Significance of transforming growth factors for ocular malignant tumors and their application in gene therapy.

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The purpose of this study is to clarify the role of transforming growth factor (TGF) for ocular malignant tumors and to apply them in gene therapy. TGF signaling is required for eliciting the effects of Sonic hedgehog (Shh). Cyclopamine is a natural compound that is capable of suppression of Smoothened activity which is critical in Shh/Gli signal activation.1. Chemical carcinogen cocktail of 9,10-dimethyl-1,2-benzanthracene and phorbol-12-myristate-13-acetate was topically applied to eyelid of XPC-null mice every two days for 2 to 8 months, and epithelial tumors developed in eyelid. These tumors were treated daily with subcutaneous ingestion of cyclopamine for 7 days. Histology showed that cylopamine treatment suppressed BrdU incorporation and induced apoptosis in the majority of cells in these tumors.2. Squamous cell carcinoma cell line established from human burned-scar-derived SCC was used. The cells were maintained in Dulbecco's MEM. The cells were enhanced by adding recombinant Shh and this effect was abolished by adding cyclopamine. However, the proliferation of SCC cell line was not affected by adding cylopamine in the abscence of recombinant Shh.3. Cell suspension of SCC cell line was implanted subcutaneously by using a injection needle in the back of nude mice. Ten days after implantation, the animals were treated systemic cyclopamine at every two days for three times. The SCC cells express Shh in vivo in tumor developed in nude mice and inhibition of Shh signaling pathway by cyclopamine induced apoptosis and suppressed proliferation in the tumor. Cyclopamine inhibits proliferation and induces apoptosis in epithelial tumor cells in vivo. The hedgehog pathway may be a potential therapeutic target for patients with eyelid tumors.