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Topotecan is anti-angiogenic in experimental hepatoblastoma
Kimberly W McCrudden1, Akiko Yokoi, Amit Thosani
1Division of Pediatric Surgery, Children's Hospital of New York, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Background:
Advanced hepatoblastoma often is lethal despite current therapies, yet development of novel approaches has been hampered by the lack of biologically relevant models. One new strategy selectively targets endothelium rather than tumor cells using frequently administered, low-dose ("metronome") chemotherapy. Metronome topotecan has antiangiogenic activity in some experimental tumors. The authors developed a xenograft model of human hepatoblastoma to test the effect of metronome topotecan in this system.
Methods:
Xenografts resulted from intrarenal injection of cultured human hepatoblastoma cells in athymic mice. Topotecan (0.36 mg/kg/dose) or vehicle was injected intraperitoneally 5 times per week. At week 6, 10 control/treated mice were killed, and remaining animals were maintained without treatment until week 8. Tumor weights were compared by Kruskal-Wallis analysis, and vascular alterations were ascertained by specific immunostaining.
Results:
Metronome topotecan affected tumor weights in a delayed fashion: weights were diminished significantly only at 8 weeks (treated v control: 6 weeks, 0.59 g v 82 g, P value, not significant; 8 weeks, 1.13 g v 3.82; P <.02). Decreased vascularity and increased endothelial cell apoptosis were observed in treated xenografts.
Conclusions:
Metronome topotecan inhibits growth and neovascularization in experimental hepatoblastoma. The durability of this effect is novel and has not been observed in other xenograft tumor models. Cytotoxic targeting of endothelial cells may hold particular promise for therapy of children with advanced hepatoblastoma. .
Insights
Metronome topotecan chemotherapy, targeting blood vessel growth, significantly reduced hepatoblastoma tumor weight and vascularity in a novel xenograft model.
Area of Science:
- Oncology
- Pharmacology
- Experimental Therapeutics
Background:
- Advanced hepatoblastoma presents a significant therapeutic challenge due to a lack of effective treatment models.
- Metronome chemotherapy, a low-dose, frequent administration strategy, shows potential by targeting tumor vasculature (antiangiogenic activity).
Purpose of the Study:
- To evaluate the efficacy of metronome topotecan in a human hepatoblastoma xenograft model.
- To assess the impact on tumor growth, vascularity, and endothelial cell apoptosis.
Main Methods:
- Human hepatoblastoma cells were xenografted into athymic mice.
- Mice received daily intraperitoneal injections of topotecan (0.36 mg/kg/dose) or vehicle for 5 weeks.
- Tumor weights and vascular alterations via immunostaining were analyzed at 6 and 8 weeks.
Main Results:
- Metronome topotecan demonstrated a delayed but significant reduction in tumor weight by week 8 (P <.02).
- Treated xenografts exhibited decreased vascularity and increased endothelial cell apoptosis.
- Tumor weights at week 6 showed no significant difference between groups.
Conclusions:
- Metronome topotecan effectively inhibits hepatoblastoma growth and neovascularization in experimental models.
- The observed durable anti-tumor effect and anti-angiogenic activity are novel findings.
- Targeting endothelial cells with metronome chemotherapy shows promise for treating advanced pediatric hepatoblastoma.