Journal of Neuro-Oncology

, Volume 24, Issue 3, pp 229–240 | Cite as

Permeability change and brain tissue damage after intracarotid administration of cisplatin studied by double-tracer autoradiography in rats

  • Shinji Sugimoto
  • Y Lucas Yamamoto
  • Shinji Nagahiro
  • Mirko Diksic
Laboratory Investigation


The present study was designed to find the reliable parameter(s) for the detection of early neurotoxicity following intracarotid (IC) administration of cisplatin. IC administration was performed for 60 minutes in female Wistar rats derived into four groups according to the dose given (1 mg, 1.2 mg, and 1.5 mg of cisplatin, and normal saline in control rats). Blood-brain barrier (BBB) permeability and local cerebral blood flow (LCBF) were measured by a double-tracer autoradiography technique using 1-[14 C]-α-aminoisobutyric acid (14 C-AIB) and 4-[18 F] fluoroantipyrine (18 F-FAP), respectively. Blood chemistry and neuropathology were also examined. BBB permeability was incereased only on the ipsilateral side. This increase was dose-dependent, preceded the brain necrosis, and was statistically significant in the hypothalamus [1.2 mg group), auditory cortex and caudoputamen (1.5 mg group). Renal dysfunction was often observed. The changes in the LCBF did not occur until brain necrosis was noticeable. These findings demonstrate that the increase in the BBB permeability provides a sensitive and reliable indication of an early toxicity to brain tissue following IC administration of cisplatin.

Key words

cisplatin intracarotid chemotherapy multi-tracer autoradiography blood brain barrier cerebral blood flow 


