Combination antiangiogenic therapy: increased efficacy in a murine model of Wilms tumor.
OBJECTIVE
Antibody to vascular endothelial growth factor (anti-VEGF) suppresses tumor growth and metastasis in experimental Wilms tumor. However, tumor growth accelerates if antibody is withdrawn. As recently shown, low-dose, frequently administered topotecan, a topoisomerase-1 inhibitor, has anti-angiogenic activity. The authors hypothesized that combined topotecan/anti-VEGF therapy would suppress tumor growth and metastasis more durably than either agent alone.


METHODS
Xenografts were induced by intrarenal injection of human Wilms tumor cells in athymic mice (n = 59). Mice were divided into control (n = 10), anti-VEGF (n = 16), topotecan (n = 17), and topotecan plus anti-VEGF (n = 16) groups. All control and half the treated mice were killed at week 6. Remaining ("rebound") mice were maintained without treatment until week 8. Tumor vasculature was mapped by fluorescein angiography/PECAM immunostaining. Endothelial apoptosis was assessed by TUNEL assay.


RESULTS
6 weeks: Tumor weights were reduced significantly in treated mice (P <.003 v control). Seven of ten control and 1 of 25 treated mice displayed lung metastases (P <.003). Rebound tumors were largest in topotecan-only, intermediate in antibody-treated, and smallest in combination-treated mice. Immunostaining and angiography results showed sparse vascularity in treated xenografts. Endothelial apoptosis was observed only in treated tumors.


CONCLUSIONS
Combination low-dose topotecan and anti-VEGF antibody therapy is antiangiogenic and suppresses tumor growth and metastasis in experimental Wilms tumor more durably than either agent alone.
Soffer
S Z
SZ
Division of Pediatric Surgery, and the Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Moore
J T
JT
Kim
E
E
Huang
J
J
Yokoi
A
A
Manley
C
C
O'Toole
K
K
Stolar
C
C
Middlesworth
W
W
Yamashiro
D J
DJ
Kandel
J J
JJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000276:immunology; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008222:Lymphokines / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012016:Reference Values; D012680:Sensitivity and Specificity; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009396:Wilms Tumor / Q000188:drug therapy* / Q000473:pathology
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019772:Topotecan