title: Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma.
abstract: OBJECTIVE
  Hepatocellular carcinoma is a leading cause of global cancer mortality, with standard chemotherapy being minimally effective in prolonging survival. We investigated if combined targeting of vascular endothelial growth factor protein and expression might affect hepatocellular carcinoma growth and angiogenesis.
  
  
  METHODS
  We treated patient-derived hepatocellular carcinoma xenografts with (i) bevacizumab; (ii) rapamycin; and (iii) bevacizumab plus rapamycin. Western blotting was employed to determine changes in the proteins. Apoptosis, vascular endothelial growth factor expression, microvessel density, and cell proliferation were analyzed by immunohistochemistry.
  
  
  RESULTS
  Hepatocellular carcinoma growth was inhibited by bevacizumab plus rapamycin treatment to a significantly greater degree than bevacizumab or rapamycin monotherapy. Reductions in tumor growth by bevacizumab plus rapamycin were associated with inhibition of downstream targets of the mammalian target-of-rapamycin pathway, reductions in vascular endothelial growth factor expression, and tumor microvessel density. Potentially additive effects of bevacizumab plus rapamycin included reductions in vascular endothelial growth factor expression, cyclin D1, and cyclin B1. In an intra-peritoneal model of hepatocellular carcinoma, bevacizumab plus rapamycin potently inhibited both intra-liver and intra-abdominal tumor growth, reduced ascites levels, and significantly prolonged mouse survival.
  
  
  CONCLUSIONS
  Bevacizumab and rapamycin, which are both clinically approved drugs, may represent a novel molecularly-targeted combination treatment for hepatocellular carcinoma.
authors.affiliation: Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, 11 Hospital Drive, Singapore 169610, Singapore. cmrhth@nccs.com.sg
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.forename: Pierce K H
authors.initials: PK
authors.lastname: Chow
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Chi Kuen
authors.initials: CK
authors.lastname: Lee
authors.forename: Anaji
authors.initials: A
authors.lastname: Somani
authors.forename: How Sung
authors.initials: HS
authors.lastname: Lee
authors.forename: Ramnarayanan
authors.initials: R
authors.lastname: Kalpana
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.forename: Jeanie
authors.initials: J
authors.lastname: Wu
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.forename: Ming Hui
authors.initials: MH
authors.lastname: Lee
authors.forename: Henley
authors.initials: H
authors.lastname: Hor
authors.forename: Khee Chee
authors.initials: KC
authors.lastname: Soo
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D046912:Multiprotein Complexes; D011506:Proteins; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus