Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Cancer Sci. 2016 Apr;107(4):514-20. doi: 10.1111/cas.12888. Epub 2016 Mar 4.

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.

Keywords: Cetuximab; drug delivery; mild hyperthermia; monoclonal antibody; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Cell Line, Tumor
  • Cetuximab / administration & dosage*
  • Disease Models, Animal
  • Drug Delivery Systems
  • ErbB Receptors / metabolism
  • Humans
  • Hyperthermia, Induced*
  • Mice
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal, Humanized
  • ErbB Receptors
  • Cetuximab