Which Drug or Drug Delivery Method Can Change Clinical Practice for Brain Tumor Therapy?
Despite advances in anticancer drug discovery and development, there has been little improvement in the prognosis and outcome of malignant brain tumors. Often and repeatedly it has been found that promising experimental agents for brain tumors have had li
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Which Drug or Drug Delivery Method Can Change Clinical Practice for Brain Tumor Therapy? Tali Siegal
Abstract Despite advances in anticancer drug discovery and development, there has been little improvement in the prognosis and outcome of malignant brain tumors. Often and repeatedly it has been found that promising experimental agents for brain tumors have had little impact on the disease in clinical trials. These disappointing results can be partially explained by the inability to deliver therapeutic agents to the CNS across the physiological barriers (the blood–brain, blood–tumor, and blood–CSF barriers). The impediment posed by these barriers leads to failure of the delivered drug to reach the desired target in adequate concentrations. This chapter shortly reviews the leading strategies that try to improve drug delivery to brain tumors in view of their likelihood to change clinical practice. Strategies that use systemic delivery and those that utilize local delivery are critically reviewed. In addition challenges posed for drug delivery by the combined treatment with antiangiogenic therapy are outlined. For future development all new drugs or delivery systems must adhere to basic clinical expectations. These include besides an antitumor effect, a verified favorable toxicity profile, an easy introduction into clinical practice, feasibility of repeated or continuous administration and compatibility of the drug or strategy for any tumor size and brain location. Adherence to these essentials will enable a change in clinical practice
Abbreviation AUC BBB CED
Area under the curve Blood–brain barrier Convection-enhanced delivery
T. Siegal, M.D. (*) Gaffin Center for Neuro-Oncology, Hadassah Hebrew University Medical Center, Ein Kerem, P.O.Box 12000, Jerusalem 91120, Israel e-mail: [email protected] M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_24, © American Association of Pharmaceutical Scientists 2014
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CNS CSF ECF EGF HD-CTx MTX P-gp PEG RES SAE VEGF
24.1
Central nervous system Cerebrospinal fluid Extracellular fluid Epidermal growth factor High-dose chemotherapy Methotrexate P-glycoprotein Polyethylene glycol Reticuloendothelial system Severe adverse effects Vascular endothelial growth factor
Introduction
Despite advances in anticancer drug discovery and development, there has been little improvement in the prognosis and outcome of malignant brain tumors. Often and repeatedly it has been found that promising experimental agents for brain tumors have had little impact on the disease in clinical trials. These disappointing results can be partially explained by the inability to deliver therapeutic agents to the CNS across the blood–brain barrier (BBB) and failure of the delivered drug to reach the desired target in adequate concentration (Muldoon et al. 2007). This chapter shortly reviews the leading strategies that try to improve drug delivery to brain tumors in view of their like
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