The long-term goal of this project is to determine the effectiveness of specific chemotherapeutic strategies for treatment of human neoplasia. This project will utilize the laboratory opossum, Monodelphis domestica, which is highly susceptible to UVR-induced cancers of the skin and eye, to evaluate several experimental treatments for malignant melanomas and mesenchymal neoplasia. Since these neoplasia frequently metastasize the respond poorly to currently available chemotherapies in humans, development and testing of new treatment strategies is necessary for improving survival in patients with these diseases. Chemotherapy testing in the Monodelphis model will allow a systematic evaluation to be made of the benefits and side-effects of the following new treatments. 1) Combined chemotherapy will be tested using a chemosensitizing agent and standard cytotoxin treatment of malignant melanomas. While increased response rates of human malignant melanomas to combined chemotherapy with triphenylethylenes and cytotoxins have been reported, the benefit of such treatments for improving patient survival is not clearly established. A new triphenylethylene compound, toremifene, will be evaluated in combination with cytotoxins currently in use for melanoma chemotherapy in humans. 2) Cytostatic chemotherapy of malignant melanomas will be tested using agents targeted to skin by topical administration. Toremifene exhibits cytostatic effects against malignant melanoma cells in vitro; however, the benefits of such treatments against tumors in vivo have not been demonstrated. The capability to target cytostatic concentrations of this drug to the skin without significant systemic exposure offers a new treatment strategy for malignant melanomas that will be evaluated in the Monodelphis model. Both combined chemotherapy and cytostatic therapy of malignant melanomas will be evaluated in comparison with standard cytotoxic chemotherapies currently used in humans. 3) Use of anti-estrogenic therapy will be tested for treatment of malignant mesenchymal tumors. The potential role of estrogenic stimulation of mesenchymal tumors has been recognized; however, the use of anti-estrogenic therapy for treatment of benign and malignant forms of mesenchymal tumors has not been thoroughly evaluated. Use of toremifene as an anti-estrogen against malignant mesenchymal tumors will be also evaluated in the Monodelphis model.
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