Acta Neurochirurgica

, Volume 87, Issue 1–2, pp 70–75 | Cite as

The intraneoplastic chemotherapy in a rat brain tumour model utilizing methotrexate-polymethylmethacrylate-pellets

  • B. Rama
  • T. Mandel
  • J. Jansen
  • E. Dingeldein
  • H. D. Mennel


In an experimental glioma model, using ethylnitrosourea induced and subsequently intracerebrally implanted tumours in BD-IX rats, the effectiveness of intratumoural application of methotrexate (MTX) by stereotactic implantation of polymethylmethacrylate (PMMA) pellets containing MTX, has been studied. Tumour volume 10 days after pellet implantation as well as survival rates of treated, untreated and control animals have been the criteria of the effect of treatment.

Tumour volume was significantly smaller in treated compared to untreated animals. The survival rate of untreated to treated animals increased 150 and 233% respectively when compared with the control animals. Thus a positive therapeutic effect of MTX-PMMA pellet implantation in the experimental glioma could be proven. Possible consequences for the treatment of human gliomas are shortly discussed.


Rat brain glioma intraneoplastic methotrexate treatment 


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  1. 1.
    Ausman JI, Levin VA, Brown WE, Rall DP, Fenstermacher JD (1977) Brain-tumour chemotherapy. Pharmacological principles derived from a monkey brain-tumor model. J Neurosurg 46: 155–164PubMedGoogle Scholar
  2. 2.
    Barker M, Hoshino T, Gurcay O, Wilson CB, Nielsen SL, Downie R, Eliason J (1973) Development of an animal brain tumor model and its response to therapy with 1, 3- bis (2-chloroethyl)-1-nitrosourea. Cancer Res 33: 976–986PubMedGoogle Scholar
  3. 3.
    Blasberg RG (1977) Methotrexate, Cytosine Arabinoside, and BCNU concentration in brain after ventriculocisternal perfusion. Cancer Treat Rep 61: 625–631PubMedGoogle Scholar
  4. 4.
    Blasberg RG, Patlak CS, Shapiro WR (1977) Distribution of Methotrexate in the cerebrospinal fluid and brain after intraventricular administration. Cancer Treat Rep 61: 633–641PubMedGoogle Scholar
  5. 5.
    Bosch DA, Hindmarsch T, Larsson S, Backlund EO (1980) Intraneoplastic administration of bleomycin in intracerebral gliomas: a pilot study. Acta Neurochir (Wien) [Suppl] 30: 441–444Google Scholar
  6. 6.
    Cserr HF, Cooper DN, Milhorat TH (1977) Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res [Suppl] 25: 461–473Google Scholar
  7. 7.
    Diemath HE, Hausmaninger D (1981) Local intraoperative chemotherapy after removal of glioblastomas. Neurochirurgia (Stuttg) [Suppl] 363Google Scholar
  8. 8.
    Edvinssson D, Nielsen KC, Owman C, West KA (1971) Alterations in intracranial pressure, blood-brain barrier, and brain edema after sub-chronic implantation of a cannula into the brain of conscious animals. Acta physiol scand 82: 527–531PubMedGoogle Scholar
  9. 9.
    Garfield J, Dayan AD (1973) Postoperative intracavitary chemotherapy of malignant gliomas. A preliminary study using methotrexate. J Neurosurg 39: 315–322PubMedGoogle Scholar
  10. 10.
    Garfield J, Dayan AD, Weller RD (1975) Postoperative intracavitary chemotherapy of malignant supratentorial astrocytomas using BCNU. Clin Oncol I: 213–222Google Scholar
  11. 11.
    Gerosa MA, Dougherty DV, Wilson CB, Rosenblum ML (1983) Improved treatment of a brain-tumor model. Part 2: Sequential therapy with BCNU and 5-fluorouracil. J Neurosurg 58: 368–373PubMedGoogle Scholar
  12. 12.
    Groothuis DR, Fischer JM, Lapin G, Bigner DD, Vick NA (1982) Permeability of different experimental brain tumor models to horseradish peroxidase. J Neuropathol Exp Neurol 41: 164–185PubMedGoogle Scholar
  13. 13.
    Hamada M, Asakura T (1981) Effects of corticosteroids on malignant brain tumors: Experimental studies and clinical intratumoral injection of corticosteroids. Neurochirurgia (Stuttg) [Suppl] 364Google Scholar
