Malignant melanoma is the most common primary intraocular neoplasm in humans. Although there have been significant advances in the diagnosis and treatment of primary intraocular melanoma, prevention of metastases has been disappointing. The five year mortality rate for patients diagnosed with uveal melanoma remains at 50%. New therapeutic strategies for preventing and treating metastases arising from uveal melanomas are desperately needed. The present research plan will evaluate several therapeutic strategies designed to either prevent or eliminate metastases arising from intraocular melanomas in a mouse model. Each category of therapeutic strategy is directed at a specific state of the metastatic process. The first major objective will examine the effect of radiotherapy and adjuvant therapy for retarding the growth and intravasation of primary intraocular melanomas and the subsequent effect on the development of spontaneous metastases. Three specific aims for this objective are: (a) effect of external beam irradiation in combination with a perfluorochemical adjuvant; (b) effect of 125- I plaques in combination with a perfluorochemical adjuvant; and (c) effect of "no-touch" enucleation and radiotherapy. The second major objective will seek methods to eliminate tumor emboli within the bloodstream and thereby reduce metastases. Two specific aims for this objective are: (a) determine effect of adhesion peptides (laminin and fibronectin) in preventing metastases; and (b) effect of augmented natural killer cell activity in reducing metastases. The third objective is to treat established metastatic foci within the parenchyma of the secondary organ. This objective will be addressed by three specific aims: (a) effect of suicide enzyme inhibition with DFMO and gamma interferon; (b) effect of a novel melanin-ricin conjugate; and (c) effect of a "mutant repressor tumor" vaccine. The long range goal of this project is to implement the optimal protocols for each step of the metastatic process into a single comprehensive plan for preventing and treating metastases arising from intraocular melanomas.