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September 1977, Vol 34, No. 9 >
Article | September 1977

Chemotherapy of Brain Tumors: Title and subTitle BreakThe "Blood-Brain Barrier" Is Not a Factor

Nicholas A. Vick, MD; Janardan D. Khandekar, MD; Darell D. Bigner, MD
Arch Neurol. 1977;34(9):523-526. doi:10.1001/archneur.1977.00500210025002
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Brain tumors are not rare. In the United States, nearly 11,000 new patients were seen in 1976.1 This number can be expected to increase as systemic cancers are controlled more effectively and as longevity is prolonged. Most patients with primary or metastatic brain tumors are treated by surgery, glucocorticoid "decompression," radiotherapy, or chemotherapy—alone or in various combinations. The therapeutic yield from surgery alone has reached its zenith. While radiotherapy prolongs survival, and radiosensitizers such as metronidazole may add to its efficacy,2,3 it seems likely that further advances in the treatment of brain tumors will come from chemotherapy. To date, chemotherapy of brain tumors has been disappointing, to say the least.

Most oncologists assume that to be useful for brain tumor chemotherapy a drug must be lipid soluble, be unionized at physiologic pH, and be of relatively small molecular size in order to enter the brain from the

REFERENCES

1 +
Seidman H, Silverberg E, Holleb AI:  Cancer statistics, 1976: A comparison of white and black populations . CA 26:2-29, 1976;.
2 +
Goldsmith MA, Carter SK:  Glioblastoma multiforme—A review of therapy . Cancer Treat Rev 1:153-165, 1974;.
3 +
Urtasun R, Band P, Chapman JD, et al:  Radiation and high-dose metronidazole in supratentorial glioblastomas . N Engl J Med 294:1364-1367, 1976;.
4 +
Oldendorf WH:  Transport of drugs across the blood-brain barrier . Annu Rev Pharmacol 14:239, 1974;.
5 +
Nystrom S:  Pathological changes in blood vessels of human glioblastoma multiforme: Comparative studies using plastic casings, angiography, light microscopy, and with reference to some other brain tumors . Acta Pathol Microbiol Scand , (suppl 137) , 1960;.
6 +
Brightman MW, Reese TS, Vick NA, et al:  A mechanism underlying the lack of a blood-brain barrier to peroxidase in virally induced brain tumors . J Neuropathol Exp Neurol 30:139-140, 1971;.
7 +
Vick NA, Bigner DD:  Microvascular abnormalities in virally-induced canine brain tumors: Structural bases for altered blood-brain barrier function . J Neurol Sci 17:29-39, 1972;.
8 +
Peters A, Palay SL, Webster HdeF: The Fine Structure of the Nervous System: The Neurons and Supporting Cells . Philadelphia, WB Saunders Co, 1976;.
9 +
Broder LE, Rall DP:  Chemotherapy of brain tumors . Prog Exp Tumor Res 17:373-399, 1972;.
10 +
Yung WK, Blank NK, Vick NA:  "Glioblastoma": Induction of a reproducible autochthonous tumor in rats with murine sarcoma virus . Neurology 26:76-83, 1976;.
11 +
Hirano A, Matsui T:  Vascular structures in brain tumors . Hum Pathol 6:611-621, 1975;.
12 +
Waggener D, Beggs JL:  Vasculature of neural neoplasms . Adv Neurol 15:27-49, 1976;.
13 +
Levin VA, Shapiro WR, Clancy TP, et al:  Uptake, distribution, and antitumor activity of CCNU in the murine ependymoblastoma . Cancer Res 30:2451-2455, 1970;.
14 +