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  1. 1.
    Fenstermacher JD, Cowles AL: Theoretic limitation of intracarotid infusion in brain tumor chemotherapy. Cancer Treat Rep 61(4): 519–526, 1977PubMedGoogle Scholar
  2. 2.
    Blasberg RG: Pharmacodynamics and the blood-brain barrier. Natl Cancer Inst Monogr 46: 19–27, 1977PubMedGoogle Scholar
  3. 3.
    Feun LG, Wallace S, Stewart DJ, Chuang V, Yung WKA, Leavens ME, Burgess MA, Savaraj N, Benjamin RS, Young SE, Tang RA, Handy S, Mavlight G, Fields WS: Intracarotid infusion of cis-diamminedichloroplatinum in the treatment of recurrent malignant brain tumors. Cancer 54: 794–799, 1983Google Scholar
  4. 4.
    Lehane DE, Bryan RN, Horowitz B, DeSantos L, Ehni G, Zubler MA, Moiel R, Rudolph L, Aldama-Leubbert A, Mahoney D, Harper R: Intraarterial cis-platinum chemotherapy for patients with primary and metastatic brain tumors. Cancer Drug Deliv 1: 69–77, 1983PubMedGoogle Scholar
  5. 5.
    Stewart DJ, Wallace S, Feun L, Leavens M, Young SL, Handel S, Mavlight G, Benjamin RS: A phase I study of intracarotid artery infusion of cis-diamminedichloroplatinum (II) in patients with recurrent malignant intracerebral tumors. Cancer Res 42: 2059–2062A, 1982PubMedGoogle Scholar
  6. 6.
    Calvo FA, Pastor MA, Dy C, Alegria E, Aparicio LMA: Intra-arterial and intravenous chemotherapy for the treatment of malignant glioma. Am J Clin Oncol 8: 200–209, 1985PubMedGoogle Scholar
  7. 7.
    Newton HB, Page MA, Junck L, Greenberg HS: Intra-arterial cisplatin for the treatment of malignant gliomas. J Neuro-Oncol 7: 39–45, 1989Google Scholar
  8. 8.
    Mahaley MS, Hipp SW, Dropcho EJ, Bertsch L, Cush S, Tirey T, Gillespie Y: Intracarotid cisplatin chemotherapy for recurrent gliomas. J Neurosurg 70: 371–378, 1989PubMedGoogle Scholar
  9. 9.
    Sciki Y, Shibata I, Terao H, Kudo M, Noguchi T: Pharmacokinetic study of selective continuous-internal carotid CDDP infusion in malignant brain tumors. Neurol Med Chir (Tokyo) 31: 695–701, 1991Google Scholar
  10. 10.
    Ichimura K, Ohno K, Hoyagi M, Tamaki M, Suzuki R, Hiratowa K: Capillary permeability in experimental rat glioma and effects of intracarotid CDDP administration on tumor drug delivery. J Neuro-Oncol 16: 211–215, 1993Google Scholar
  11. 11.
    Stewart DJ, Benjamin RS, Zimmerman S, Caprioli RM, Wallace S, Chuang V, Calvo III D, Samuels M, Bonura J, Loo TL: Clinical pharmacology of intra-arterial cis-diamminedichloroplatinum (II). Cancer Res 43: 917–920, 1983PubMedGoogle Scholar
  12. 12.
    Kapp JP, Vance RB: Supraophthalmic carotid infusion for recurrent glioma. Rationale, technique, and preliminary results for cisplatin and BCNU. J Neuro-Oncol 3: 5–11, 1985Google Scholar
  13. 13.
    Kapp JP, Sanford RA: Neurological deficit after carotid infusion of cisplatin and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) for malignant glioma: an analysis of risk factors. Neurosurgery 19: 779–783, 1986PubMedGoogle Scholar
  14. 14.
    Saris SC, Wright DC, Oldfield EH, Blasberg RG: Intravascular streaming and variable delivery to brain following carotid artery infusion in the Sprague-Dawley rat. J Cereb Blood Flow & Metab 8: 116–120, 1988Google Scholar
  15. 15.
    Blacklock JB, Wright DC, Dedrick RL, Blasberg RG, Lutz RJ, Doppman JL, Oldfield EH: Drug streaming during intra-arterial chemotherapy. J Neurosurg 64: 284–291, 1986PubMedGoogle Scholar
  16. 16.
    Lutz RJ, Dedrick RL, Boretos JW, Oldfield EH, Blacklock JB, Doppman JL: Mixing studies during intracarotid artery infusions in anin vitro model. J Neurosurg 64: 277–283, 1986PubMedGoogle Scholar
  17. 17.
    Sako K, Kato A, Diksic M, Tamamoto YL: Use of short-lived18 F and long-lived14 C in double tracer autoradiography for simultaneous measurement of LCBF and LCGU. Stroke 15: 896–900, 1984PubMedGoogle Scholar
  18. 18.
    Sako K, Diksic M, Yamamoto YL, Feindel W: Evaluation of [18 F]F-4-fluoroantipyrine as a new blood flow tracer for multiradionuclide autoradiography. J Cereb Blood Flow & Metab 4: 259–263, 1984Google Scholar
  19. 19.
    Blasberg RG, Fenstermacher JD, Patlack CS: Transport of α-aminoisobutyric acid across brain capillary and cellular membranes. J Cereb Blood Flow & Metab 3: 215–225, 1983Google Scholar
  20. 20.
    Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L: Measurement of local cerebral blood flow with iodol (14 C) antipyrine. Am J Physiol 234: H59-H66, 1978PubMedGoogle Scholar
  21. 21.
    Lange RC, Spencer RP, Harder HC: Synthesis and distribution of a radiolabelled antitumor agent: cis-diamminedichloroplatinum (II). J Nucl Med 13: 328–330, 1972PubMedGoogle Scholar
