title: Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer.
abstract: Even with current promising antitumor antibodies, their antitumor effects on stroma-rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa-2; moderate, BxPC-3; and abundant, Capan-1 and Ope-xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra-abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa-2 model, moderate (1063) in the BxPC-3 model, and negative in the Capan-1 and Ope-xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8-fold (2980, 3015) in the BxPC-3 model, 2.5- or 4.8-fold (1881, 3615) in the Capan-1 model, and 3.2- or 4.2-fold (1469, 1922) in the Ope-xeno model, respectively. Cetuximab was effective in treating even stroma-rich and k-ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Miyamoto
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Oda
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurokawa
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimomura
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohara
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Akashi
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Institute of Applied Physics, University of Tsukuba, Tsukuba, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Kishimoto
authors.affiliation: Institute of Applied Physics, University of Tsukuba, Tsukuba, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Yanagihara
authors.affiliation: Institute of Applied Physics, University of Tsukuba, Tsukuba, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kita
authors.affiliation: Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohkohchi
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Cetuximab; drug delivery; mild hyperthermia; monoclonal antibody; pancreatic cancer