Levin VA, Clancy TP, Ausman JI, et al:  The uptake and distribution of 3H-methotrexate by the murine ependymoblastoma . J Natl Cancer Inst 48:875-883, 1972;.
15 +
Levin VA, Kabra P:  Effectiveness of the nitrosureas as a function of their lipid solubility in the chemotherapy of experimental rat brain tumors . Cancer Chemother Rep 58:787-792, 1974;.
16 +
Levin VA, Freeman-Dove MA, Landahl HD:  Permeability characteristics of brain adjacent to tumors in rats . Arch Neurol 32:785-791, 1975;.
17 +
Levin VA, Landahl HD, Freeman-Dove, MA:  The application of brain capillary permeability coefficient measurements to pathological conditions and the selection of agents which cross the blood-brain barrier . J Pharmacokinetics Biopharmaceutics 4:499-519, 1976;.
18 +
Hoshino TB, Wilson CB, Ellis WG:  Gemistocytic astrocytes in gliomas . J Neuropathol Exp Neurol 34:263-281, 1975;.
19 +
Bourke RS, West CR, Chheda G, et al:  Kinetics of entry and distribution of 5-fluorouracil in cerebrospinal fluid and brain following intravenous injection in a primate . Cancer Res 33:1735-1746, 1973;.
20 +
Levin VA, Chadwick M:  Distribution of 5-fluorouracil-2 -14c and its metabolites in a murine gliomas . J Natl Cancer Inst 49:1577-1584, 1972;.
21 +
Tator CH:  The uptake of tritiated methotrexate by an experimental glioma . Cancer Res 31:1600-1605, 1971;.
22 +
Tator CH:  Chemotherapy of brain tumors: Uptake of tritiated methotrexate by a transplantable intracerebral ependymoblastoma in mice . J Neurosurg 37:1-8, 1972;.
23 +
Ushio Y, Hayakawa T, Mogami H:  Uptake of triated methotrexate by mouse brain tumors after intrathecal administration . J Neurosurg 40:706, 1974;.
24 +
Ho DHW:  Clinical pharmacology of 1-B-D-arabinofuranosylcytosine . Clin Pharmacol Ther 12:944-954, 1971;.
25 +
Mihich E:  Pharmacologic principles and the basis for selectivity of drug action , in Holland JF, Frei E (eds): Cancer Medicine . Philadelphia, Lea & Febiger, 1973;, pp 357-370.
26 +
Ushio Y, Posner J, Shapiro W:  Chemotherapy of experimental meningeal carcinomatosis . Cancer Res 37:1232-1237, 1977;.
27 +
Gershwin ME, Goetzl EJ, Steinberg AD:  Cyclophosphamide: Use in practice . Ann Intern Med 80:531-540, 1974;.
28 +
Walker MD, Strike TA:  An evaluation of methyl CCNU, BCNU, and radiotherapy in the treatment of malignant glioma . Proc Am Assoc Cancer Res 17:163, 1976;.
29 +
Bigner DD, Self DJ, Frey J, et al:  Refinement of the avian oncornavirus-induced primary rat brain tumor model for therapeutic screening , in Hekmatpanah J (ed): Gliomas . Recent Results in Cancer Research, Berlin, Springer-Verlag, 1975;, vol 51, pp 20-34.
30 +
Volpe JJ, Fujimoto K, Marasa JC, et al:  Relation of C-6 glial cells in culture to myelin . Biochem J 152:701-703, 1975;.
31 +
Pfeiffer SE, Wechsler W:  Biochemically differentiated neoplastic clone of Schwann cells . Proc Natl Acad Sci USA 69:2885-2889, 1972;.
32 +
Folkman J:  Tumor angiogenesis: A possible central point in tumor growth . Ann Intern Med 82:96-100, 1975;.
33 +
Simpson-Herren L, Sanford AH, Holmquist JP:  Cell population kinetics of transplanted and metastatic Lewis lung carcinoma . Cell Tissue Kinet 7:349-361, 1974;.
34 +
Bigner DD, Swenberg JA: Janisch and Schreibers Experimental Tumors of the Central Nervous System ed 1. Kalamazoo, WE Upjohn Co, 1977;.

