IOVS Proceedings of the National Academy of Sciences
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(Investigative Ophthalmology and Visual Science. 2008;49:2337-2342.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0819
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Oral Picropodophyllin (PPP) Is Well Tolerated In Vivo and Inhibits IGF-1R Expression and Growth of Uveal Melanoma

Mario A. Economou,1,2 Sandra Andersson,2 Diana Vasilcanu,2 Charlotta All-Ericsson,1 Eline Menu,3 Ada Girnita,2 Leonard Girnita,2 Magnus Axelson,4 Stefan Seregard,1 and Olle Larsson2

1From St. Erik’s Eye Hospital and the 2Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; the 3Department of Haematology and Immunology, Vrije Universiteit Brussel-VUB, Brussels, Belgium; and the 4Department of Clinical Chemistry, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

PURPOSE. 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 µM). 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.






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