Heuristic modeling of drug delivery to malignant brain tumors

  • Victor A. Levin
  • Clifford S. Patlak
  • Herbert D. Landahl


It is apparent that chemotherapy against malignant brain tumors is generally ineffective. While some agents are more effective than others, none appreciably alters the clinical course of and the poor prognosis for patients with brain tumors. Even though new and more effective agents are being or will be developed, chemotherapy depends as much on the delivery of drug as it does on the drug used. Therefore, we have defined factors that we believe are of primary importance in drug delivery to brain tumors, and, using computer simulation, we have modeled the effects of these factors. In this article we discuss (a) the extent of the “breakdown” in the blood-brain barrier (BBB) that accompanies the development of malignant tumors in the brain, (b) factors that influence drug transport from tumor capillaries to tumor cells at varying distances from the capillaries, (c) the problems inherent in drug delivery from a well-vascularized tumor outward to normal brain tissue that might harbor malignant cells but that does not have leaky vessels (i.e., normal BBB), and (d) the difficulties in drug delivery from a well-perfused, highly permeable outer tumor shell to a central, poorly perfused tumor core.

Key words

chemotherapy pharmacokinetics brain tumors modeling solid tumors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    V. A. Levin and C. B. Wilson. Chemotherapy: Agents in current use.Sem. Oncol. 2:63–67 (1975).Google Scholar
  2. 2.
    R. I. Geran, G. F. Congleston, and L. E. Dudeck. A mouse ependymoblastoma as an experimental model for screening potential antineoplastic drugs.Cancer Chemother. Rep. 4:53–87 (1974).Google Scholar
  3. 3.
    V. A. Levin and P. M. Kabra. Effectiveness of the nitrosoureas as a function of their lipid solubility in the chemotherapy of experimental rat brain tumors.Cancer Chemother. Rep. 58:787–792 (1974).PubMedGoogle Scholar
  4. 4.
    J. D. Fenstermacher, D. P. Rall, C. S. Patlak, and V. A. Levin. Ventriculocisternal perfusion as a technique for analysis of brain capillary permeability and extracellular transport. InCapillary Permeability, Munksgaard, Copenhagen, 1970, pp. 483–490.Google Scholar
  5. 5.
    C. S. Patlak and J. D. Fenstermacher. Measurement of dog blood-brain barrier transfer constants by ventriculocisternal perfusion.Am. J. Physiol. 229:877–884 (1975).PubMedGoogle Scholar
  6. 6.
    E. J. Schantz and M. A. Lauffer. Diffusion measurements in agar gel.Biochemistry 1:658–663 (1962).PubMedCrossRefGoogle Scholar
  7. 7.
    R. J. Weinkam and H.-S. Lin. Direct reaction mixture analysis by probe intersection chemical ionization mass spectrometry.Anal. Chem. 51:972–975 (1979).CrossRefGoogle Scholar
  8. 8.
    R. G. Blasberg, C. S. Patlak, and J. D. Fenstermacher. Intrathecal chemotherapy: Brain tissue profiles after ventriculo-cisternal perfusion.J. Pharmacol. Exp. Ther. 195:73–83 (1975).PubMedGoogle Scholar
  9. 9.
    V. A. Levin, J. D. Fenstermacher, and C. S. Patlak. Sucrose and inulin space measurements of cerebral cortex in four mammalian species.Am. J. Physiol. 219:1528–1533 (1970).PubMedGoogle Scholar
  10. 10.
    V. A. Levin, H. D. Landahl, and M. A. Freeman-Dove. The application of brain capillary permeability coefficient measurements of pathologic conditions and the selection of agents which cross the blood-brain barrier.J. Pharmacokin. Biopharm. 4:499–519 (1976).CrossRefGoogle Scholar
  11. 11.
