title: mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo.
abstract: VEGF receptor blockage has been reported to increase serum VEGF. We hypothesized that mTOR inhibition by everolimus counteracts VEGF induction by sunitinib resulting in an improved anti-tumor activity of sunitinib. In vitro, sunitinib in combination with everolimus did not outperform the respective monotherapies. In vivo, monotherapies reduced tumor growth by 60%, whereas the combination of sunitinib and everolimus led to an almost complete tumor growth inhibition. This superior anti-tumor activity coincided with attenuation of VEGF peaks. In conclusion mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and results in significant reduction of tumor burden and long-lasting tumor growth control.
authors.affiliation: Department of Clinical Pharmacology, Medical University Vienna, Austria.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Fuereder
authors.forename: Agnes
authors.initials: A
authors.lastname: Jaeger-Lansky
authors.forename: Doris
authors.initials: D
authors.lastname: Hoeflmayer
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.forename: Sabine
authors.initials: S
authors.lastname: Strommer
authors.forename: Daniel
authors.initials: D
authors.lastname: Cejka
authors.forename: Stefan
authors.initials: S
authors.lastname: Koehrer
authors.forename: Richard
authors.initials: R
authors.lastname: Crevenna
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D000068338:Everolimus; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068338:Everolimus; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib; D020123:Sirolimus