Summary
Leukotriene E4 (LTE4) infused into the carotid artery ipsilateral to an experimental glial tumor will selectively increase the blood-tumor permeability within the tumor. In this study the effects of intracarotid infusion of LTE4 on blood-tumor barrier (BTB) permeability for intravenously administered14C-aminoisobutyric acid,14C-5-fluorouracil (5-FU)14C-sucrose and3H-methotrexate (MTX) were examined in C6 gliomas of rats. The intracarotic administration of LTE4 selectively opened the BTB, without affecting permeability of normal brain tissue, to all of the above tracers. Intracarotid infusion of LTE4 had the tendency to increase the uptake of intravenously administered 5-FU within the tumor, but this effect was not statistically significant. The intracarotid infusion of LTE4, however, increased the uptake of intravenously injected MTX about twofolds within the tumor (Ki = 19.48 ±1.06 vs 10.12 ±1.19, p < 0.01) without increasing the uptake in the normal brain tissue.
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Fenstermacher JD, Cowles AL: Theoretic limitations of intracarotid infusions in brain tumor chemotherapy. Cancer Treat Rep 61: 519–526, 1977
Groothuis DR, Fischer JR, Lapin G, Binger DD, Vick NA: Permeability of different experimental brain tumor models to horseradish peroxidase. J Neuropathol Exp Neurol 41: 164–185, 1982
Neuwelt EA, Barnett PA, Bigner DD, Frenkel EP: Effects of adrenal cortical steroid and osmotic blood-brain barrier opening on methotrexate delivery to gliomas in the rodent: The factor of the blood-brain barrier. Proc Natl Acad Sci USA 79: 4420–4423, 1982
Levin VA, Hoffman WF, Pischer TL, Seager ML, Boldrey EB, Wilson CB: BCNU-5-fluorouracil combination therapy for recurrent malignant brain tumors. Cancer Treat Rep 62: 2071–2076, 1978
Fine HA, Antman KH: High dose chemotherapy with autologous bone marrow transplantation in the treatment of high grade astrocytomas in adults: Therapeutic rationale and clinical experience. Bone Marrow Transplant 10: 315–321, 1992
Shapiro WR, Green SB, Burger PC, Selker RG, VanGilder JC, Robertson JT, Mealey J Jr., Ransohoff J, Mahaley MS Jr.: A randomized comparison of intra-arterial versus intravenous BCNU, with or without intravenous 5-fluorouracil, for newly diagnosed patients with malignant glioma. J Neurosurg 76: 772–781, 1992
Brem H, Mahaley MS Jr., Vick NA, Black KL, Schold SC Jr., Burger PC, Friedman AH, Ciric IS, Eller TW, Cozzens JW, Kenealy JN: Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74: 441–446, 1991
Neuwelt EA, Rapoport SI: Modification of the blood-brain barrier in the chemotherapy of malignant brain tumors. Fed Proc 43: 214–219, 1984
Kumagai AK, Eisenberg JB, Pardridge WM: Absorptive-mediated endocytosis of cationized albumin and a β-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. J Biol Chem 262: 15214–15219, 1987
Pardridge WM, Kumagai AK, Eisenberg JB: Chimeric peptides as a vehicle for peptide pharmaceutical delivery through the blood-brain barrier. Biochem Biophys Res Comm 146: 307–313, 1987
Neuwelt EA, Hill SA, Frenkel EP: Osmotic blood-brain barrier modification and combination chemotherapy: concurrent tumor regression in areas of barrier opening and progression in brain regions distant to barrier opening. Neu-rosurg 15: 362–366, 1984
Neuwelt EA, Barnett PA, McCormick CI, Frenkel EP, Minna JD: Osmotic blood-brain barrier modification: monoclonal antibody, albumin, and methotrexate delivery to cerebrospinal fluid and brain. Neurosurg 17: 419–423, 1985
Hiesiger EM, Voorhies RM, Basler GA, Lipschutz LE, Posner JB, Shapiro WR: Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: The effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow. Ann Neurol 19: 50–59, 1986
Inoue T, Fukui M, Nishio S, Kitamura K, Nagara H: Hyperosmotic blood-brain barrier disruption in brains of rats with an intracerebrally transplanted RG-C6 tumor. J Neurosurg 66: 256–263, 1987
Kondo A, Inoue T, Nagara H, Tateishi J, Fukui M: Neuro-toxicity of adriamycin passed through the transiently disrupted blood-brain barrier by mannitol in the rat brain. Brain Res 412: 73–83, 1987