  14. 14.
    Hasegawa H, Ushio Y, Hayakawa T, Yamada K, Mogami H (1983) Changes of the blood-brain barrier in experimental metastatic brain tumors. J Neurosurg 59: 304–310PubMedGoogle Scholar
  15. 15.
    Heppner F, Diemath HE (1963) Lokale Chemotherapie der Hirntumoren. Acta Neurochir (Wien) 11: 287–293Google Scholar
  16. 16.
    Hossman KA, Blöink M (1981) Blood flow and regulation of blood flow in experimental peritumoural edema. Stroke 12: 211–217PubMedGoogle Scholar
  17. 17.
    Itoh Y, Nakazawa S, Ohwaki K, Shimura T, Yamjima K (1981) Treatment of malignant brain tumor by local injection of adriamycin. Neurochirurgia (Stuttg) [Suppl] 363Google Scholar
  18. 18.
    Katakura R, Kuwahara K, Mori T (1981) A newly devised tablet with prolonged release of bleomycin in brain tumors. Neurochirurgia (Stuttg) [Suppl] 367Google Scholar
  19. 19.
    Levin VA, Freeman-Dove M, Landahl HD (1975) Permeability characteristics of brain adjacent to tumors in rats. Arch Neurol 32: 785–791PubMedGoogle Scholar
  20. 20.
    McKeran RO, Firth G, Oliver S, Uttley D, O'Laoire S (1985) A potential application for the intracerebral injection of drugs entrapped within liposomes in the treatment of human cerebral gliomas. J Neurol Neurosurg Psychiatry 48: 1213–1219PubMedGoogle Scholar
  21. 21.
    Mehta BM, Glass JP, Shapiro WR (1983) Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-Ommaya methotrexate administration in patients with meningeal carcinomatosis. Cancer Res 43: 435–438PubMedGoogle Scholar
  22. 22.
    Mennel H (1985) Personal commandGoogle Scholar
  23. 23.
    Mennel HD, Hellwig D, Simon HL (1986) Chemotherapy in intracerebrally transplanted tumours induced with transplacental administration of ethylnitrosourea in rats. J Cancer Res Clin Oncol 112: 240–244PubMedGoogle Scholar
  24. 24.
    Nakazawa S, Ohwaki K, Shimura T, Itoh Y, Yajima K (1981) A new treatment of malignant brain tumor -1: local injection of bleomycin. No Shinkei Geka 9: 1487–1493PubMedGoogle Scholar
  25. 25.
    Nomura K, Hoshino T, Pentecost SM (1981) Post treatment kinetics of BCNU in a 9 L rat tumor model. Neurol Med Chir (Tokyo) 21: 19–25Google Scholar
  26. 26.
    Oda Y, Uchida Y, Murata T, Mori K, Tokuriki Y, Handa H, Kobayashi A, Hashi K, Kieler J (1982) Treatment of brain tumors with anticancer pellet-experimental and clinical study. No Shinkei Geka 10: 375–381PubMedGoogle Scholar
  27. 27.
    Pollay M, Roberts PA (1980) Blood-brain barrier: A definition of normal and altered function. Neurosurgery 6: 675–685PubMedGoogle Scholar
  28. 28.
    Rama B, Spoerri O, Holzgraefe M, Mennel HD (1986) Current brain tumor models with particular consideration of the transplantation techniques. Acta Neurochir (Wien) 79: 35–41Google Scholar
  29. 29.
    Rapoport SI (1976) Blood-brain barrier in physiology and medicine. Raven Press, New YorkGoogle Scholar
  30. 30.
    Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34: 207–217PubMedGoogle Scholar
  31. 31.
    Reulen HJ, Tsuyumu M, Tack A, Fenske AR, Prioleau GR (1978) Clearance of edema fluid into cerebrospinal fluid. A mechanism for resolution of vasogenic brain edema. J Neurosurg 48: 754–764PubMedGoogle Scholar
  32. 32.
    Ringjöb R (1968) Treatment of intracranial gliomas and metastatic carcinomas by local application of cytostatic agents. Acta Neurol Scand 44: 318–322PubMedGoogle Scholar
  33. 33.
    Rosenblum ML, Bowie DL, Walker MD (1973) Diffusion in vitro and in vivo of 1- (2-chloroethyl) 3-(trans-4-methylcyclohexyl)-I-nitrosourea from silicone rubber capsules, a potentially new mode of chemotherapy administration. Cancer Res 33: 909–914Google Scholar
  34. 34.
    Rosenblum ML, Gerosa MA, Dougherty DV, Wilson CB (1983) Improved treatment of a brain-tumor model. Part 1: Advantages of single-over multiple-dose BCNU schedules. J Neurosurg 58: 177–182PubMedGoogle Scholar
