Although toxin may have some advantages compared to chemotherapeutic drugs in
cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid
tumors still remains to be fully demonstrated. In this study, we genetically modified the structure of the plant-derived single-chain
ribosome inactivating protein saporin (SAP) by fusing its N-terminus to the ACDCRGDCFCG
peptide (RGD-4C), an αv-
integrin ligand, and explored the anti-
tumor activity of the resulting
protein (called RGD-SAP) in vitro and in vivo, using a model of muscle invasive
bladder cancer. We found that the RGD-4C targeting domain enhances the cytotoxic activity of SAP against various tumor cell lines, in a manner dependent on αv-
integrin expression levels. In a subcutaneous syngeneic model of
bladder cancer, RGD-SAP significantly reduced
tumor growth in a dose-dependent manner. Furthermore, systemic administration of RGD-SAP in combination with
mitomycin C, a chemotherapeutic drug currently used to treat patients with
bladder cancer, increased the survival of mice bearing orthotopic
bladder cancer with no evidence of systemic toxicity. Overall, the results suggest that RGD-SAP represents an efficient drug that could be exploited, either alone or in combination with the state-of-the-
art therapies, for the treatment of
bladder cancer and, potentially, of other solid
tumors.