Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in ovarian cancer.
This study aimed to investigate the antitumor and antiangiogenic effects utilizing a novel therapy regimen of metronomic topotecan and pazopanib, a multireceptor tyrosine kinase inhibitor. In vitro (Western blot) and in vivo dose-finding experiments were done following pazopanib therapy in ovarian cancer models. Pazopanib and metronomic (daily) oral topotecan therapy was examined in an orthotopic model of ovarian cancer. Tumor weights, survival, and markers of the tumor microenvironment [angiogenesis (CD31 and pericyte coverage), proliferation (Ki-67), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)] were analyzed by immunostaining following therapy. Pazopanib therapy reduced vascular endothelial growth factor receptor 2 (VEGFR-2) activity in vitro and vivo in a dose-dependent manner. Compared with control mice, pazopanib reduced tumor weight by 28% to 82% (P < 0.01 in the SKOV3ip1 model) and metronomic topotecan reduced tumor weight by 40% to 59% in the HeyA8 (P = 0.13) and SKOV3ip1 (P = 0.07) models. Combination therapy had the greatest effect with 79% to 84% reduction (P < 0.01 for both models). In the SKOV3ip1 and A2780 models, mouse survival was significantly longer (P < 0.001 versus controls) with pazopanib and metronomic topotecan therapy. Pazopanib therapy reduced murine endothelial cell migration in vitro in a dose-dependent manner following VEGF stimulation and decreased tumor microvessel density and pericyte coverage when given in combination with metronomic topotecan. Tumor cell proliferation decreased in all treatment arms compared with controls (P < 0.01 for combination groups) and increased tumor cell apoptosis by 4-fold with combination therapy. Pazopanib therapy in combination with metronomic topotecan therapy showed significant antitumor and antiangiogenic properties in preclinical ovarian cancer models and warrants further investigation as a novel therapeutic regimen in clinical trials. Mol Cancer Ther; 9(4); 985-95. (c)2010 AACR.
Merritt
William M
WM
Departments of Gynecologic Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, TX 77230-1439, USA.
Nick
Alpa M
AM
Carroll
Amy R
AR
Lu
Chunhua
C
Matsuo
Koji
K
Dumble
Melissa
M
Jennings
Nicholas
N
Zhang
Shuyun
S
Lin
Yvonne G
YG
Spannuth
Whitney A
WA
Kamat
Aparna A
AA
Stone
Rebecca L
RL
Shahzad
Mian M K
MM
Coleman
Robert L
RL
Kumar
Rakesh
R
Sood
Anil K
AK
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001691:Biological Therapy; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007191:Indazoles; D053208:Kaplan-Meier Estimate; D051379:Mice; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D019772:Topotecan / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D019772:Topotecan; C516667:pazopanib; D040262:Receptors, Vascular Endothelial Growth Factor