Selective Killing of IL6 Receptor Bearing Myeloma Cells Using Recombinant IL6-Pseudomonas Toxin

  • Clay B. Siegall
  • David J. FitzGerald
  • Ira Pastan
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 166)

Abstract

Chemotherapy is widely used in the treatment of human cancer but unfortunately is not successful against many cancers and has undesirable side effects. If the chemotherapeutic agent was only delivered to the tumor cell, it should be possible to eliminate cancer cells without killing normal cell populations. Recently, a new field has emerged which addresses the possibility that one can selectively eliminate malignant cell populations. This new discipline takes advantage of the fact that many cancer cells display higher numbers of growth factor receptor on their surface than normal cells. By taking advantage of this increase, one can target these receptors with cytotoxic reagents such as protein toxins. These reagents are cytotoxic to target cells because a receptor specific ligand is linked to a potent toxin (reviewed in Pastan 1986; Vitetta 1987; FitzGerald and Pastan 1989). In this review, we will describe specific reagents which can target and kill multiple myeloma cells.

Keywords

Clay Toxicity Filtration Carboxyl Interferon 

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References

  1. Allured V, Collier RJ, Carroll SF, McKay DB (1986) Structure of exotoxin A of Pseudomonas aeruginosa at 3.0-angstrom resolution. Proc Natl Acad Sci USA 83:1320–1324PubMedCrossRefGoogle Scholar
  2. Asaoku H, Kawano M, Iwato K, Tanabe O, Tanaka H, Hirano T, Kishimoto T, Kuramoto A (1988) Decrease in BSF-2/IL-6 response in advance cases of multiple myeloma. Blood 72:429–432PubMedGoogle Scholar
  3. Chaudhary VK, Jinno Y, FitzGerald D, Pastan I (1990) Pseudomonas exotoxin contains a specific sequence at the carboxyl terminus that is required for cytotoxicity. Proc Natl Acad Sci USA 87:308–312PubMedCrossRefGoogle Scholar
  4. Chaudhary VK, Jinno Y, Gallo MG, FitzGerald D, Pastan I (1990) Sequences responsible for the animal toxicity of pseudomonas exotoxin. (submitted) FitzGerald D, Pastan I (1989) Targeted toxin therapy for the treatment of cancer. J Natl Cancer Inst 81:1455–1463Google Scholar
  5. Gauldie J, Richards C, Harnish D, Landsdorp P, Baumann H (1987) Interferon β2/B-cell stimulating factor type 2 shares identity with monocyte-derivedPubMedCrossRefGoogle Scholar
  6. hepatocyte-stimulating factor and regulates the major acute phase protein responsive in liver cells. Proc Natl Acad Sci USA 84:7251–7255PubMedCrossRefGoogle Scholar
  7. Hirano T, Yasukawa K, Hirada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwanatu A, Tsunaswa S, Sakiyama F, Matsui H, Takahara Y, Taniguchi T, Kishimoto T (1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76PubMedCrossRefGoogle Scholar
  8. Hwang J, FitzGerald DJ, Adhya S, Pastan I (1987) Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli. Cell 48:129–136PubMedCrossRefGoogle Scholar
  9. Jinno Y, Chaudhary VK, Kondo T, Adhya S, FitzGerald DJ, Pastan I (1988) Mutational analysis of domain I of Pseudomonas exotoxin which reduce cell binding and animal toxicity. J Biol Chem 263:13203–13207PubMedGoogle Scholar
  10. Jinno Y, Ogata M, Chaudhary VK, Willingham MC, Adhya S, FitzGerald D, Pastan I (1989) Domain II mutants of Pseudomonas exotoxin deficient in trans-location. J Biol Chem 264:15953–15959PubMedGoogle Scholar
  11. Kondo T, FitzGerald D, Chaudhary VK, Adhya S, Pastan I (1988) Activity of immunotoxins constructed with modified Pseudomonas exotoxin A lacking the cell recognition domain. J Biol Chem 263:9470–9475PubMedGoogle Scholar
  12. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanaba O, Tanaka H, Kuramoto A, Kishimoto T (1988) Autocrine generation and requirement of BSF-2/IL6 for human multiple myeloma. Nature 332:83–85PubMedCrossRefGoogle Scholar
  13. Nordan RP, Potter M (1986) A macrophage-derived factor required by plasmacytomas for survival and proliferation in vitro. Science 233:566–569PubMedCrossRefGoogle Scholar
  14. Pastan I, Willingham MC, FitzGerald DJ (1986) Immunotoxins. Cell 47:641– 648PubMedCrossRefGoogle Scholar
  15. Pastan I, FitzGerald D (1989) Pseudomonas exotoxin: chimeric toxins. J Biol Chem 264:15157–15160PubMedGoogle Scholar
  16. Schwab G, Siegall CB, Aarden LA, Neckers LM, Nordan RP (1990) Characterization of an interleukin-6 mediated autocrine growth loop in the human multiple myeloma cell line, U266. (submitted)Google Scholar
  17. Siegall CB, Chaudhary VK, FitzGerald DJ, Pastan I (1988) Cytotoxic activity of an interleukin 6-Pseudomonas exotoxin fusion protein on human myeloma cells. Proc Natl Acad Sci USA 85:9738–9742PubMedCrossRefGoogle Scholar
  18. Siegall CB, Nordan RP, FitzGerald DJ, Pastan I (1990) Cell-specific toxicity of a chimeric protein composed of interleukin-6 and Pseudomonas exotoxin (IL6-PE40) on tumor cells. Mol Cell Biol (in press)Google Scholar
  19. Siegall CB, FitzGerald DJ, Pastan I (1990) Cytotoxicity of IL6-PE40 and derivatives on tumor cells expressing a range of IL6 receptor levels (submitted)Google Scholar
  20. Studier FW, Moffatt BA (1986) Use of bacteriophage T7 RNA polymerase to direct selective high level expression of cloned genes. J Mol Biol 189:113–130PubMedCrossRefGoogle Scholar
  21. Taga T, Kawanishi K, Hardy RR, Hirano T, Kishimoto T (1987) Receptors for B cell stimulatory factor 2: quantitation, specificity, distribution and regulation of their expression. J Exp Med 166:967–981PubMedCrossRefGoogle Scholar
  22. Van Snick JA, Vink S, Cayphas S, Uyttenhove C (1987) Interleukin-HP1, a T cell-derived hybridoma growth factor that supports the in vitro growth of murine plasmacytomas. J Exp Med 165:641–649PubMedCrossRefGoogle Scholar
  23. Vitteta ES, Fulton RJ, May RD, Till M, Uhr JW (1987) Redesigning natures poisons to create anti-tumor reagents. Science 238:1098–1104CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • Clay B. Siegall
    • 1
  • David J. FitzGerald
    • 1
  • Ira Pastan
    • 1
  1. 1.Laboratory of Molecular Biology, Division of Cancer Biology and Diagnosis and CentersNational Cancer Institute, National Institutes of Health BethesdaUSA

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