Abrogation of Head and Neck Squamous Cell Carcinoma Growth by Epidermal Growth Factor Receptor Ligand Fused to Pseudomonas Exotoxin Transforming Growth Factor α-PE38

Abstract

Purpose: This study was undertaken to determine whether low intratumoral doses of the epidermal growth factor receptor ligand-transforming growth factor ␣ (TGF-␣) fused to Pseudomonas exotoxin (TGF-␣-PE38)-abrogated head and neck squamous cell carcinoma (HNSCC) tumor growth in vitro and in vivo.Experimental Design: In vitro cytotoxicity assays were carried out to determine the sensitivity of HNSCC cells to TGF-␣-PE38. TGF-␣-PE38-treated HNSCC cells were examined by immunoblotting for cleaved poly(ADP-ribose) polymerase to evaluate apoptosis. Nude mice bearing established HNSCC xenografts were treated with several doses of TGF-␣-PE38 to evaluate the antitumor efficacy in vivo. Tumor sections were stained with terminal deoxynucleotidyl transferase-mediated nick end labeling for apoptosis. To determine the effect of oral administration of TGF-␣-PE38, gavage injections of TGF-␣-PE38 were administered, and the esophagus and surrounding soft tissue were then stained for apoptotic cells.Results: HNSCC cell lines examined were sensitive to low doses of TGF-␣-PE38 (EC 50 in the range of 1.6 to 10 ng/mL). HNSCC cells treated with TGF-␣-PE38 undergo apoptosis. Antitumor effects were observed using 0.1 and 0.03 g of TGF-␣-PE38 administered intratumorally. At these doses, the treatment was well tolerated. Tumors treated with the toxin had a higher number of apoptotic cells compared with the control tumors. No apoptotic cells were observed in the pharyngoesophageal tissues of the mice after gavage administration of the toxin suggesting that the toxin could be orally administered without toxicity.Conclusions: These results indicate that topical or intratumoral administration of low doses of TGF-␣-PE38 may demonstrate antitumor effects in HNSCC without associated systemic toxicity.

Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma

“…Antibodies can be subject to decreased internalization to antibody-target complexes, variable expression of tumor antigens, and limited cytotoxicity [87]. TGF-alpha conjugated to alpha-PE38, was used in HNSCC models, where cleaved PARP, a marker of apoptosis, was significantly higher in HNSCC cells that received treatment as opposed to controls [88]. Mice treated with this toxin-ligand conjugate intratumorally, exhibited a decrease in tumor volume and increased numbers of tumor cells when compared to controls [88].…”

Fusion protein of adenovirus E4orf4 and human epidermal growth factor inhibits tumor cell growth

“…The commonly used toxins are diphtheria toxin (DT) 26 and Pseudomonas exotoxin (PE). 6 Although these compounds have demonstrated anticancer activity in cell culture and xenograft tumor models, they also exhibited a systemic toxicity because of their nonselectiveness of toxins. EGF-E4orf4 showed the low toxicity in mice model including no loss weight and no histopathological lesions in the liver and kidney after multiple ip injections.…”

“…Up to date, there were many kinds of antitumor protein adopting the EGFR-mediated endocytosis strategy to introduce toxin into the tumor cells. 6,26,28,29 All these studies have unanimously indicated the effectiveness of the strategy in many situations. Nonetheless, the delivery pathway has not yet been accounted.…”

“…3 Therefore, EGFR can be a target on tumor cell. EGFR ligand fused with a cytotoxin, [4][5][6] such as TP-38 6 and DAB 389 EGF, 4 have been developed for cancer therapy.…”

EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells

“…Toxin-based therapy has several potential advantages over conventional therapies because recombinant immunotoxins are highly specific, extraordinarily potent, and lack an identified mechanism for resistance [3,5,[19][20][21]. As a result, these agents have shown promise in the treatment of a variety of human neoplasms [2,7,15,17,22,23,27,28].…”