title: IL-13 cytotoxin has potent antitumor activity and synergizes with paclitaxel in a mouse model of oral squamous cell carcinoma.
abstract: Interleukin-13 receptor-targeted cytotoxin (IL13-PE38) is highly cytotoxic to certain types of human cancers expressing abundant levels of IL-13Ralpha2 chain. Although IL13-PE38 is being tested in a Phase III clinical trial in brain tumors, the activity of IL13-PE38 alone or when combined with taxane, a chemotherapeutic drug for oral squamous cell carcinoma (OSCC), has not been investigated. Here, we show that approximately 40% of OSCCs (n = 50) in a tissue array are strongly positive for IL-13Ralpha2, whereas normal oral mucosa (n = 10) expresses very low or undetectable levels evaluated by immunohistochemistry. IL13-PE38 was highly cytotoxic to OSCC cell lines, but not cytotoxic to normal oral fibroblasts. IL13-PE38 mediated a synergistic antitumor effect with paclitaxel in OSC-19 in vitro and in vivo in the orthotopic OSCC tongue tumor model. Real-time tumor growth was monitored by optical imaging using a Xenogen-IVIS imaging system. Treated animals showed significant (p < 0.05) improvement in survival, which correlated with in vivo imaging of tumor response without evidence of visible toxicity. Gene transfer of IL-13Ralpha2 in oral cancer cells increased sensitivity of OSCC cell line to IL13-PE38 in vitro. Retrovirus-mediated gene-transfer of IL-13Ralpha2 in HSC-3 into tongue tumors in vivo dramatically enhanced the antitumor activity of IL13-PE38, providing complete elimination of established tumors and prolonging survival of these animals. These results indicate that IL13-PE38 in combination with paclitaxel acting via different mechanisms may be a potential treatment option for IL-13Ralpha2 expressing OSCC or for the treatment of non-IL-13Ralpha2 expressing OSCC combined with gene transfer of IL-13Ralpha2.
authors.affiliation: Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Mitomu
authors.initials: M
authors.lastname: Kioi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirota
authors.forename: Iwai
authors.initials: I
authors.lastname: Tohnai
authors.forename: Syed R
authors.initials: SR
authors.lastname: Husain
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005098:Exotoxins / Q000627:therapeutic use*; D006801:Humans; D018793:Interleukin-13 / Q000627:therapeutic use*; D051379:Mice; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017239:Paclitaxel / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014062:Tongue Neoplasms / Q000188:drug therapy; D014183:Transplantation, Heterologous
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005098:Exotoxins; C521502:IL13-PE38; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins; D017239:Paclitaxel