Nakagawa H, Groothuis D, Blasberg RG: The effect of graded hypertonic intracarotid infusions on drug delivery to experimental RG-2 gliomas. Neurology 34: 1571–1581, 1984
Shapiro WR, Voorhies RM, Hiesiger EM, Sher PB, Basler GA, Lipschutz: Pharmacokinetics of tumor cell exposure to [14C] Methotrexate after intracarotid administration without and with hyperosmotic opening of the blood-brain and blood-tumor barriers in rat brain tumors: A quantitative autoradiographic study. Cancer Res 48: 694–701, 1988
Tomiwa K, Hazama F, Mikawa H: Neurotoxicity of vincristine after the osmotic opening of the blood-brain barrier. Neuropathol Appl Neurobiol 9: 345–354, 1983
Warnke PC, Blasberg RG, Groothuis DR: The effect of hyperosmotic blood-brain barrier disruption on blood-to-tissue transport in ENU-induced gliomas. Ann Neurol 22: 300–305, 1987
Black KL, King WA, Ikezaki K: Selective opening of bloodtumor barrier by intracarotid infusion of leukotriene C4. J Neurosurg 72: 912–916, 1990
Chio CC, Baba T, Black KL: Selective blood-tumor barrier disruption by leukotrienes. J Neurosurg 77: 407–410, 1992
Blasberg RG, Patlak CS, Jehle JW, Fenstermacher JD: An autoradiographic technique to measure the permeability of normal and abnormal brain capillaries (abstract). Neurology 28: 363, 1978
Blasberg RG, Kobayashi T, Horowitz M, Rice JM, Groothuis D, Molnar P, Fenstermacher JD: Regional blood-to-tissue transport in ethylnitrosourea-induced brain tumors. Ann Neurol 14: 202–215, 1983
Black KL, Hoff JT: Leukotrienes and blood-brain barier permeability. J Cereb Blood Flow Metab 5 (Suppl 1): S263–264, 1985
Black KL, Hoff JT: Leukotrienes increase blood-brain barrier permeability following intraparenchymal injections in rats. Ann Neurol 18: 349–351, 1985
Chan PH, Fishman RA: Brain edema: induction in cortical slices by polyunsaturated fatty acids. Science 201: 358–360, 1978
Chan PH, Fishman RA, Caronna J, Schmidley JW, Prioleau G, Lee J: Induction of brain edema following intracerebral injection of arachidonic acid. Ann Neurol 13: 625–632, 1983
Chan PH, Fishman RA: The role of arachidonic acid in vasogenic brain edema: Fed Proc 43: 210–213, 1984
Samuelsson B: Leukotrienes: Mediators of immediate hypersensitivity reactions and inflammations. Science 220: 568–575, 1983
Ueno A, Tanaka K, Katori M, Hayashi M, Arai Y: Species difference in increased vascular permeability by synthetic leukotriene C4 and D4. Prostaglandins 21: 637–647
Aharony D, Dobson P: Discriminative effect of γ-glutamyl transpeptidase inhibitors on metabolism of leukotriene C4 in peritoneal cells. Life Sci 35: 2135–2142, 1984
Black KL, Baba T, Pardridge WM: Enzymatic barrier protects brain capillaries from leukotriene C4. J Neurosurg 81: 745–751, 1994
Black KL, Hoff JT, McGillicuddy JE, Gebarski SS: Increased leukotriene C4 and vasogenic edema surrounding brain tumors in humans. Ann Neurol 19: 592–595, 1986
Moskowitz MA, Kiwak KJ, Hekimian K, Levine L: Synthesis of compounds with properties of leukotriene C4 and D4 in gerbil brains after ischemia and reperfusion. Science 224: 886–888, 1984
Black KL, Chio CC: Increased opening of blood-tumour barrier by leukotriene C4 is dependent on size of molecules. Neurol Res 14: 402–404, 1992
Fenstermacher JD, Rapoport SI: The blood-brain barrier. In: Renkin EM, Michel CC (eds) Handbook of Physiology: The Cardiovascular System IV. American Physiological Society. Bethesda, 1984, pp 969–1000
Blasberg RG, Fenstermacher JD, Patlak CS: Transport of α-aminoisobutyric acid across brain capillary and cellular membranes. J Cerebr Blood Flow Metabol 3: 8–32, 1983
Blasberg RG, Groothuis DR: Chemotherapy of brain tumors: Physiological and pharmacokinetic considerations. Semin Oncol 13: 70–82, 1986
Levin VA: A pharmacologic basis for brain tumor chemotherapy. Semin Oncol 2: 57–61, 1975
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Chio, C.C., Lin, S.J. & Lin, M.T. Leukotriene E4 selectively increase the delivery of methotrexate to the C6 gliomas in rats. J Neuro-Oncol 25, 89–95 (1995). https://doi.org/10.1007/BF01057752
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DOI: https://doi.org/10.1007/BF01057752