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Strategies for Increasing Drug Delivery to the Brain

Lessons derived from treatment of brain tumors
  • Tali Siegal
Chapter

Abstract

Numerous chemotherapeutic agents with favourable activity in in-vitro studies, prove ineffective in animal models or in patients. This in-vivo ineffectiveness is often explained as insufficient penetration of the drug to the desired site of action in concentrations adequate to exert pharmacologic effect (Tunggal et al., 1999). The blood-brain barrier (BBB) is one such typical impediment. The BBB is both a physical and a functional gait that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). But, brain tumours may disrupt the function of this barrier locally and non-homogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial issue. On the whole, inadequate drug delivery and development of tumour cell resistance are the major factors used to explain the lack of clinical response of brain tumours to chemotherapy. However, as stated by Vick et al (Vick et al., 1977) there are other aspects of the drug delivery process that must be understood besides the BBB. These include tumour cell uptake, metabolic fate within the tumour cells and the washout or sink effect of the extracellular space and the cerebrospinal fluid (CSF). In the last two decades the main focus was on ways to increase delivery across the BBB with little gain in understanding of the other factors that limit effective brain tumour therapy. There have been numerous recent reviews about this focus of increasing drug delivery across the normal BBB and through the variably abnormal blood-tumour barrier (BTB) (Bartus, 1999; Groothuis, 2000; Kroll and Neuwelt, 1998; Pardridge, 1998; Rapoport, 1996; Rapoport, 2000; Tamai and Tsuji, 1996). The present review aims to evaluate strategies used to increase drug delivery in view of current knowledge of drug pharmacokinetics and its relevance to clinical studies of chemosensitive brain tumours. We shall focus on primary CNS lymphoma (PCNSL) which is an aggressive Non-Hodgkin’s lymphoma that arises in the brain, leptomeninges and the eyes, sites located behind physiologic barriers that restrict delivery of chemotherapeutic drugs. PCNSL is considered a chemosensitive and a radiosenstive neoplasm, which unlike its systemic counterpart is not sufficiently controlled by systemic therapy. As a result, local failure with tumour recurrence in the CNS is extremely common (Bataille et al, 2000; Blay et al., 1998; Corn et al., 2000; Ferreri et al., 2000; O’Neill et al., 1999). PCNSL attracts increasing attention in the literature because of the recognition that its incidence is probably increasing in the immunocompetent population (Corn et al., 1997; Krogh-Jensen et al., 1994; Lutz and Coleman, 1994) and because strategies to increase drug delivery to the brain are successfully practiced in the treatment of this unique brain tumour (Abrey et al., 2000; Ferreri et al., 2000; Guha-Thakurta et al., 1999; McAllister et al., 2000; Zylber-Katz et al., 2000). These specialised approaches are required because it has been established that systemic lymphoma regimens are ineffective for the treatment of PCNSL (O’Neill et al., 1995; Schultz et al., 1996) and therefore treatment modalities should take into consideration the fact that a chemosensitive neoplasm is residing behind an intact BBB.

Keywords

Primary Central Nervous System Lymphoma Leptomeningeal Metastasis Leptomeningeal Seeding Increase Drug Delivery Osmotic Disruption 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Tali Siegal
    • 1
  1. 1.Neuro-Oncology CenterHadassah Hebrew University HospitalJerusalemIsrael

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