Summary
Phase I and phase II clinical studies of interferon (IFN) were conducted in malignant brain tumours (47 cases of glioblastoma, medulloblastoma and others) using three preparations of the drug. The drug was administered daily in doses 3.0 − 9.0 × 106 I.U. locally or intravenously (β-type) or intramuscularly (α-type). The administration was continued as many days as possible, eight weeks being the shortest period. The efficacy of the therapy was assessed mainly by the CT findings (computed volume of the tumour).
As for efficacy against glioblastomas, the highest effectiveness rate (40%) was obtained with Human Fibroblast IFN (HFIF) (β-type) (Toray) (one case of complete remission and seven cases of partial remission out of 20 cases) as compared to Human Lymphoblastoid IFN (HLBI) (αa-type) (Wellcome) (one case of partial remission out of three cases) and recombinant IFN (rIFN-αA) (α-type) (Roche) (two cases of partial remission out of nine cases). The high rate of responsiveness of HFIF seems to be largely attributable to the local, rather than systemic, administration of the drug. Our pharmacokinetic study revealed that, by means of intrathecal administration a much higher IFN titre was detected in the cerebrospinal fluid, while by intravenous or intramuscular route, the IFN titre in the CSF was undetectably low. The generally lower incidence of side-effects with HFIF compared to other preparations was also largely ascribable to the route of administration. IFN therapy in combination with radiotherapy and/or chemotherapy should also be investigated.
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Ball, L. A.: Induction, purification, and properties of 2′5′-oligoadenylate synthetase. Ann. N. Y. Acad. Sci. 350 (1980) 486–496
Billiau, A., P. De Somer, V. G. Edy, E. De Clercq, H. Heremans: Human fibroblast interferon for clinical trials: Pharmacokinetics and tolerability in experimental animals and humans. Antimicrob. Agents Chemother. 16 (1979) 56–63
Blalock, J. E., J. A. Georgiades, M. P. Langford, H. M. Johnson: Purified human immune interferon has more potent anticellular activity than fibroblast or leucocyte interferon. Cell. Immunol., 49 (1980) 390–394
Blomgren, H., K. Cantell, B. Johansson, C. Lagergren, U. Ringborg, H. Strander: Interferon therapy in Hodgkin's disease. Acta Med. Scand. 199 (1976) 527–532
Borden, E., T. Dao, J. Holland, J. Gutterman, T. Merigan: Interferon in recurrent breast carcinoma: preliminary report of the American Cancer Society clinical trials program. Proc. Am. Assoc. Cancer Res. Abstr., 750, 1980
Boëtius, J., H. Blomgren, V. P. Collins, T. Greitz, H. Strander: The effect of systemic human interferonalpha administration to patients with glioblastoma multiforme. Acta Neurochir. 68 (1983) 239–251
Cathala, F., S. Baron: Interferon in rabbit brain, cerebrospinal fluid and serum following administration of polyinosinic-polycytidylic acid. J. Immunol. 104 (1970) 1355–1358
Cook, A. W., W. A. Carter, F. Nidzgorski, L. Akhtar: Human brain tumor-derived cell lines: Growth rate reduced by human fibroblast interferon. Science 18. Febr. (1983) 881–883
De Clercq, E., V. G. Edy, H. Vlieger, R. Eckels, J. Desmyter: Intrathecal administration of interferon in neonatal herpes. J. Pediatr. 86 (1975) 736–739
Donahoe, R. M., K. Huang: Interferon preparations enhance phagocytosis in vivo. Infect. Immun. 13 (1976) 1250–1257
