Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma.
OBJECTIVE
The cyclolignan picropodophyllin (PPP) efficiently blocks the activity of insulin-like growth factor-1 receptor (IGF-1R) and inhibits growth of uveal melanoma cells in vitro and in vivo. In this study, we aimed to investigate the efficiency of orally administered PPP on growth of uveal melanoma xenografts. Further, we focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established anti-tumor agents in vitro.


METHODS
Four different uveal melanoma cell lines (OCM-1, OCM-3, OCM-8, 92-1) were treated with PPP alone and in combination with imatinib mesylate, cisplatin, 5-FU and doxorubicin. Cell viability was determined by XTT assay. SCID mice xenografted with uveal melanoma cells were used to determine anti-tumor efficacy of oral PPP in vivo. Tumor samples obtained from the in vivo experiments were analyzed for VEGF and IGF-1R expression by western blotting.


RESULTS
PPP was found to be superior to the other anti-tumor agents in killing uveal melanoma cells. Oral PPP inhibited uveal melanoma growth in vivo and was well tolerated by the animals. PPP decreased VEGF expression in the tumors.


CONCLUSIONS
Oral PPP is well tolerated in vivo and caused total growth inhibition of uveal melanoma xenografts as well as it decreased the levels of VEGF in the tumors.
Economou
Mario A
MA
St Erik's Eye Hospital, Karolinska Institute, Stockholm, Sweden. mario-alexander.economou@sankterik.se
Andersson
Sandra
S
Vasilcanu
Diana
D
All-Ericsson
Charlotta
C
Menu
Eline
E
Girnita
Ada
A
Girnita
Leonard
L
Axelson
Magnus
M
Seregard
Stefan
S
Larsson
Olle
O
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D014604:Uveal Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin