We use bacterial toxins as killing agents to eliminate cancer cells. To accomplish this, we modify the toxin so it no longer binds via its own cell-binding domain and substitute in place of the binding domain a monoclonal antibody. The antibody is chosen to bind cancer cells preferentially over normal cells. These toxin-antibody molecules are called immunotoxins. Immunotoxins are promising but imperfect anticancer agents. Our goal is to understand the interaction of various toxins with eukaryotic cells and use this information to design better agents for treating cancer. To study interactions, we add toxins to mammalian cells and study the pathway of death. In tracking the killing of cancer cells by immunotoxins, we made the observation that cells grown to high density are resistant to killing. We wish to understand this phenomenon and determine its relevance for cancer therapy in general. A convenient and potentially useful way to study cell-killing pathways is to use RNA interference to identify pathways that participate in toxin delivery to the cytosol - where it acts. Recently, we initiated studies with a newly described toxin from V cholera, called Vibrio Cholera Exotoxin (CET). This toxin is related to the exotoxin from Pseudomonas, exhibiting about 50% identity in selected domains (domains II and III). However, antibodies that neutralize the exotoxin from Pseudomonas do not neutralize CET, despite the close similarity.
| Kreitman, Robert J; Stetler-Stevenson, Maryalice; Margulies, Inger et al. (2009) Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia. J Clin Oncol 27:2983-90 |
| Pastrana, Diana V; FitzGerald, David J (2006) A nonradioactive, cell-free method for measuring protein synthesis inhibition by Pseudomonas exotoxin. Anal Biochem 353:266-71 |
| Pastan, Ira; Hassan, Raffit; Fitzgerald, David J et al. (2006) Immunotoxin therapy of cancer. Nat Rev Cancer 6:559-65 |
| Hsieh, Jennifer C; Tham, Doris M; Feng, Weijun et al. (2005) Intranasal immunization strategy to impede pilin-mediated binding of Pseudomonas aeruginosa to airway epithelial cells. Infect Immun 73:7705-17 |
| Kreitman, Robert J; Squires, David R; Stetler-Stevenson, Maryalice et al. (2005) Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies. J Clin Oncol 23:6719-29 |
| Pastrana, Diana V; Hanson, Alison J; Knisely, Jane et al. (2005) LRP 1 B functions as a receptor for Pseudomonas exotoxin. Biochim Biophys Acta 1741:234-9 |
| Wilderman, Paula J; Sowa, Nathaniel A; FitzGerald, David J et al. (2004) Identification of tandem duplicate regulatory small RNAs in Pseudomonas aeruginosa involved in iron homeostasis. Proc Natl Acad Sci U S A 101:9792-7 |
