title: Synergistic antitumor activity of ixabepilone (BMS-247550) plus bevacizumab in multiple in vivo tumor models.
abstract: OBJECTIVE
  Angiogenesis is a critical step in the establishment, growth, and metastasis of solid tumors, and combination of antiangiogenic agents with chemotherapy is an attractive therapeutic option. We investigated the potential of ixabepilone, the first in a new class of antineoplastic agents known as epothilones, to synergize with antiangiogenic agents to inhibit tumor growth.
  
  
  METHODS
  In vitro and in vivo cytotoxicity of ixabepilone as single agent and in combination with two targeted antiangiogenic agents, bevacizumab or sunitinib, were examined in preclinical tumor models. Direct effects of the agents against endothelial cells was also examined and compared with the effects of paclitaxel as single agent and in combination with bevacizumab.
  
  
  RESULTS
  Ixabepilone showed robust synergistic antitumor activity in combination with bevacizumab and sunitinib in preclinical in vivo models derived from breast, colon, lung, and kidney cancers. The synergistic antitumor effect was greater with ixabepilone compared with paclitaxel. Furthermore, ixabepilone was more effective than paclitaxel at killing endothelial cells expressing P-glycoprotein in vitro and inhibiting endothelial cell proliferation and tumor angiogenesis in vivo.
  
  
  CONCLUSIONS
  Ixabepilone may enhance the antitumor effects of antiangiogenic therapy by direct cytotoxicity and also indirectly via the killing of tumor-associated endothelial cells. Given that ixabepilone has reduced susceptibility to drug efflux pumps compared with taxanes, these data may explain the increased antiangiogenic and antitumor activity of ixabepilone in combination with antiangiogenic agents. Phase II studies to assess the efficacy and safety of ixabepilone plus bevacizumab in locally recurrent or metastatic breast cancer are planned.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. francis.lee@bms.com
authors.forename: Francis Y F
authors.initials: FY
authors.lastname: Lee
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Covello
authors.forename: Stephen
authors.initials: S
authors.lastname: Castaneda
authors.forename: Donald R
authors.initials: DR
authors.lastname: Hawken
authors.forename: David
authors.initials: D
authors.lastname: Kan
authors.forename: Anne
authors.initials: A
authors.lastname: Lewin
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Wen
authors.forename: Rolf-Peter
authors.initials: RP
authors.lastname: Ryseck
authors.forename: Craig R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Robert
authors.initials: R
authors.lastname: Kramer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000068258:Bevacizumab; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects; D034261:Epothilones / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D034261:Epothilones; D007211:Indoles; D011758:Pyrroles; D000068258:Bevacizumab; C430592:ixabepilone; D000077210:Sunitinib