Strategies for Increasing Drug Delivery to the Brain

Lessons derived from treatment of brain tumors
  • Tali Siegal


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.


Primary Central Nervous System Lymphoma Leptomeningeal Metastasis Leptomeningeal Seeding Increase Drug Delivery Osmotic Disruption 
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  1. Abrey, L.E., Yahalom, J. and DeAngelis, L.M. (2000). Treatment for primary CNS lymphoma: the next step. J Clin Oncol, 18, 3144–3150.PubMedGoogle Scholar
  2. Aubree-Lecat, A., Duban, M.C., Demignot, S., Domurado, M., Fournie, P. and Domurado, D. (1993). Influence of barrier-crossing limitations on the amount of macromolecular drug taken up by its target. J Pharmacokinet Biopharm, 21, 75–98.PubMedCrossRefGoogle Scholar
  3. Balis, F.M., Blaney, S.M., McCully, C.L., Bacher, J.D., Murphy, R.F. and Poplack, D.G. (2000). Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol, 45, 259–264.PubMedCrossRefGoogle Scholar
  4. Balis, F.M., Savitch, J.L., Bleyer, W.A., Reaman, G.H. and Poplack, D.G. (1985). Remission induction of meningeal leukemia with high-dose intravenous methotrexate. J Clin Oncol, 3, 485–489.PubMedGoogle Scholar
  5. Balmaceda, C., Gaynor, J.J., Sun, M., Gluck, J.T. and DeAngelis, L.M. (1995). Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol, 38, 202–209.PubMedCrossRefGoogle Scholar
  6. Barth, R.F., Yang, W., Bartus, R.T., Moeschberger, M.L. and Goodman, J.H. (1999). Enhanced delivery of boronophenylalanine for neutron capture therapy of brain tumors using the bradykinin analog Cereport (Receptor-Mediated Permeabilizer-7). Neurosurgery, 44, 351–359; discussion 359-360.PubMedCrossRefGoogle Scholar
  7. Bartus, R.T. (1999). The blood-brain barrier as a target for pharmacological modulation. Current Opinion in Drug Discovery and Development, 2, 152–167.Google Scholar
  8. Bartus, R.T., Snodgrass, P., Marsh, J., Agostino, M., Perkins, A. and Emerich, D.F. (2000). Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival. J Pharmacol Exp Ther, 293, 903–911.PubMedGoogle Scholar
  9. Bataille, B., Delwail, V., Menet, E., Vandermarcq, P., Ingrand, P., Wager, M., Guy, G. and Lapierre, F. (2000). Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg, 92, 261–266.PubMedCrossRefGoogle Scholar
  10. Black, K.L., Cloughesy, T., Huang, S.C., Gobin, Y.P., Zhou, Y., Grous, J., Nelson, G., Farahani, K., Hoh, C.K. and Phelps, M. (1997). Intracarotid infusion of RMP-7, a bradykinin analog, and transport of gallium-68 ethylenediamine tetraacetic acid into human gliomas. J Neurosurg, 86, 603–609.PubMedCrossRefGoogle Scholar
  11. Blasberg, R.G., Patlak, C.S. and Shapiro, W.R. (1977). Distribution of methotrexate in the cerebrospinal fluid and brain after intraventricular administration. Cancer Treat Rep, 61, 633–641.PubMedGoogle Scholar
  12. Blay, J.Y., Conroy, T., Chevreau, C., Thyss, A., Quesnel, N., Eghbali, H., Bouabdallah, R., Coiffier, B., Wagner, J.P., Le Mevel, A., Dramais-Marcel, D., Baumelou, E., Chauvin, F. and Biron, P. (1998). High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol, 16, 864–871.PubMedGoogle Scholar
  13. Bleyer, W.A. and Poplack, D.G. (1979). Intraventricular versus intralumbar methotrexate for central-nervous-system leukemia: prolonged remission with the Ommaya reservoir. Med Pediatr Oncol, 6, 207–213.PubMedCrossRefGoogle Scholar
  14. Chamberlain, M.C. and Kormanik, P.A. (1996). Prognostic significance of 11 lindium-DTPA CSF flow studies in leptomeningeal métastases. Neurology, 46, 1674–1677.PubMedCrossRefGoogle Scholar
  15. Chatelut, E., Roche, H., Plusquellec, Y., Peyrille, F., De Biasi, J., Pujol, A., Canal, P. and Houin, G. (1991). Pharmacokinetic modeling of plasma and cerebrospinal fluid methotrexate after high-dose intravenous infusion in children. J Pharm Sci, 80, 730–734.PubMedCrossRefGoogle Scholar
  16. Chen, M.Y., Lonser, R.R., Morrison, P.F., Governale, L.S. and Oldfield, E.H. (1999). Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg, 90, 315–320.PubMedCrossRefGoogle Scholar
  17. Cher, L., Glass, J., Harsh, G.R. and Hochberg, F.H. (1996). Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results. Neurology, 46, 1757–1759.PubMedCrossRefGoogle Scholar
  18. Corn, B.W., Dolinskas, C., Scott, C., Donahue, B., Schultz, C., Nelson, D.F. and Fisher, B. (2000). Strong correlation between imaging response and survival among patients with primary central nervous system lymphoma: a secondary analysis of RTOG studies 83-15 and 88-06. Int J Radiat Oncol Biol Phys, 47, 299–303.PubMedCrossRefGoogle Scholar
  19. Corn, B.W., Marcus, S.M., Topham, A., Hauck, W. and Curran, W.J., Jr. (1997). Will primary central nervous system lymphoma be the most frequent brain tumor diagnosed in the year 2000? Cancer, 79, 2409–24713.PubMedCrossRefGoogle Scholar
  20. Dahlborg, S.A., Petrillo, A., Crossen, J.R., Roman-Goldstein, S., Doolittle, N.D., Fuller, K.H. and Neuwelt, E.A. (1998). The potential for complete and durable response in nonglial primary brain tumors in children and young adults with enhanced chemotherapy delivery [see comments]. Cancer J Sci Am, 4, 110–124.PubMedGoogle Scholar
  21. Davson, H. (1978). The environment of the neurons. Trends Neuroscience, 1, 39–41.CrossRefGoogle Scholar
  22. Doolittle, N.D., Miner, M.E., Hall, W.A., Siegal, T., Jerome, E., Osztie, E., McAllister, L.D., Bubalo, J.S., Kraemer, D.F., Fortin, D., Nixon, R, Muldoon, L.L. and Neuwelt, E. A. (2000). Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer, 88, 637–647.PubMedCrossRefGoogle Scholar
  23. Dukic, S., Heurtaux, T., Kaltenbach, M.L., Hoizey, G., Lallemand, A., Gourdier, B. and Vistelle, R. (1999). Pharmacokinetics of methotrexate in the extracellular fluid of brain C6-glioma after intravenous infusion in rats. Pharm Res, 16, 1219–1225.PubMedCrossRefGoogle Scholar
  24. Dukic, S.F., Heurtaux, T., Kaltenbach, M.L., Hoizey, G., Lallemand, A. and Vistelle, R (2000). Influence of schedule of administration on methotrexate penetration in brain tumours. Eur J Cancer, 36, 1578–1584.PubMedCrossRefGoogle Scholar
  25. Ferreri, A.J., Reni, M. and Villa, E. (2000). Therapeutic management of primary central nervous system lymphoma: lessons from prospective trials [In Process Citation]. Ann Oncol, 11, 927–937.PubMedCrossRefGoogle Scholar
  26. Fortin, D., McAllister, L.D., Nesbit, G., Doolittle, N.D., Miner, M., Hanson, E.J. and Neuwelt, E.A. (1999). Unusual cervical spinal cord toxicity associated with intraarterial carboplatin, intra-arterial or intravenous etoposide phosphate, and intravenous cyclophosphamide in conjunction with osmotic blood brain-barrier disruption in the vertebral artery. AJNR Am J Neuroradiol, 20, 1794–1802.PubMedGoogle Scholar
  27. Freilich, R.J., Krol, G. and DeAngelis, L.M. (1995). Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol, 38, 51–57.PubMedCrossRefGoogle Scholar
  28. Friden, P.M., Olson, T.S., Obar, R., Walus, L.R. and Putney, S.D. (1996). Characterization, receptor mapping and blood-brain barrier transcytosis of antibodies to the human transferrin receptor. J Pharmacol Exp Ther, 278, 1491–1498.PubMedGoogle Scholar
  29. Glantz, M.J., Cole, B.F., Recht, L., Akerley, W., Mills, P., Saris, S., Hochberg, F., Calabresi, P. and Egorin, M.J. (1998). High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol, 16, 1561–1567.Google Scholar
