title: In vitro and in vivo evidence that a combination of lapatinib plus S-1 is a promising treatment for pancreatic cancer.
abstract: Lapatinib is a small molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR). We investigated the effect of treatment with lapatinib alone or in combination with a fluoropyrimidine derivative S-1 against pancreatic cancer. The HER2/EGFR expression in each of the four pancreatic cancer cell lines MiaPaca-2, PANC-1, Capan-1 and Capan-2 was measured by flow cytometry. The anti-tumor effects of lapatinib (30 mg/kg) and/or S-1 (10 mg/kg) were evaluated using female BALB/c nude mice xenografts generated using these four cell lines. Synergy between lapatinib and S-1 was examined by median effect analysis in vitro. Resected pancreatic cancer tissues from 137 patients were immunohistochemically stained with anti-human HER2 and EGFR antibodies. The administration of lapatinib as a single agent substantially suppressed tumor growth in vivo of all pancreatic cancer cell lines examined. A strong correlation was observed between HER2 expression and the anti-tumor effect of lapatinib in vivo. Lapatinib synergized with S-1 to inhibit the tumor growth of MiaPaca-2 and PANC-1 xenografts. When used as a single agent in vitro, lapatinib barely inhibit the cell growth of any cell line. However, lapatinib synergized with the anti-tumor activity of the S-1 components 5-fluorouracil and 5-chloro-2,4-dihydrogenase against all cell lines. Immunohistochemical staining demonstrated that 70% of the pancreatic cancers overexpressed HER2 and/or EGFR. Both lapatinib monotherapy and combined treatment with S-1 may be promising treatments for patients with pancreatic cancers; the majority these cancers express lapatinib target molecules.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Komoto
authors.forename: Bunzo
authors.initials: B
authors.lastname: Nakata
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nishii
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kawajiri
authors.forename: Osamu
authors.initials: O
authors.lastname: Shinto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Amano
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yamada
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004338:Drug Combinations; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D010094:Oxonic Acid / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage*; D005641:Tegafur / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004338:Drug Combinations; D011799:Quinazolines; D000077341:Lapatinib; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid