Synergistic antitumor activity of ixabepilone (BMS-247550) plus bevacizumab in multiple in vivo tumor models.
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.
Lee
Francis Y F
FY
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. francis.lee@bms.com
Covello
Kelly L
KL
Castaneda
Stephen
S
Hawken
Donald R
DR
Kan
David
D
Lewin
Anne
A
Wen
Mei-Li
ML
Ryseck
Rolf-Peter
RP
Fairchild
Craig R
CR
Fargnoli
Joseph
J
Kramer
Robert
R
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
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