  30. Golden, P.L. and Pollack, G.M. (1998). Rationale for influx enhancement versus efflux blockade to increase drug exposure to the brain. Biopharm Drug Dispos, 19, 263–272.PubMedCrossRefGoogle Scholar
  31. Gomori, J.M., Heching, N. and Siegal, T. (1998). Leptomeningeal metastases: evaluation by gadolinium enhanced spinal magnetic resonance imaging. J Neurooncol, 36, 55–60.PubMedCrossRefGoogle Scholar
  32. Gregor, A., Lind, M., Newman, H., Grant, R., Hadley, D.M., Barton, T. and Osborn, C. (1999). Phase II studies of RMP-7 and carboplatin in the treatment of recurrent high grade glioma. RMP-7 European Study Group. J Neurooncol, 44, 137–145.PubMedCrossRefGoogle Scholar
  33. Groothuis, D.R. (2000). The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery. Neuro-Oncology, 2, 45–59.PubMedGoogle Scholar
  34. Groothuis, D.R., Benalcazar, H., Allen, C.V., Wise, R.M., Dills, C., Dobrescu, C., Rothholtz, V. and Levy, R.M. (2000). Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration. Brain Res, 856, 281–290.PubMedCrossRefGoogle Scholar
  35. Groothuis, D.R., Ward, S., Itskovich, A.C., Dobrescu, C., Allen, C.V., Dills, C. and Levy, R.M. (1999). Comparison of 14C-sucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion. J Neurosurg, 90, 321–331.PubMedCrossRefGoogle Scholar
  36. Guha-Thakurta, N., Damek, D., Pollack, C. and Hochberg, F.H. (1999). Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol, 43, 259–268.PubMedCrossRefGoogle Scholar
  37. Hiraga, S., Arita, N., Ohnishi, T., Kohmura, E., Yamamoto, K., Oku, Y., Taki, T., Sato, M., Aozasa, K. and Yoshimine, T. (1999). Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas. J Neurosurg, 91, 221–230.PubMedCrossRefGoogle Scholar
  38. Huang, T.Y., Arita, N., Hayakawa, T. and Ushio, Y. (1999). ACNU, MTX and 5-FU penetration of rat brain tissue and tumors. J Neurooncol, 45, 9–17.PubMedCrossRefGoogle Scholar
  39. Iacoangeli, M., Roselli, R., Pagano, L., Leone, G., Marra, R., Pompucci, A., Trignani, R. and Scerrati, M. (1995). Intrathecal chemotherapy for treatment of overt meningeal leukemia: comparison between intraventricular and traditional intralumbar route. Ann Oncol, 6, 377–382.PubMedGoogle Scholar
  40. Inamura, T. and Black, K.L. (1994). Bradykinin selectively opens blood-tumor barrier in experimental brain tumors. J Cereb Blood Flow Metab, 14, 862–870.PubMedCrossRefGoogle Scholar
  41. Jain, R.K. (1990). Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev, 9, 253–266.PubMedCrossRefGoogle Scholar
  42. Krogh-Jensen, M., d’Amore, F., Jensen, M.K., Christensen, B.E., Thorling, K., Pedersen, M., Johansen, P., Boesen, A.M. and Andersen, E. (1994). Incidence, clinicopathological features and outcome of primary central nervous system lymphomas. Population-based data from a Danish lymphoma registry. Danish Lymphoma Study Group, LYFO. Ann Oncol, 5, 349–354.PubMedGoogle Scholar
  43. Kroll, R.A. and Neuwelt, E.A. (1998). Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery, 42, 1083–1099; discussion 1099-1100.PubMedCrossRefGoogle Scholar
  44. Kroll, R.A., Pagel, M.A., Langone, J.J., Sexton, G.J. and Neuwelt, E.A. (1994). Differential permeability of the blood-tumour barrier in intracerebral tumour-bearing rats: antidrug antibody to achieve systemic drug rescue. Ther Immunol, 1, 333–341.PubMedGoogle Scholar
  45. Kroll, R.A., Pagel, M.A., Muldoon, L.L., Roman-Goldstein, S., Fiamengo, S.A. and Neuwelt, E.A. (1998). Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers [see comments]. Neurosurgery, 43, 879–886; discussion 886-889.PubMedCrossRefGoogle Scholar
