title: Regorafenib as a potential adjuvant chemotherapy agent in disseminated small colon cancer: Drug selection outcome of a novel screening system using nanoimprinting 3-dimensional culture with HCT116-RFP cells.
abstract: Colon cancer is one of the leading causes of cancer death worldwide. Adjuvant chemotherapy following primary surgical treatment is suggested to be beneficial in eradicating invisible disseminated small tumors in colon cancer; however, an effective drug remains to be developed. Recently, we reported a novel drug screening system using a nanoimprinting 3-dimensional (3D) culture that creates multicellular spheroids, which simulate in vivo conditions and, thereby, predict effective drugs in vivo. This study aimed to perform drug selection using our recently developed 3D culture system in a human colon cancer HCT116 cell line stably expressing red fluorescent protein (HCT116-RFP), to determine the most effective agent in a selection of clinically used antitumor agents for colon cancer. In addition, we confirmed the efficacy of the selected drug regorafenib, in vivo using a mouse model of disseminated small tumors. HCT116-RFP cells were cultured using a nanoimprinting 3D culture and in vitro drug selection was performed with 8 clinically used drugs [bevacizumab, capecitabine, cetuximab, 5-fluorouracil (5-FU), irinotecan, oxaliplatin, panitumumab and regorafenib]. An in vivo study was performed in mice bearing HCT116-RFP intraperitoneally disseminated small tumors using 3'-[18F]-fluoro-3'-deoxythymidine-positron emission tomography and fluorescence microscopy imaging to evaluate the therapeutic effects. Regorafenib was determined to be the most effective drug in the 3D culture, and significantly inhibited tumor growth in vivo, compared to the untreated control and 5-FU-treated group. The drug 5-FU is commonly used in colon cancer treatment and was used as a reference. Our results demonstrate that regorafenib is a potentially efficacious adjuvant chemotherapeutic agent for the treatment of disseminated small colon cancer and, therefore, warrants further preclinical and clinical studies.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yoshii
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Aoyama
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Adachi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D018929:Cell Culture Techniques / Q000379:methods*; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005472:Fluorouracil / Q000008:administration & dosage; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D000077544:Panitumumab; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000097573:Red Fluorescent Protein
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002166:Camptothecin; D005472:Fluorouracil; D000077146:Irinotecan; D008164:Luminescent Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077544:Panitumumab; D010671:Phenylurea Compounds; D011725:Pyridines; D000097573:Red Fluorescent Protein; C559147:regorafenib