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 insulinlike growth factor-1 receptor (IGF-1R) and inhibits the growth of uveal melanoma cells in vitro and in vivo. In this study, the authors investigated the efficiency of orally administered PPP on the growth of uveal melanoma xenografts. In addition, they focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established antitumor 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-fluorouracil, and doxorubicin. Cell viability was determined by XTT assay. SCID mice that underwent xenografting with uveal melanoma cells were used to determine antitumor efficacy of oral PPP in vivo. Five mice were used per group. 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 antitumor agents in killing uveal melanoma cells in all four cell lines (IC50 < 0.05 microM). Oral PPP inhibited uveal melanoma growth in vivo in OCM-3 (P = 0.03) and OCM-8 (P = 0.01) xenografts and was well tolerated by the animals. PPP decreased VEGF expression in the OCM-1 (P = 0.006) and OCM-8 (P = 0.01) tumors.


CONCLUSIONS
Oral PPP was well tolerated in vivo, caused total growth inhibition of uveal melanoma xenografts, and decreased VEGF levels in the tumors.
St. Erik's Eye Hospital, Karolinska Institutet, Stockholm, Sweden. mario-alexander.economou@sankterik.se
Mario A
MA
Economou
Sandra
S
Andersson
Diana
D
Vasilcanu
Charlotta
C
All-Ericsson
Eline
E
Menu
Ada
A
Girnita
Leonard
L
Girnita
Magnus
M
Axelson
Stefan
S
Seregard
Olle
O
Larsson
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014604:Uveal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin