mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo.
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.
Fuereder
Thorsten
T
Department of Clinical Pharmacology, Medical University Vienna, Austria.
Jaeger-Lansky
Agnes
A
Hoeflmayer
Doris
D
Preusser
Matthias
M
Strommer
Sabine
S
Cejka
Daniel
D
Koehrer
Stefan
S
Crevenna
Richard
R
Wacheck
Volker
V
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
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