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1 +
Seidman H, Silverberg E, Holleb AI:  Cancer statistics, 1976: A comparison of white and black populations . CA 26:2-29, 1976;.
2 +
Goldsmith MA, Carter SK:  Glioblastoma multiforme—A review of therapy . Cancer Treat Rev 1:153-165, 1974;.
3 +
Urtasun R, Band P, Chapman JD, et al:  Radiation and high-dose metronidazole in supratentorial glioblastomas . N Engl J Med 294:1364-1367, 1976;.
4 +
Oldendorf WH:  Transport of drugs across the blood-brain barrier . Annu Rev Pharmacol 14:239, 1974;.
5 +
Nystrom S:  Pathological changes in blood vessels of human glioblastoma multiforme: Comparative studies using plastic casings, angiography, light microscopy, and with reference to some other brain tumors . Acta Pathol Microbiol Scand , (suppl 137) , 1960;.
6 +
Brightman MW, Reese TS, Vick NA, et al:  A mechanism underlying the lack of a blood-brain barrier to peroxidase in virally induced brain tumors . J Neuropathol Exp Neurol 30:139-140, 1971;.
7 +
Vick NA, Bigner DD:  Microvascular abnormalities in virally-induced canine brain tumors: Structural bases for altered blood-brain barrier function . J Neurol Sci 17:29-39, 1972;.
8 +
Peters A, Palay SL, Webster HdeF: The Fine Structure of the Nervous System: The Neurons and Supporting Cells . Philadelphia, WB Saunders Co, 1976;.
9 +
Broder LE, Rall DP:  Chemotherapy of brain tumors . Prog Exp Tumor Res 17:373-399, 1972;.
10 +
Yung WK, Blank NK, Vick NA:  "Glioblastoma": Induction of a reproducible autochthonous tumor in rats with murine sarcoma virus . Neurology 26:76-83, 1976;.
11 +
Hirano A, Matsui T:  Vascular structures in brain tumors . Hum Pathol 6:611-621, 1975;.
12 +
Waggener D, Beggs JL:  Vasculature of neural neoplasms . Adv Neurol 15:27-49, 1976;.
13 +
Levin VA, Shapiro WR, Clancy TP, et al:  Uptake, distribution, and antitumor activity of CCNU in the murine ependymoblastoma . Cancer Res 30:2451-2455, 1970;.
14 +
Levin VA, Clancy TP, Ausman JI, et al:  The uptake and distribution of 3H-methotrexate by the murine ependymoblastoma . J Natl Cancer Inst 48:875-883, 1972;.
15 +
Levin VA, Kabra P:  Effectiveness of the nitrosureas as a function of their lipid solubility in the chemotherapy of experimental rat brain tumors . Cancer Chemother Rep 58:787-792, 1974;.
16 +
Levin VA, Freeman-Dove MA, Landahl HD:  Permeability characteristics of brain adjacent to tumors in rats . Arch Neurol 32:785-791, 1975;.
17 +
Levin VA, Landahl HD, Freeman-Dove, MA:  The application of brain capillary permeability coefficient measurements to pathological conditions and the selection of agents which cross the blood-brain barrier . J Pharmacokinetics Biopharmaceutics 4:499-519, 1976;.
18 +
Hoshino TB, Wilson CB, Ellis WG:  Gemistocytic astrocytes in gliomas . J Neuropathol Exp Neurol 34:263-281, 1975;.
19 +
Bourke RS, West CR, Chheda G, et al:  Kinetics of entry and distribution of 5-fluorouracil in cerebrospinal fluid and brain following intravenous injection in a primate . Cancer Res 33:1735-1746, 1973;.
20 +
Levin VA, Chadwick M:  Distribution of 5-fluorouracil-2 -14c and its metabolites in a murine gliomas . J Natl Cancer Inst 49:1577-1584, 1972;.
21 +
Tator CH:  The uptake of tritiated methotrexate by an experimental glioma . Cancer Res 31:1600-1605, 1971;.
22 +
Tator CH:  Chemotherapy of brain tumors: Uptake of tritiated methotrexate by a transplantable intracerebral ependymoblastoma in mice . J Neurosurg 37:1-8, 1972;.
23 +
Ushio Y, Hayakawa T, Mogami H:  Uptake of triated methotrexate by mouse brain tumors after intrathecal administration . J Neurosurg 40:706, 1974;.
24 +
Ho DHW:  Clinical pharmacology of 1-B-D-arabinofuranosylcytosine . Clin Pharmacol Ther 12:944-954, 1971;.
25 +
Mihich E:  Pharmacologic principles and the basis for selectivity of drug action , in Holland JF, Frei E (eds): Cancer Medicine . Philadelphia, Lea & Febiger, 1973;, pp 357-370.
26 +
Ushio Y, Posner J, Shapiro W:  Chemotherapy of experimental meningeal carcinomatosis . Cancer Res 37:1232-1237, 1977;.
27 +
Gershwin ME, Goetzl EJ, Steinberg AD:  Cyclophosphamide: Use in practice . Ann Intern Med 80:531-540, 1974;.
28 +
Walker MD, Strike TA:  An evaluation of methyl CCNU, BCNU, and radiotherapy in the treatment of malignant glioma . Proc Am Assoc Cancer Res 17:163, 1976;.
29 +
Bigner DD, Self DJ, Frey J, et al:  Refinement of the avian oncornavirus-induced primary rat brain tumor model for therapeutic screening , in Hekmatpanah J (ed): Gliomas . Recent Results in Cancer Research, Berlin, Springer-Verlag, 1975;, vol 51, pp 20-34.
30 +
Volpe JJ, Fujimoto K, Marasa JC, et al:  Relation of C-6 glial cells in culture to myelin . Biochem J 152:701-703, 1975;.
31 +
Pfeiffer SE, Wechsler W:  Biochemically differentiated neoplastic clone of Schwann cells . Proc Natl Acad Sci USA 69:2885-2889, 1972;.
32 +
Folkman J:  Tumor angiogenesis: A possible central point in tumor growth . Ann Intern Med 82:96-100, 1975;.
33 +
Simpson-Herren L, Sanford AH, Holmquist JP:  Cell population kinetics of transplanted and metastatic Lewis lung carcinoma . Cell Tissue Kinet 7:349-361, 1974;.
34 +
Bigner DD, Swenberg JA: Janisch and Schreibers Experimental Tumors of the Central Nervous System ed 1. Kalamazoo, WE Upjohn Co, 1977;.

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