Einhorn, S., H. Blomgren, H. Strander: Interferon and spontaneous cytotoxicity in man. II. Studies in patients receiving exogenous leucocyte interferon. Acta Med. Scand. 204 (1978) 477–483
Emödi, G., J. R. Hernandez, H. R. Hirt: Circulating interferon in man after administration of exogenous human leucocyte interferon. J. Natl. Cancer Inst. 54 (1975) 1045–1049
Feun, L., J. Gutterman, J. Quesada, D. Stewart, M. Leavens, M. A. Burgess, R. S. Benjamin: Phase I study of interferon administered via indwelling Ommaya reservoir for the treatment of progressive malignant gliomas. Abstr. of 13th Internatl. Cancer Congr. No. 963, Sheattle 1982
Fleischmann, Jr., W. R., K. M. Kleyn, S. Baron: Potentiation of antitumour effect of virus-induced interferon by mouse immune interferon preparations. J. Natl. Cancer Inst. 65 (1980) 963–966
Gidlund, M., A. Oern, H. Wigzell, A. Senik, I. Gresser: Enhanced NK cell activity in mice injected with interferon and interferon inducers. Nature 273 (1978) 759–761
Gresser, I., C. Bourali, J. P. Levy, D. F. Brouty-Boye, M. T. Thomas: Increased survival in mice inoculated with tumour cells and treated with interferon preparations. Proc. Natl. Acad. Sci. 63 (1969) 51–57
Gresser, I.: Antitumour effects of interferon. Adv. Cancer Res. 16 (1972) 97–140
Gresser, I., M. G. Tovey: Antitumour effects of interferon. Biochem. Biophys. Acta 516 (1978) 231–247
Gutterman, J. U., G. R. Blumenschein, R. Alexanian, H. Y. Yap, A. U. Buzdar: Leucocyte interferoninduced tumour regression in human metastatic breast cancer, multiple myeloma, and malignant lymphoma. Ann. Intern. Med., 93 (1980) 399–406
Gutterman, J. U., S. Fine, J. Quesada, S. J. Horning, J. F. Levine, R. Alexanian, L. Bernhardt, M. Kramer, H. Spiegel, W. Colburn, P. Troen, T. Merigan, Z. Sziewanowski: Recombinant leucocyte A Interferon: Pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann. Int. Med. 96 (1982) 549–556
Gutterman, J., J. Quesada: Clinical investigation of partially pure and recombinant DNA derived leucocyte interferon in human cancer. Texas Rep. Biol. Med. 41 (1982) 626–633
Habif, D. V., R. Lipton, K. Cantell: Interferon crosses blood-cerebrospinal fluid barrier in monkeys. Proc. Soc. Exp. Biol. Med. 149 (1975) 287–289
Hanley, D. F., M. Wiranowska-Stewart, W. E. Stewart II: Pharmacology of interferon I. Pharmacologic distinctions between human leucocyte and fibroblast interferons. Int. J. Immunopharmacol. 1 (1979) 219–226
Hill, N. O., E. Loeb, A. S. Pardue, G. L. Dorn, A. Khan, M. Hill: Response of acute leukemia to leucocyte interferon. J. Clin. Hematol. Oncol. 9 (1979) 137–149
Hill, N. O., A. Pardue, A. Khan, C. Aleman, R. Hilario, J. M. Hill: Clinical trials of human leucocyte interferon in malignancy. Texas Rep. Biol. Med. 41 (1982) 634–640
Hirakawa, K., S. Ueda, Y. Nakagawa, K. Suzuki, S. Fukuma, M. Kita, J. Imanishi, T. Kishida: Effect of human leucocyte interferon on malignant brain tumours. Cancer 51 (1983) 1976–1981
Ho, M., C. Nash, C. W. Morgan, J. A. Armstrong, R. G. Carroll, B. Postic: Interferon administered in the cerebrospinal space and its effect on rabies in rabbits. Infect. Immun. 9 (1974) 286–293
Horning, S. J., J. F. Levine, R. A. Miller, S. A. Rosenberg, T. C. Merigan: Clinical and immunologic effects of recombinant leucocyte A interferon in eight patients with advanced cancer. JAMA 247 (1982) 1718–1722
Horoszewitz, J. S., S. S. Leong, M. Ito, R. F. Buffett, C. Karakousis, E. Holyode: Human fibroblast interferon in human neoplasia: Clinical and laboratory study. Cancer Treat. Rep. 62 (1978) 1899–1906
Hovanessian, A. G., J. N. Wood: Anticellular and antiviral effects of pppA (2′5′A) n. Virol. 101 (1980) 81–90
Huddlestone, J. R., T. C. Merigan, M. B. A. Oldstone: Induction and kinetics of natural killer cell in humans following interferon therapy. Nature 282 (1979) 417–419
Ikic, D., J. Krusic, V. Kirhmajer, M. Knezevic, Z. Maricic: Application of human leucocyte interferon in patients with carcinoma of the uterine cervix. Lancet, May 9 (1981) 1027–1030
Isaacs, A., J. Lindenmann: Virus interference. I. The interferon. Proc. Royal Soc., B 147 (1957) 258–267
Isaacs, A., J. Lindenmann, R. C. Valentine: Virus interference. II. Some properties of interferon. Proc. Royal Soc., B 147 (1957) 268–273
Karnovsky, D. A.: Meaningful clinical classification of therapeutic responses to anticancer drugs. Clin. Pharmacol. Therapeut. 2 (1961) 709–712
Kimchi, A., H. Shure, M. Revel: Anti-mitogenic function of interferon-induced (2′-5′)Oligo(adenylate) and growth-related variations in enzymes that synthesize and degrade this oligonucleotide. Eur. J. Biochem. 114 (1981) 5–10
Kohase, M., S. Kohno, S. Yamazaki, A. Shishido, R. Kono: Potency standardization of human interferon preparations for clinical trials. In: Kono, R., J. Vilcek: The clinical potential of interferons Univ. of Tokyo Press, Tokyo (1982) 299–309
Korose, K., I. Takeshita, H. Mannoji, M. Fukui: Interferon effects on multiplication, cytoplasmic protein and GFAP content, and morphology in human glioma cells. J. Neurooncol. 1 (1983) 69–76
Larsson, I., L.-E. Landström, E. Larner, E. Lundgren, H. Miörner, O. Strannegard: Interferon production in glia and glioma cell lines. Infect. Immun. 22 (1978) 786–789
Lundblad, D., E. Lundgren: Block of a glioma cell line in S by interferon. Int. J. Cancer 27 (1981) 749–754
Mellstedt, H., A. Ahre, M. Bjorkholm, G. Holm, B. Johansson, H. Strander: Interferon therapy in myelomatosis. Lancet, Febr. 3 (1979) 245–247
Merigan, T. C.: Pharmacokinetics and side effects of interferon in man. Texas Rep. Biol. Med. 35 (1977) 541–547
Merigan, T. C., K. Sikora, J. H. Breeden, R. Levy, S. A. Rosenberg: Preliminary observations on the effect of human leukocyte interferon in non-Hodgkin's lymphoma. New Engl. J. Med. 299 (1978) 1449–1453
Merlin, G., M. Revel, D. Wallach: The interferoninduced enzyme oligo-isoadenylate synthetase: Rapid determination of its in vitro products. Analyt. Biochem. 110 (1981) 190–196
Mogensen, K. E., Ph. Daubas, I. Gresser, D. Sereni, B. Varet: Patient with circulating antibodies to α-interferon. Lancet, Nor. 28 (1981) 1227
Murphy, G. P.: Current report on the interferon program at Rosewell Park Memorial Institute. J. Surg. Oncol. 17 (1981) 99–111
Nagai, M., T. Arai, S. Kohno, M. Kohase: Interferon therapy for malignant brain tumours. In: Kono. R., J. Vilcek: The clinical potential of interferons, 257–273. Univ. of Tokyo Press, Tokyo 1982
Nagai, M., T. Arai: Interferon as a treatment for malignant brain tumours. Abstr. of 7th Internatl. Congr. of Neurol. Surg. No. 8.8.10. Munich 1981
Nagai, M., T. Arai: Interferon therapy for malignant brain tumors — Present and future —. Neurol. Surg. 10 (1982) 463–476
Nagai, M., T. Arai, S. Kohno, M. Kohase: Local application of interferon to malignant brain tumours. Texas Rep. Biol. Med. 41 (1982) 693–698
Nagai, M., T. Arai, S. Kohno, E. Iizuka: Present state of interferon therapy on malignant brain tumours. Jap. J. Cancer Clin. 29 (1983) 608–615
