Topotecan is anti-angiogenic in experimental hepatoblastoma.
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. .
McCrudden
Kimberly W
KW
Division of Pediatric Surgery, Children's Hospital of New York, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Yokoi
Akiko
A
Thosani
Amit
A
Soffer
Samuel Z
SZ
Kim
Eugene S
ES
Huang
Jianzhong
J
Manley
Christina
C
O'toole
Kathleen
K
Yamashiro
Darrell J
DJ
Kandel
Jessica J
JJ
Middlesworth
William
W
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D005260:Female; D018197:Hepatoblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology; D019772:Topotecan / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D019772:Topotecan