    V. A. Levin, M. S. Edwards, and A. Byrd. Quantitative observations of the acute effects of X-irradiation on brain tumor capillary permeability.Int. J. Radiat. Oncol. Biol. Phys. 5:1627–1631 (1979).PubMedCrossRefGoogle Scholar
  12. 12.
    V. A. Levin, P. M. Kabra, and M. A. Freeman-Dove. Relationship of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-P-chloroethyO-S-cyclohexyl-1-nitrosourea (CCNU) pharmacokinetics to uptake, distribution, and tissue/plasma partitioning in rat organs and intracerebral tumors.Cancer Chemother. Pharmacol. 1:233–242 (1978).PubMedGoogle Scholar
  13. 13.
    V. A. Levin and M. Chadwick. Distribution of 5-fluorouracil-2-14C and its metabolites in a murine glioma.J. Natl. Cancer Inst. 49:1577–1584 (1972).PubMedGoogle Scholar
  14. 14.
    V. A. Levin, M. A. Freeman-Dove, and C. E. Maroten. Dianhydrogalactitol (NCS-132313) pharmacokinetics in normal and tumor bearing rat brain and antitumor activity against three intracerebral rodent tumors.J. Natl. Cancer Inst. 56:535–539 (1976).PubMedGoogle Scholar
  15. 15.
    P. A. Harris and J. F. Gross. Preliminary pharmacokinetic model for adriamycin.Cancer Chemother. Rep. 59:819–825 (1975).PubMedGoogle Scholar
  16. 16.
    P. G. W. Plagemann, R. Marz, and R. M. Wohlhueter. Transport and metabolism of deoxycytidine and 1-3-d-arabino-furanosyl-cytosine into cultured Novikoff rat hepatoma cells, relationship to phosphorylation, and regulation of triphosphate synthesis.Cancer Res. 38:978–989 (1978).PubMedGoogle Scholar
  17. 17.
    V. A. Levin, M. A. Freeman-Dove, and H. D. Landahl. The permeability characteristics of the brain adjacent to intracerebral rodent tumors.Arch. Neurol. 32:785–791 (1975).PubMedCrossRefGoogle Scholar
  18. 18.
    R. G. Blasberg, C. S. Patlak, W. R. Shapiro, and J. D. Fenstermacher. Metastatic brain tumors: Local blood flow and capillary permeability.Neurology (Minneapolis) 29:547 (1979) (abstr.).CrossRefGoogle Scholar
  19. 19.
    N. A. Vick and D. Bigner. Microvascular abnormalities in virally induced canine brain tumors.J. Neurol. Sci. 17:29–39 (1972).PubMedCrossRefGoogle Scholar
  20. 20.
    V. A. Levin, D. C. Wright, H. D. Landahl, C. S. Patlak, and J. Csejtey.In situ drug delivery.Br. J. Cancer 41:74–78 (1980) (Suppl. IV).Google Scholar
  21. 21.
    A. Krogh.The Anatomy and Physiology of Capillaries, Yale University Press, New Haven, 1929.CrossRefGoogle Scholar
  22. 22.
    D. G. Levitt. Theoretical model of capillary exchange incorporating interaction between capillaries.Am. J. Physiol. 220:250–255 (1972).Google Scholar
  23. 23.
    P. M. Gullimo and F. M. Grantham. Studies on the exchange of fluids between host and tumor. II. Blood flow studies of hepatomas and other tumors in rats and mice.J. Natl. Cancer. Inst. 27:1465–1491 (1960).Google Scholar
  24. 24.
    E. Siracka, N. Poppova, V. Pipa, and J. Durkovsky. Changes in blood flow of growing experimental tumor determined by the clearance of133Xe.Neoplasma 26:173–177 (1979).PubMedGoogle Scholar
  25. 25.
    J. D. Weinstein, F. J. Toy, M. E. Jaffe, and H. I. Goldgerg. The effects of dexamethasone on brain edema in patients with metastatic brain tumors.Neurology (Minneapolis) 23:121–129 (1973).CrossRefGoogle Scholar
  26. 26.
    D. Norman, W. Berninger, D. Boyd, V. A. Levin, and T. H. Newton. Dynamic computed tomography. Presented at the XIth Symposium Neuroradiologicum, 4–10 June, 1978, Wiesbaden, West Germany (abstr.).Google Scholar
  27. 27.
    K. T. Wheeler, E. F. Tel, M. E. Williams, S. Sheppard, V. A. Levin, and P. M. Kabra. Factors influencing the survival of rat brain tumor cells afterin vitro treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea.Cancer Res. 35:1464–1469 (1975).PubMedGoogle Scholar
  28. 28.
    V. A. Levin, J. Stearns, A. Byrd, A. Finn, and R. J. Weinkam. The effect of phenobarbital pretreatment on the antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU), and on the plasma pharmacokinetics and bio-transformation of BCNU.J. Pharmacol. Exp. Ther. 208:1–7 (1979).PubMedGoogle Scholar
  29. 29.
    R. J. Weinkam, T.-Y. Liu, and H.-S. Lin. Protein mediated chemical reactions of chloroethylnitrosoureas.Chem. Biol. Interact. (in press).Google Scholar
  30. 30.
    M. R. Rosenblum, K. T. Wheeler, C. B. Wilson, M. Barker, and K. D. Knebel.In vitro evaluation ofin vivo brain tumor chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea.Cancer Res. 35:1387–1391 (1975).PubMedGoogle Scholar
  31. 31.
    V. A. Levin, K. T. Wheeler, and C. B. Wilson. Chemotherapeutic approaches to brain tumors: Clinical and experimental observations with dianhydrogaiactitol and dibromodulcitol.Cancer Treat. Rep. (in press).Google Scholar
  32. 32.
    P. Espana, P. H. Wiernik, and M. D. Walker. Phase II study of dianhydrogaiactitol in malignant glioma.Cancer Chemother. Rep. 62:1199–1200 (1978).Google Scholar
  33. 33.
    J. I. Ausman, V. A. Levin, W. E. Brown, D. P. Rall, and J. D. Fenstermacher. Brain tumor chemotherapy: Pharmacologic principles derived from a monkey tumor model.J. Neurosurg. 46:155–164 (1977).PubMedCrossRefGoogle Scholar
  34. 34.
    M. G. Donelli, M. Broggini, T. Colombo, and S. Garattini. Importance of the presence of necrosis in studying drug distribution within a tumor tissue.Ear. J. Drug Metabol. Pharmacokin. 2:63–67 (1977).CrossRefGoogle Scholar
  35. 35.
    R. J. Goldacre. Viable tumor regions accessible to chemotherapeutic agents and a possible new strategy for inactivating them.Br. J. Cancer 36:406 (1977).Google Scholar
  36. 36.
    V. A. Levin. Relationship of octanal/water partition coefficients and molecular weight to rat brain capillary permeability.J. Med. Chem. 23:682–684 (1980).PubMedCrossRefGoogle Scholar
  37. 37.
    I. F. Tannock. The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumor.Br. J. Cancer 22:258–273 (1968).PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    H. S. Carslaw and J. C. Jaeger,Conduction of Heat in Solids, 2nd ed., Oxford University Press, New York, 1959, pp. 63, 247.Google Scholar
  39. 39.
    T. Hoshino, C. B. Wilson, M. L. Rosenblum, and M. Barker. Chemotherapeutic implication of growth fraction and cell cycle time in glioblastoma.J. Neurosurg. 43:127–137 (1975).PubMedCrossRefGoogle Scholar
  40. 40.
    N. A. Lassen and W. A. Perl.Tracer Kinetic Methods in Medical Physiology. Raven Press, New York, 1979.Google Scholar
  41. 41.
    J. J. Blum. Concentration profiles in and around capillaries.Am. J. Physiol. 198:991–998 (1960).PubMedGoogle Scholar
  42. 42.
    S. Kety. The theory and application of the exchange of inert gas at the lungs and tissues.Pharmacol. Rev. 3:1–41 (1951).PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1980

Authors and Affiliations

  • Victor A. Levin
    • 1
  • Clifford S. Patlak
    • 2
  • Herbert D. Landahl
    • 3
  1. 1.Brain Tumor Research Center, Department of Neurological Surgery, and the Departments of Neurology and Pharmaceutical Chemistry, Schools of Medicine and PharmacyUniversity of CaliforniaSan Francisco
  2. 2.Theoretical Statistics and Mathematics BranchNational Institute of Mental Health, National Institutes of HealthBethesda
  3. 3.Department of Biophysics and Biomathematics, School of MedicineUniversity of CaliforniaSan Francisco

Personalised recommendations