  46. Kroll, R.A., Pagel, M.A., Muldoon, L.L., Roman-Goldstein, S. and Neuwelt, E.A. (1996). Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. Neurosurgery, 38, 746–752; discussion 752-754.PubMedCrossRefGoogle Scholar
  47. Laske, D.W., Morrison, P.F., Lieberman, D.M., Corthesy, M.E., Reynolds, J.C., Stewart-Henney, P.A., Koong, S.S., Cummins, A., Paik, C.H. and Oldfield, E.H. (1997a). Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging. J Neurosurg, 87, 586–594.PubMedCrossRefGoogle Scholar
  48. Laske, D.W., Youle, R.J. and Oldfield, E.H. (1997b). Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors [see comments]. Nat Med, 3, 1362–1368.PubMedCrossRefGoogle Scholar
  49. Lutz, J.M. and Coleman, M.P. (1994). Trends in primary cerebral lymphoma. Br J Cancer, 70, 716–718.PubMedCrossRefGoogle Scholar
  50. Madara, J.L. (1998). Regulation of the movement of solutes across tight junctions. Annu Rev Physiol, 60, 143–159.PubMedCrossRefGoogle Scholar
  51. Markowsky, S.J., Zimmerman, C.L., Tholl, D., Soria, I. and Castillo, R. (1991). Methotrexate disposition following disruption of the blood-brain barrier. Ther Drug Monit, 13, 24–31.PubMedCrossRefGoogle Scholar
  52. Masereeuw, R., Jaehde, U., Langemeijer, M.W., de Boer, A.G. and Breimer, D.D. (1994). In vitro and in vivo transport of zidovudine (AZT) across the blood-brain barrier and the effect of transport inhibitors. Pharm Res, 11, 324–330.PubMedCrossRefGoogle Scholar
  53. McAllister, L.D., Doolittle, N.D., Guastadisegni, P.E., Kraemer, D.F., Lacy, C.A., Crossen, J.R. and Neuwelt, E.A. (2000). Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery, 46, 51–60; discussion 60-1.PubMedCrossRefGoogle Scholar
  54. Miller, K.T. and Wilkinson, D.S. (1989). Pharmacokinetics of methotrexate in the cerebrospinal fluid after intracerebroventricular administration in patients with meningeal carcinomatosis and altered cerebrospinal fluid flow dynamics. Ther Drug Monit, 11, 231–237.PubMedCrossRefGoogle Scholar
  55. Millot, F., Rubie, H., Mazingue, F., Mechinaud, F. and Thyss, A. (1994). Cerebrospinal fluid drug levels of leukemic children receiving intravenous 5 g/m2 methotrexate. Leuk Lymphoma, 14, 141–144.PubMedCrossRefGoogle Scholar
  56. Morrison, P.F., Chen, M.Y., Chadwick, R.S., Lonser, R.R. and Oldfield, E.H. (1999). Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics. Am J Physiol, 277, R1218-1229.Google Scholar
  57. Morse, M., Savitch, J., Balis, F., Miser, J., Feusner, J., Reaman, G., Poplack, D. and Bleyer, A. (1985). Altered central nervous system pharmacology of methotrexate in childhood leukemia: another sign of meningeal relapse. J Clin Oncol, 3, 19–24.PubMedGoogle Scholar
  58. Nag, S. (1995). Role of the endothelial cytoskeleton in blood-brain-barrier permeability to protein. Acta Neuropathol, 90, 454–460.PubMedCrossRefGoogle Scholar
  59. Neuwelt, E.A., Barnett, P.A., McCormick, C.I., Remsen, L.G., Kroll, R.A. and Sexton, G. (1998a). Differential permeability of a human brain tumor xenograft in the nude rat: impact of tumor size and method of administration on optimizing delivery of biologically diverse agents. Clin Cancer Res, 4, 1549–1555.PubMedGoogle Scholar
  60. Neuwelt, E.A., Brummett, R.E., Doolittle, N.D., Muldoon, L.L., Kroll, R.A., Pagel, M.A., Dojan, R., Church, V., Remsen, L.G. and Bubalo, J.S. (1998b). First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther, 286, 77–84.PubMedGoogle Scholar