Niethammer, D., J. Treuner: Pharmacological and therapeutical experience with human interferon-β in malignant tumours in children. Texas Rep. Biol. Med. 41 (1982) 641–645
Nuwer, M. R., E. De Clercq, T. C. Merigan: Interferon clearance rate decreased after repeated injections. J. Gen. Virol. 12 (1971) 191–194
Ommaya, A. K., M. A. Okon, M. B. Punjab: Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. Lancet, 2 (1963) 983–984
Pape, G. R., M. R. Hadam, J. Eisenburg, G. Riethmüller: Kinetics of natural cytotoxicity in patients treated with human fibroblast interferon. Cancer Immunol. Immunother. 11 (1981) 1–6
Paucker, K., K. Cantell, W. Henle: Quantitative studies on viral interference in suspended L cells. III. Effect of interfering viruses and interferon on the growth rate of cells. Virol. 17 (1962) 327–334
Priestman, T. J.: Initial evaluation of human lymphoblastoid interferon in patients with advanced malignant desease. Lancet. July 19 (1980) 113–118
Rubin, B. Y., S. L. Gupta: Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents. Proc. Natl. Acad. Sci. 77 (1980) 5928–5932
Salford, L. G., S. Borgström, J. Brismar, A. Brun, S. Cronqvist: Intratumoral and systemic interferon treatment of astrocytomas grade III-IV. Abstr. of U.S.-Japanese Confer. on Brain Tumor Therapy. Nikko, Japan, (1981)
Senik, A., I. Gresser, C. Naury, M. Gidlund, A. Orn, H. Wigzell: Enhancement by interferon of natural killer cell activity in mice. Cell. Immunol. 44 (1979) 186–200
Schultz, R. M.: Factors limiting tumouricidal function of interferon-induced effector systems — Activated macrophages and natural killer cells. Cancer Immunol. Immunother. 10 (1981) 61–66
Sherwin, S. A., J. A. Knost, S. Fein, P. G. Abrams, K. A. Foon, J. J. Ochs, C. Schoenberger, A. E. Maluish, R. K. Oldham: A multiple-dose phase I trial of recombinant leucocyte A interferon in cancer patients. JAMA 248 (1982) 2461–2466
Strander, H., K. Cantell, G. Carlström, P. A. Jakobsson: Clinical and laboratory investigations on man: Systemic administration of potent interferon to man. J. Natl. Cancer Inst. 51 (1973) 733–742
Strander, H., K. Cantell, P. A. Jakobsson, U. Nilsonne, G. Söderberg: Exogenous interferon therapy of osteogenic sarcoma. Acta Orthop. Scand. 45 (1974) 958–959
Strander, H., S. Einhorn: Effect of human leucocyte interferon on the growth of human osteosarcoma cells in tissue culture. Int. J. Cancer 19 (1977) 468–473
Strander, H.: Interferon therapy of malignant disease. In: Kono, R., J. Vilcek: The clinical potential of interferons (1982) 179–185, Univ. of Tokyo Press, Tokyo
Trinchieri, G., D. Santoli: Anti-viral activity induced by culturing lymphocytes with tumour-derived or virus-transformed cells. Enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis. J. Exp. Med. 147 (1978) 1314–1320
Trinchieri, G., D. Santoli, H. Koprowski: Spontaneous cellmediated cytotoxicity in humans: Role of interferon and immunoglubulins. J. Immunol. 120 (1978) 1849–1855
Vallbracht, A., J. Treuner, B. Flemig, K.-E. Joester, D. Niethammer: Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon. Nature 289 (1981) 496–497
Wood, J. N., A. G. Hovanessian: Interferon enhances 2-5A synthetase in embryonal carcinoma cells. Nature 282 (1979) 74–79
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Nagai, M., Arai, T. Clinical effect of interferon in malignant brain tumours. Neurosurg. Rev. 7, 55–64 (1984). https://doi.org/10.1007/BF01743290
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DOI: https://doi.org/10.1007/BF01743290