Tumor-Targeted Salmonella
Genetically engineered Salmonella offer an intriguing new approach to selectively target solid tumors, including melanoma, lung, colon, breast, kidney and liver. These bacteria target tumors after systemic administration and selectively replicate within t
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TUMOR-TARGETED SALMONELLA Highly Selective Delivery Vectors
David Bermudes1*, Brooks Low2, and John Pawelek3 1
Vion Pharmaceuticals, Inc. 4 Science Park, New Haven Connecticut 06511 USA and Yale University School of Medicine Departments of Therapeutic Radiology2 and Dermatology3 333 Cedar Street, New Haven Connecticut 06520 USA
1. BACKGROUND The development of novel cancer therapies presents a formidable challenge to find means to selectively target and eradicate neoplastic cells while sparing healthy tissue. Cancerous cells arising from normal cells in the body have few and often subtle differences from their normal counterparts. Vasculature supplying the tumor is generally irregular and positive pressure within the tumor combines to create a physical barrier to penetration, often reducing the effectiveness of therapeutic agents (Boucher et al., 1996; Jain, 1994). Thus the mandate for new therapeutic agents is not only to exploit differences that tumors may exhibit whereby the agent used is more toxic to cancerous cells than to normal cells, but to overcome the barriers that limit their delivery to the tumor. One approach has been to develop methods to selectively bind to tumor cells using antibodies. Highly specific monoclonal antibodies directed to tumor-associated antigens such as Lewis y or HER2/neu, have the ability to be administered sysemically and to preferentially accumulate at the site of the tumor cells to which they bind. The anti-cancer activity of these antibodies has been enhanced in several ways. Such antibodies have been used to target cells overexpressing certain antigens and carry enzymes that activate nontoxic prodrug forms of chemotherapeutic agents, inducing selective toxicity at the site of *To whom correspondence should be sent: [email protected], Tel: (203) 498-4210×304, Fax: (203) 498-4211 Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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accumulation. These antibodies have also been directly coupled to toxic agents, or used in combination with them, including small molecule chemotherapeutics such as doxirubicin (Trail et al., 1993; Baselga et al., 1998) or protein toxins such as pseudomonas endotoxin (Friedman et al., 1993; Siegall, 1995). Yet while these or similar agents hold promise for providing selective delivery to tumors, they are subject to the same limitations posed by the fundamental barriers encountered by other agents requiring both the vasculature and diffusion to accomplish delivery into poorly vascularized tumors having positive pressure. Thus, antibody agents would be expected to be limited to the periphery of tumors and the selective accumulation in tumors predicted to be relatively low (Jain, 1994). Gene therapy agents directed towards cancer are based on the principle of altering the cancer cells by introduction of genetic material in the form of modified viruses, plasmids, ribozymes, and other nucleic acid-based vectors. Specificity for cancerous cells
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