Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF‐1R expression and growth of uveal melanoma

• Published in: Acta ophthalmologica (Oxford, England) Vol. 86; no. thesis4; pp. 35 - 41
• Main Authors: Economou, Mario A., Andersson, Sandra, Vasilcanu, Diana, All‐Ericsson, Charlotta, Menu, Eline, Girnita, Ada, Girnita, Leonard, Axelson, Magnus, Seregard, Stefan, Larsson, Olle
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2008
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - pharmacology; Cell Death; Cell Line, Tumor; Cell Survival - drug effects; Humans; IGF‐1R; in vivo; Medicin och hälsovetenskap; Melanoma - metabolism; Melanoma - pathology; Melanoma - physiopathology; Mice; Mice, SCID; Neoplasm Transplantation; picropodophyllin; Podophyllotoxin - administration & dosage; Podophyllotoxin - analogs & derivatives; Podophyllotoxin - pharmacology; Receptor, IGF Type 1 - antagonists & inhibitors; Transplantation, Heterologous; uveal melanoma; Uveal Neoplasms - metabolism; Uveal Neoplasms - pathology; Uveal Neoplasms - physiopathology; Vascular Endothelial Growth Factor A - antagonists & inhibitors; VEGF
• ISSN: 1755-375X; 1755-3768; 1755-3768
• DOI: 10.1111/j.1755-3768.2008.01184.x

Purpose:  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.