title: Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts.
abstract: E7080 is an inhibitor of multiple tyrosine kinases, several of which have pro-angiogenic properties, including receptors for VEGF, FGF, SCF and PDGF. We undertook our study to evaluate the preclinical activity of E7080 in human sarcomas. The antitumour activity of orally administered E7080 was tested in ten human tumour xenografts representing different sarcoma histotypes. Concomitant changes in microvessel density were assayed by immunohistochemistry to CD31. Immunohistochemistry was also used to assess the expression of kinases that E7080 is known to inhibit. The MTS assay was applied to determine effects on tumour cell viability in vitro. At the Q1D5 × 2 schedule, E7080 (30 mg/kg) was active (T/C<40%) in 7/10 xenografts. The effects were accompanied by marked decrease in microvessel densities. Given at the Q1D5 × 4 schedule, E7080 (30, 10, 3 mg/kg) showed antitumour activity in a dose dependent manner in two different xenografts. E7080 growth inhibition did not correlate with the expression of VEGFR1-3, PDGFRA, PDGFRB, FGFR1 or KIT on tumour cells but was significantly correlated with expression of VEGFR2 on tumour microvessels. In vitro E7080 did not show potent effects on tumour cell viability in four different sarcoma cell lines, with IC50 values ≥ 10 μM. In conclusion, E7080 showed broad in vivo antitumour activity in sarcoma, mainly attributable to angiogenesis inhibition. E7080 was also active in xenografts resistant to one or more clinically relevant reference drugs given at MTD (doxorubicin, cisplatin or ifosfamide). The present results encourage further investigation of a potential role of E7080 in sarcoma therapy in the clinic.
authors.affiliation: Department of Tumour Biology, Institute for Cancer Research University in Oslo, Oslo, Norway. skjalg.bruheim@rr-research.no
authors.forename: Skjalg
authors.initials: S
authors.lastname: Bruheim
authors.forename: Alexandr
authors.initials: A
authors.lastname: Kristian
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uenaka
authors.forename: Zhenhe
authors.initials: Z
authors.lastname: Suo
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuruoka
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Fodstad
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000627:therapeutic use*; D012509:Sarcoma / Q000098:blood supply* / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D011505:Protein-Tyrosine Kinases; C531958:lenvatinib