  61. Neuwelt, E.A., Brummett, R.E., Remsen, L.G., Kroll, R.A., Pagel, M.A., McCormick, C.I., Guitjens, S. and Muldoon, L.L. (1996). In vitro and animal studies of sodium thiosulfate as a potential chemoprotectant against carboplatin-induced ototoxicity. Cancer Res, 56, 706–709.PubMedGoogle Scholar
  62. Neuwelt, E.A., Frenkel, E.P., Rapoport, S. and Barnett, P. (1980). Effect of osmotic blood-brain barrier disruption on methotrexate pharmacokinetics in the dog. Neurosurgery, 7, 36–43.PubMedCrossRefGoogle Scholar
  63. Neuwelt, E.A., Pagel, M., Barnett, P., Glassberg, M. and Frenkel, E.P. (1981). Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification. Cancer Res, 41, 4466–4470.PubMedGoogle Scholar
  64. O’Neill, B.P., O’Fallon, J.R., Earle, J.D., Colgan, J.P., Brown, L.D. and Krigel, R.L. (1995). Primary central nervous system non-Hodgkin’s lymphoma: survival advantages with combined initial therapy? [see comments]. Int J Radiat Oncol Biol Phys, 33, 663–673.PubMedCrossRefGoogle Scholar
  65. O’Neill, B.P., Wang, C.H., Tallon, J.R., Colgan, J.D., Earle, J.D., Krigel, R.L., Brown, L.D. and McGinnis, W.L. (1999). Primary central nervous system non-Hodgkin’s lymphoma (PCNSL): survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) Study 86-72-52. Int J Radiat Oncol Biol Phys, 43, 559–563.PubMedCrossRefGoogle Scholar
  66. Pardridge, W.M. (1997). Drug delivery to the brain. JCereb Blood Flow Metab, 17, 713–731.CrossRefGoogle Scholar
  67. Pardridge, W.M. (1998). CNS drug design based on principles of blood-brain barrier transport. J Neurochem, 70, 1781–1792.PubMedCrossRefGoogle Scholar
  68. Pardridge, W.M. (1999). Vector-mediated drug delivery to the brain. Adv Drug Deliv Rev, 36, 299–321.PubMedCrossRefGoogle Scholar
  69. Rapoport, S.I. (1996). Modulation of blood-brain barrier permeability. J Drug Target, 3, 417–425.PubMedCrossRefGoogle Scholar
  70. Rapoport, S.I. (2000). Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol, 20, 217–230.PubMedCrossRefGoogle Scholar
  71. Robinson, P.J. and Rapoport, S.I. (1990). Model for drug uptake by brain tumors: effects of osmotic treatment and of diffusion in brain [see comments]. J Cereb Blood Flow Metab, 10, 153–161.PubMedCrossRefGoogle Scholar
  72. Sandor, V., Stark-Vancs, V., Pearson, D., Nussenblat, R., Whitcup, S.M., Brouwers, P., Patronas, N., Heiss, J., Jaffe, E., deSmet, M., Köhler, D., Simon, R. and Wittes, R. (1998). Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma [see comments]. J Clin Oncol, 16, 3000–3006.PubMedGoogle Scholar
  73. Schinkel, A.H. (1999). P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev, 36, 179–194.PubMedCrossRefGoogle Scholar
  74. Schlageter, K.E., Molnar, P., Lapin, G.D. and Groothuis, D.R. (1999). Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc Res, 58, 312–328.PubMedCrossRefGoogle Scholar
  75. Schultz, C., Scott, C., Sherman, W., Donahue, B., Fields, J., Murray, K., Fisher, B., Abrams, R. and Meis-Kindblom, J. (1996). Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol, 14, 556–564.PubMedGoogle Scholar
  76. Seidel, H., Andersen, A., Kvaloy, J.T., Nygaard, R., Moe, P.J., Jacobsen, G., Lindqvist, B. and Slordal, L. (2000). Variability in methotrexate serum and cerebrospinal fluid pharmacokinetics in children with acute lymphocytic leukemia: relation to assay methodology and physiological variables. Leuk Res, 24, 193–199.PubMedCrossRefGoogle Scholar
  77. Shapiro, W.R., Young, D.F. and Mehta, B.M. (1975). Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med, 293, 161–166.PubMedCrossRefGoogle Scholar
  78. Shibata, S. (1989). Sites of origin of primary intracerebral malignant lymphoma. Neurosurgery, 25, 14–19.PubMedCrossRefGoogle Scholar
