology, Northwestern University, Feinberg School of Medicine, Abbott Hall, Suite 1123, 710 N Lake Shore Drive, Chicago, Illinois 60611, USA.
Das
Sunit
S
Raizer
Jeffrey J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000493:pharmacokinetics; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018481:Convection; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005098:Exotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000008:administration & dosage / Q000493:pharmacokinetics; D015847:Interleukin-4 / Q000008:administration & dosage / Q000493:pharmacokinetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D014168:Transferrin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D016211:Transforming Growth Factor alpha / Q000008:administration & dosage / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D004167:Diphtheria Toxin; D005098:Exotoxins; C521502:IL13-PE38; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins; D014168:Transferrin; D016211:Transforming Growth Factor alpha; C479467:interleukin-4-Pseudomonas exotoxin; C044179:transferrin-diphtheria toxin conjugate; D015847:Interleukin-4