  22. 22.
    Litterst CL, LeRoy AF, Guarino AM: Disposition and distribution of platinum following parenteral administration of cis-dichlorodiammineplatinum (II) to animals. Cancer Treat Rep 63: 1485–1492, 1979PubMedGoogle Scholar
  23. 23.
    Kociba RJ, Sleight SD: Acute toxicologic and pathologic effect of cis-diamminedichloroplatinum (NCS-119875) in the male rat. Cancer Chemotherapy Reports 55: 1–8, 1971Google Scholar
  24. 24.
    Stewart DJ, Leavens M, Maor M, Feun L, Luna M, Bonura J, Caprioli R, Loo TL, Benjamin RS: Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Cancer Research 42: 2474–2479, 1982PubMedGoogle Scholar
  25. 25.
    Ginos JZ, Cooper AJL, Dhawan V, Lai JCK, Strother SC, Alcock N, Rottenberg DA: (13 N) cisplatin PET to assess pharmacokinetics of intra-arterial versus intravenous chemotherapy for malignant brain tumors. J Nucl Med 28: 1844–1852, 1987PubMedGoogle Scholar
  26. 26.
    Neuwelt EA, Glasberg M, Frenkel E, Barnett P: Neurotoxicity of chemotherapeutic agents after blood-brain modification: neuropathological studies. Ann Neurol 14: 316–324, 1983PubMedGoogle Scholar
  27. 27.
    Ward JM, Fauvie KA: The nephrotoxic effects of cis-diamminedichloroplatinum (II) (NSC-119875) in male F344 rats. Toxicol Appl Pharmacol 38: 535–547, 1976PubMedGoogle Scholar
  28. 28.
    Spigelman MK, Zappula RA, Johnson J, Goldsmith SJ, Malis LI, Holland JF: Etoposide-induced blood-brain barrier disruption. J Neurosurg 61: 674–678, 1984PubMedGoogle Scholar
  29. 29.
    Phillips PC, Thaler HT, Berger CA, Fleisher M, Wellner D, Allen JC, Rottenberg DA: Acute high-dose methotrexate neurotoxocity in the rat. Ann Neurol 20: 583–589, 1986PubMedGoogle Scholar
  30. 30.
    Phillips PC, Dhawan V, Strother SC, Sidtis JJ, Evance AC, Allen JC, Rottenberg DA: Reduced cerebral glucose metabolism and increased brain capillary permeability following high-dose methotrexate chemotherapy. Ann Neurol 21: 59–63, 1987PubMedGoogle Scholar
  31. 31.
    Gouyette A, Apchin A, Foka M, Richard J-M: Pharmacokinetics of intra-arterial and intravenous cisplatin in head and neck cancer patients. Eur J Cancer Clin Oncol 22: 257–263, 1986PubMedGoogle Scholar
  32. 32.
    Gormley PE, Bull JM, LeRoy AF, Cysyk P: Kinetics of cisdichlorodiammineplatinum. Clin Pharmacol Ther 25: 351–357, 1979PubMedGoogle Scholar
  33. 33.
    Vermorken JB, Vijgh WJFVD, Klein I, Hart AAM, Gall HE, Pinedo HM: Pharmacokinetics of free and total platinum species after short-term infusion of cisplatin. Cancer Treat Rep 68: 505–515, 1984PubMedGoogle Scholar
  34. 34.
    Degregorio MW, King OY, Holleran WM, Wilbur BJ, Cadman EC, Deisseroth AB, Wilbur JR: Ultra filtrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma. Cancer Treat Rep 69: 1441–1442, 1985PubMedGoogle Scholar
  35. 35.
    Madias NE, Harrington JT: Platinum nephrotoxicity. Am J Medicine 65: 307–314, 1978Google Scholar
  36. 36.
    Leonard B, Eccleston E, Jones D, Todd P, Walpole A: Antileukemic and nephrotoxic properties of platinum compounds. Nature 234: 43–45, 1971PubMedGoogle Scholar
  37. 37.
    Klatzo I, Suzuki R, Orzi F, Schuier F, Nitsch C: Mechanisms of ischemic brain edema. In: Recent Progress in the Study and Therapy of Brain Edema. Go KG, Baathmann A (Eds.) Plenum Press, NY. pp 1–10, 1982Google Scholar
  38. 38.
    Steinwall O, Klatzo I: Selective vulnerability of the bloodbrain barrier in chemically induced lesions. J Neuropathol Exp Neurol 25: 542–559, 1966PubMedGoogle Scholar
  39. 39.
    Sokoloff L, Reivich M, Kennedy C, Rosiers HD, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M: The14C-deoxyglucose method for the measurement of local glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28: 897–910, 1977PubMedGoogle Scholar
  40. 40.
    Kato A, Diksic M, Yamamoto YL, Strother SC, Feindel W: An improved approach for measurement of regional cerebral rate constants in deoxyglucose method with positron emission tomography. J Cereb Blood Flow Metab 4: 555–563, 1984PubMedGoogle Scholar
  41. 41.
    Schmall B, Conti PS, Bigler BE, Zanzonico PB, Reiman RE, Benua RS, Yeh SD, Dahl JR, Lee R, Laughlin JS: Imaging studies of patients with malignant fibrous histiocytoma using11 C-alpha-aminoisobutiric acid (AIB). Clin Nucl Med 12: 22–26, 1987PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Shinji Sugimoto
    • 1
  • Y Lucas Yamamoto
    • 1
  • Shinji Nagahiro
    • 1
  • Mirko Diksic
    • 1
  1. 1.Cone Laboratory Neurosurgical Research and Neuroisotope Laboratory, Montreal Neurological InstituteMcGill UniversityMontrealCanada

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