Targeted Prodrug Therapy of Liver Cancers

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DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) and advanced colorectal cancer (CRC) are among the most deadly diseases of mankind. CRC is the second leading cause of cancer-related death in the United States, mostly due to metastases. Hepatic metastases are the main threat for successful treatment of CRC. 5-fluorouracil (5-FU). remains the mainstay of combination chemotherapy for nonresectable liver metastases. Recent studies have demonstrated that regional 5-FU-based chemotherapy by directly hepatic fusion showed improved response rates and survival for advanced CRC patients as compared with those undergone systemic infusion treatment. However, this delivery system is technically complicated and highly invasive. The present application describes the development of a novel delivery system for the treatment of hepatic metastases of CRC. The approach involves the use of a recombinant fusion protein consisting of malarial circumsporozoite (CS) protein, a hepatocyte-specific targeting ligand, linked to bacterial cytosine deaminase (CD), a "suicide gene" product which catalyzes the synthesis of 5-fluorouracil (5-FU) from its prodrug 5-fluorocytosine (5-FC). We have demonstrated in cultured cells that the CD-CS fusion protein can be internalized by a cell type-specific manner. More importantly, the internalized recombinant protein is stable for at least four weeks and exerts bystander cell killing effects upon the administration of prodrug 5-FC. The prolonged stability is probably attributed to the mechanism that the internalized fusion recombinant protein is entrapped in particular compartment(s) that are free from cytoplasmic degradation machinery. To further develop this system, we propose the following three specific aims: (A) to elucidate the mechanism(s) underlying the prolonged stability of CD-CS in cultured cells; (B) to investigate the targeting specificity, protein stability, and enzymatic activity of CD-CS in normal mice; and (C) to investigate the efficacy of CDCS/5-FC strategy in the treatment of liver metastases of colorectal cancers in animal model. We envision that the novel hepatic prodrug targeted therapy strategy proposed here, if successfully, is technically simple and non-invasive, and cost effective, therefore, should greatly improve the treatment efficacy of these life threatening diseases.