Transducible peptide therapy for uveal melanoma and retinoblastoma.
OBJECTIVE
To determine whether transducible peptides that inhibit the oncoproteins HDM2 and Bcl-2 may selectively kill uveal melanoma and retinoblastoma cells.


METHODS
Peptides were tested by viability assay, flow cytometry, TUNEL (terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labeling) assay, Western blot analysis, and reverse transcription-polymerase chain reaction in cultured eye tumor cells and normal cells. Preclinical studies were performed in a rabbit xenograft model of retinoblastoma.


METHODS
Cell survival, apoptosis, gene expression, and tumor regression.


RESULTS
The anti-Bcl-2 peptide induced apoptosis in tumor cells, but it also caused apoptosis in normal cells in culture and induced retinal damage after intravitreal injection. In contrast, the anti-HDM2 peptide induced rapid accumulation of p53, activation of apoptotic genes, preferential killing of tumor cells, and minimal retinal damage after intravitreal injection. The anti-HDM2 peptide also induced regression of human retinoblastoma cells in rabbit eyes.


CONCLUSIONS
Peptide transduction is a promising new approach to molecular eye cancer therapy. Inhibition of HDM2 can selectively activate p53 in transformed cells and may be an effective strategy for inducing apoptosis in eye cancer cells with minimal damage to normal ocular tissues.


CONCLUSIONS
Molecular characteristics of uveal melanoma and retinoblastoma may be used to design novel therapeutic agents that have greater specificity and fewer adverse effects than current therapies.
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D008545:Melanoma / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D010455:Peptides / Q000235:genetics* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D051736:Proto-Oncogene Proteins c-mdm2; D011817:Rabbits; D012175:Retinoblastoma / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014604:Uveal Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2