Modulation of the blood-brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours?
Systemically administered chemotherapy is not very effective in the treatment of primary or metastatic brain tumours. An important reason for this low efficacy is insufficient drug delivery to the tumour site due to the presence of the blood-brain barrier (BBB). In this review, we give an overview of strategies that were tested to bypass the BBB or to increase its permeability for anticancer drugs. Local drug administration through intracerebral implants offers only little benefit to patients with brain tumours, probably due to the limited diffusion of the drugs in brain tissue. Temporary disruption of the BBB can be achieved with intracarotid infusions of hypertonic mannitol. This method has been used with some success; however, toxic side effects and the high complexity of the surgical procedure limit its usefulness. More recently, the use of the bradykinin agonist cereport was shown to be useful in preclinical studies, but unfortunately clinical studies did not show improved efficacy. Since P-glycoprotein in the BBB restricts the brain entry of many anticancer drugs, inhibition of this drug transporter may be an option for improved drug delivery to brain tumours. Pre-clinical studies have shown the feasibility to enhance the penetration of paclitaxel into the brain by co-administration with a potent P-glycoprotein inhibitor and further clinical research is warranted.
Kemper
E Marleen
EM
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Boogerd
Willem
W
Thuis
Ingrid
I
Beijnen
Jos H
JH
van Tellingen
Olaf
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D004234:Diuretics, Osmotic / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008353:Mannitol / Q000008:administration & dosage / Q000009:adverse effects; D017239:Paclitaxel / Q000493:pharmacokinetics; D010539:Permeability
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004234:Diuretics, Osmotic; D008353:Mannitol; D017239:Paclitaxel