  35. 35.
    Saito Y, Hori T, Takami M, Muraoka K, Hokama Y, Numata H (1983) Study on postoperative local chemotherapy of malignant brain tumors using ACNU and PSK. Gan 10: 1963–1971Google Scholar
  36. 36.
    Sasahira M, Ichitubo H (1981) Intratumoral chemotherapy for gliomas and metastatic brain tumor. A clinicopathological study. Neurochirurgia (Stuttg) [Suppl] 363Google Scholar
  37. 37.
    Schultheis KH, Hennekking K, Rehm KE, Ecke H, Schiefer HG, Breithaupt H (1982) Untersuchungen über die Freisetzungskinetik verschiedener Chemotherapeutika aus einer viskösen, im feuchten Milieu schnell aushärtenden Aminosäurelösung und ihre mögliche klinische Anwendung. In: Weller S (ed) Chirurgisches Forum 82 für exp und klin Forschung, Langenbecks Arch Chir [Suppl], pp 199–205Google Scholar
  38. 38.
    Stevens JM, Ruiz JS, Kendall BE (1983) Observations on peritumoural oedema in meningioma. Part II: Mechanisms of oedema production. Neuroradiology 25: 125–131PubMedGoogle Scholar
  39. 39.
    Strohecker J (1980) Schädeldachplastik mit Refobacin-Palacos. Acta Chir Austriaca 12: 105–108Google Scholar
  40. 40.
    Tamura M, Mennel HD, Zülch KJ (1979) Brain tumor chemotherapy using a rat glioma model. J Cancer Res Clin Oncol 94: 39–46PubMedGoogle Scholar
  41. 41.
    Tator CH (1977) Intraneoplastic injection of CCNU for experimental brain tumor chemotherapy. Surg Neurol 7: 73–77PubMedGoogle Scholar
  42. 42.
    Tator CH, Wassenaar W (1977) Intraneoplastic injection of methotrexate for experimenal brain-tumor chemotherapy. J Neurosurg 46: 165–174PubMedGoogle Scholar
  43. 43.
    Tator CH, Wassenaar W, Day A, So WS (1977) Therapy of an experimental glioma with systemic or intraneoplastic methotrexate or radiation. J Neurosurg 46: 175–184PubMedGoogle Scholar
  44. 44.
    Tel E, Hoshino T, Barker M, Wilson CB (1980) Effect of surgery on BCNU chemotherapy in a rat brain tumor model. J Neurosurg 52: 529–532PubMedGoogle Scholar
  45. 45.
    Ushio Y, Akagi K, Bitoh S, Hayakawa T, Ikeda H, Kamikawa H, Mogami H, Oku Y, Yamada K (1981) Phase 3 study of methyl-CCNU and bleomycin combination chemotherapy in the treatment of malignant gliomas. Neurochirurgia (Stuttg) [Suppl] 362Google Scholar
  46. 46.
    Vats TS, Kimler BF, Henderson SD, Morantz RA (1982) Combination chemotherapy for the 9 L rat brain tumor model system. Cancer Treat Rep 66: 575–580PubMedGoogle Scholar
  47. 47.
    Vats TS, Morantz RA, Wood GW, Tilzer S (1979) Study of effectiveness of bleomycin in rat brain tumor model intravenously and intracerebrally. Int J Radiat Oncol Biol Phys 5: 1527–1529PubMedGoogle Scholar
  48. 48.
    Vick NA, Khandekar JD, Bigner DD (1977) Chemotherapy of brain tumors. “The Blood-Brain Barrier” is not a factor. Arch Neurol 34: 523–526PubMedGoogle Scholar
  49. 49.
    Wahlig H, Dingeldein E, Bergmann R, Reuss K (1978) The release of gentamycin from polymethylmethacrylate beads. An experiment and pharmacokinetic study. J Bone Joint Surg 60-B: 270–275Google Scholar
  50. 50.
    Weiss SR, Raskind R (1969) Treatment of malignant brain tumors by local methotrexate. Int Surg 51: 149–155PubMedGoogle Scholar
  51. 51.
    Yamada K, Hayakawa T, Ushio Y, Arita N, Kato A, Mogami H (1981) Regional blood flow and capillary permeability in the ethylnitrosourea-induced rat glioma. J Neurosurg 55: 922–928PubMedGoogle Scholar
  52. 52.
    Zeman W, Innes JRM (1963) Craigie's neuroanatomy of the rat. Academic Press, New YorkGoogle Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • B. Rama
    • 1
  • T. Mandel
    • 1
  • J. Jansen
    • 1
  • E. Dingeldein
    • 2
  • H. D. Mennel
    • 3
  1. 1.Neurochirurgische Klinik der Universität GöttingenGöttingen
  2. 2.Darmstadt 1
  3. 3.Abteilung Neuropathologie der Universität MarburgMarburgGermany

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