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The dose-limiting toxicity of interleukin-2 (IL-2) and immunotoxin (IT) therapy in humans is vascular leak syndrome (VLS). VLS has a complex etiology involving damage to vascular endothelial cells (ECs), extravasation of f luids and proteins, interstitial edema, and organ failure. IL-2 and ITs prepared with the catalytic A chain of the plant toxin, ricin (RTA), and other toxins, damage human ECs in vitro and in vivo. Damage to ECs may initiate VLS; if this damage could be avoided without losing the efficacy of ITs or IL-2, larger doses could be administered. In this paper, we provide evidence that a three amino acid sequence motif, (x)D(y), in toxins and IL-2 damages ECs. Thus, when peptides from RTA or IL-2 containing this sequence motif are coupled to mouse IgG, they bind to and damage ECs both in vitro and, in the case of RTA, in vivo. In contrast, the same peptides with a deleted or mutated sequence do not. Furthermore, the peptide from RTA attached to mouse IgG can block the binding of intact RTA to ECs in vitro and vice versa. In addition, RTA, a fragment of Pseudomonas exotoxin A (PE38-lys), and fibronectin also block the binding of the mouse IgG-RTA peptide to ECs, suggesting that an (x)D(y) motif is exposed on all three molecules. Our results suggest that deletions or mutations in this sequence or the use of nondamaging blocking peptides may increase the therapeutic index of both IL-2, as well as ITs prepared with a variety of plant or bacterial toxins.

Recent studies have documented changes in adhesion molecule expression and function after exposure to ionizing radiation. Adhesion molecules mediate cell-cell and cell-matrix interactions and are essential for a variety of physiological and pathological processes including maintenance of normal tissue integrity as well as tumor development and progression. Consequently, modulation of adhesion molecules by radiation may have a role in radiation-induced tumor control and normal tissue damage by interfering with cell signaling, radioresistance, metastasis, angiogenesis, carcinogenesis, immune response, inflammation and fibrosis. In addition, the interactions of radiation with adhesion molecules could have a major impact in developing new strategies to increase the efficacy of radiation therapy. Remarkable progress has been made in recent years to design targeted drug delivery to radiation-up-regulated adhesion molecules. Furthermore, the inhibition of adhesion, migration, invasion and angiogenesis by blocking adhesion receptors may represent a new therapeutic approach to improve tumor control and decrease radiation toxicity. This review is focused on current data concerning the mechanistic interactions of radiation with adhesion molecules and the possible clinical-pathological implications in radiotherapy.

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