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Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check

Leslie L. Muldoon, Carole Soussain, Kristoph Jahnke, Conrad Johanson, Tali Siegal, Quentin R. Smith, Walter A. Hall, Kullervo Hynynen, Peter D. Senter, David M. Peereboom, Edward A. Neuwelt

From the Departments of Neurology and Medicine, Oregon Health and Science University, and the Veterans Administration Medical Center, Portland, OR; Department of Neurosurgery Research, Brown Medical School, Providence, RI; Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center; Amarillo, TX; University of Minnesota, Department of Neurosurgery, Minneapolis, MN; Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Seattle Genetics, Bothell, WA; Brain Tumor Institute/Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH; Centre René Huguenin, Hématologie, Saint-Cloud, France; and the Gaffin Center for Neuro-Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel

Address reprint requests to Edward A. Neuwelt, MD, Oregon Health and Science University, Department of Neurology, 3181 SW Sam Jackson Park Rd, L603, Portland, OR 97239-3098; e-mail: neuwelte{at}ohsu.edu

Purpose: This review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006.

Results: Chemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking.

Conclusion: In this article, we review drug delivery across the BBB, as well as blood-tumor and –cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.

Supported by National Institutes of Health Grant No. NS33618 from the National Institute of Neurological Disorders and Stroke, and a National Institutes of Health Meeting Grant No. 4R13 CA86959-06 through the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders (E.A.N.).

Presented in part at the 12th Annual Blood-Brain Barrier Meeting, March 23-25, 2006, Sunriver Resort, Sunriver, OR.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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