  79. Siegal, T. (1998). Leptomeningeal metastases: rationale for systemic chemotherapy or what is the role of intra-CSF-chemotherapy? J Neurooncol, 38, 151–157.PubMedCrossRefGoogle Scholar
  80. Siegal, T., Rubinstein, R, Bokstein, F., Schwartz, A., Lossos, A., Shalom, E., Chisin, R. and Gomori, J.M. (2000). In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans. J Neurosurg, 92, 599–605.PubMedCrossRefGoogle Scholar
  81. Siegal, T., Rubinstein, R., Tzuk-Shina, T. and Gomori, J.M. (1997). Utility of relative cerebral blood volume mapping derived from perfusion magnetic resonance imaging in the routine follow up of brain tumors. J Neurosurg, 86, 22–27.PubMedCrossRefGoogle Scholar
  82. Siegal, T., Sandbank, U., Gabizon, A., Mizrachi, R., Ben-David, E. and Catane, R. (1987). Alteration of blood-brain-CSF barrier in experimental meningeal carcinomatosis. A morphologic and adriamycin-penetration study. J Neurooncol, 4, 233–242.PubMedCrossRefGoogle Scholar
  83. Tamai, I. and Tsuji, A. (1996). Drug delivery through the blood-brain barrier. Adv Drug Deliv Rev, 19, 401–424.CrossRefGoogle Scholar
  84. Terae, S. and Ogata, A. (1996). Nonenhancing primary central nervous system lymphoma. Neuroradiology, 38, 34–37.PubMedCrossRefGoogle Scholar
  85. Tetef, M.L., Margolin, K.A., Doroshow, J.H., Akman, S., Leong, L.A., Morgan, R.J., Jr., Raschko, J.W., Slatkin, N., Somlo, G., Longmate, J.A., Carroll, M.I. and Newman, E.M. (2000). Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol, 46, 19–26.PubMedCrossRefGoogle Scholar
  86. Tunggal, J.K., Cowan, D.S., Shaikh, H. and Tannock, I.F. (1999). Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors. Clin Cancer Res, 5, 1583–1586.PubMedGoogle Scholar
  87. van de Waterbeemd, H., Camenisch, G., Folkers, G., Chretien, J.R. and Raevsky, O.A. (1998). Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J Drug Target, 6, 151–165.PubMedCrossRefGoogle Scholar
  88. Vick, N.A., Khandekar, J.D. and Bigner, D.D. (1977). Chemotherapy of brain tumors: The “blood-brain barrier” is not a factor. Arch Neurol, 34, 523–526.PubMedCrossRefGoogle Scholar
  89. Williams, P.C., Henner, W.D., Roman-Goldstein, S., Dahlborg, S.A., Brummett, R.E., Tableman, M., Dana, B.W. and Neuwelt, E.A. (1995). Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms. Neurosurgery, 37, 17–27; discussion 27-28.PubMedCrossRefGoogle Scholar
  90. Wong, S.L., Van Belle, K. and Sawchuk, R.J. (1993). Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis. J Pharmacol Exp Ther, 264, 899–909.PubMedGoogle Scholar
  91. Yoshikawa, T., Sakaeda, T., Sugawara, T., Hirano, K. and Stella, V.J. (1999). A novel chemical delivery system for brain targeting. Adv Drug Deliv Rev, 36, 255–275.Google Scholar
  92. Zunkeler, B., Carson, R.E., Olson, J., Blasberg, R.G., DeVroom, H., Lutz, R.J., Saris, S.C., Wright, D.C., Kammerer, W., Patronas, N.J., Dedrick, R.L., Herscovitch, P. and Oldfield, E.H. (1996a). Quantification and pharmacokinetics of blood-brain barrier disruption in humans. J Neurosurg, 85, 1056–1065.PubMedCrossRefGoogle Scholar
  93. Zunkeler, B., Carson, R.E., Olson, J., Blasberg, R.G., Girton, M., Bacher, J., Herscovitch, P. and Oldfield, E.H. (1996b). Hyperosmolar blood-brain barrier disruption in baboons: an in vivo study using positron emission tomography and rubidium-82. J Neurosurg, 84, 494–502.PubMedCrossRefGoogle Scholar
  94. Zylber-Katz, E., Gomori, J.M., Schwartz, A., Lossos, A., Bokstein, F. and Siegal, T. (2000). Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma. Clin Pharmacol Ther, 67, 631–641.PubMedCrossRefGoogle Scholar

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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