Targeted toxin therapy for the treatment of cancer.
Protein toxins such as Pseudomonas exotoxin, diphtheria toxin, and ricin may be useful in cancer therapy because they are among the most potent cell-killing agents. One molecule of a toxin delivered to the cytoplasm of a cancer cell will be lethal for that cell. However, to be therapeutically useful, these toxins need to be targeted to specific sites on the surface of cancer cells, then be internalized and ultimately reach the cell cytoplasm. This process is accomplished by eliminating binding to toxin receptors and redirecting the cell-killing activity of the toxin to receptors or antigens present on cancer cells. Typically, toxins are conjugated to cell-binding proteins such as monoclonal antibodies or growth factors. These conjugates bind and kill cancer cells selectively while normal cells, which don't bind the conjugates, are spared. Because the genes for many protein toxins have been cloned, it is possible to make genetic modifications to their structure. By deleting the DNA that codes for the toxin binding region and replacing it with various complementary DNA encoding other cell-binding proteins, it has been possible to make chimeric toxins that kill cells on the basis of the newly acquired binding activity. The ability to make these chimeras may be useful in designing future toxin-based anticancer therapies.
FitzGerald
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Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
Pastan
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I
D000818:Animals; D000911:Antibodies, Monoclonal; D004167:Diphtheria Toxin / Q000627:therapeutic use; D005098:Exotoxins / Q000627:therapeutic use; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011549:Pseudomonas; D011956:Receptors, Cell Surface / Q000187:drug effects; D012276:Ricin / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D004167:Diphtheria Toxin; D005098:Exotoxins; D000922:Immunotoxins; D011956:Receptors, Cell Surface; D012276:Ricin