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Combination antiangiogenic therapy: increased efficacy in a murine model of Wilms tumor
1Division of Pediatric Surgery, and the Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Background/Purpose:
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 However, tumor growth accelerates if antibody is withdrawn.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.
Conclusion:
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.
Insights
Combined anti-VEGF antibody and topotecan therapy offers durable suppression of Wilms tumor growth and metastasis by inhibiting angiogenesis. This combination therapy proved more effective than either agent alone in preclinical models.
Area of Science:
- Oncology
- Angiogenesis Research
- Preclinical Cancer Models
Background:
- Vascular endothelial growth factor (VEGF) antibody therapy suppresses experimental Wilms tumor growth but leads to accelerated regrowth upon withdrawal.
- Low-dose, frequent topotecan exhibits anti-angiogenic properties.
Purpose of the Study:
- To investigate the hypothesis that combined topotecan and anti-VEGF therapy provides more durable suppression of Wilms tumor growth and metastasis than monotherapy.
Main Methods:
- Human Wilms tumor xenografts were established in athymic mice.
- Mice were treated with anti-VEGF antibody, topotecan, combination therapy, or served as controls.
- Tumor growth, metastasis, vascularity (angiography, PECAM staining), and endothelial apoptosis (TUNEL assay) were assessed.
Main Results:
- Combination therapy significantly reduced tumor weight and lung metastasis compared to controls.
- Tumor regrowth was slowest in the combination therapy group after treatment withdrawal.
- Treated tumors exhibited reduced vascularity and increased endothelial apoptosis.
Conclusions:
- Combined low-dose topotecan and anti-VEGF antibody therapy demonstrates potent anti-angiogenic effects.
- This combination therapy durably suppresses experimental Wilms tumor growth and metastasis.
- The combination strategy is superior to monotherapy in preclinical Wilms tumor models.
