While various treatment approaches for cancer include reversal of the transformed phenotype, stimulation of immune responses, inhibition of metastatic spread and deprivation of key nutrients, the goal of immunotoxin treatment is the direct killing of malignant cells. Because they are enzymatic proteins that act catalytically to kill cells, bacterial and plant toxins are often employed as the cell-killing component of immunotoxins. Here we provide background information into the structure-function relationships of toxins and discuss how they can be combined with cell-binding antibodies or other ligands to generate immunotoxins.
KeywordsToxicity Leukemia Arginine Disulfide Pseudomonas
Unable to display preview. Download preview PDF.
- Bird RE, Hardman KD, Jacobson JW, Johnson S, Kaufman BM, Lee SM, Lee T, Pope SH, Riordan GS, Whitlow M (1988) Single-chain antigen-binding proteins [published erratum appears in Science 1989 Apr 28;244(4903):409]. Science 242: 423–426Google Scholar
- FitzGerald DJ, Fryling CM, Zdanovsky A, Saelinger CB, Kounnas M. Winkles JA, Strickland D, Leppla S (1995) Pseudomonas exotoxin-mediated selection yields cells with altered expression of low-density lipoprotein receptor-related protein [published erratum appears in J Cell Biol 1995 Aug;130(4):1015]. J Cell Biol 129: 1533–1541CrossRefGoogle Scholar
- Gray GL, Smith DH, Baldridge JS, Harkins RN, Vasil ML, Chen EY, Heyneker HL (1984) Cloning, nucleotide sequence, and expression in E. coli of the exotoxin a structural gene of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 81: 2645–2649Google Scholar
- Huston JS, Levinson D, Mudgett HM, Tai MS, Novotny J, Margolies MN, Ridge RJ, Bruccoleri RE, Haber E, Crea R et al (1988) Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci USA 85: 5879–5883PubMedCrossRefGoogle Scholar
- Lambert JM, McIntyre G, Gauthier N, Zullo D, Rao V, Steeves RM, Goldmacher VS, Blattler WA (1991) The galactose-binding sites of the cytotoxic lectin ricin can be chemically blocked in high yields with reactive ligands prepared by chemical modification of glycopeptides containing triantennary N-linked oligosaccharides. Biochemistry 30: 3234–3247PubMedCrossRefGoogle Scholar
- Li M, Dyda F, Benhar I, Pastan I, Davies DR (1996) Crystal structure of the catalytic domain of Pseudomonas exotoxin A complexed with a nicotinamide adenine dinucleotide analog: implications for the activation process and for ADP ribosylation. Proc Natl Acad Sci USA 93: 6902–6906PubMedCrossRefGoogle Scholar
- Reiter Y, Brinkmann U, Webber KO, Jung SH, Lee B, Pastan I (1994b) Engineering interchain disulfide bonds into conserved framework regions of Fv fragments: improved biochemical characteristics of recombinant immunotoxins containing disulfide-stabilized Fv. Protein Eng 7: 697–704PubMedCrossRefGoogle Scholar
- Ryser HJ, Mandel R, Ghani F (1991) Cell surface sulthydryls are required for the cytotoxicity of diphtheria toxin but not of ricin in Chinese hamster ovary cells. J Biol Chem 266:1 843 9–1 8442Google Scholar