Development of anti-cancer reagent utilizing cytotoxic potential of human ribonucleases

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Pancreatic-type RNases are considered to have cytotoxic potential, because they can degrade RNA molecules when enter the cytosol. However, most of these RNases are virtually little toxic because cells have no active uptake mechanism for these RNases and because ubiquitous cytoplasmic RNase inhibitor is considered to play protective role against endocytotic leak of RNases from outside of cells. To study the cytotoxic potential of RNase toward malignant cells targeting growth factor receptors, the carboxyl terminus of human RNase 1 was fused to the amino terminus of human basic fibroblast growth factor (bFGF). This RNase-FGF fused protein was found to effectively inhibited the growth of mouse melanoma cell line B 16/BL6 with the high level of cell surface FGF receptor.This effect appeared to result from prolongation of overall cell cycle rather than killing cells or specific arrest in a particular phase of cell cycle. Thus human RNase 1 fused to a ligand of cell surface molecules such as FGF receptor is shown to be an effective candidate for selective cell targeting agent toward malignant cells with low toxic effects on normal cell types.