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Departments of Dermatology and Pharmacology [J. M. P.], Therapeutic Radiology [K. B. L.], and Internal Medicine [D. B.], Yale University School of Medicine, New Haven, Connecticut 06520
There has been little investigation of bacteria as gene delivery vectors. Here, we demonstrate that genetically engineered Salmonella have many of the desirable properties of a delivery vector, including targeting of multiple tumors from a distant inoculation site, selective replication within tumors, tumor retardation, and the ability to express effector genes, such as the herpes simplex virus thymidine kinase (HSV TK). When wild-type Salmonella were introduced into melanoma-bearing mice, the bacteria were found within the tumor at levels exceeding 109 per g, although as pathogens, they caused the death of the mice. However, when attenuated, hyperinvasive auxotrophic mutants were used, the tumor-targeting and amplification phenomena were retained, whereas their pathogenicity was limited. With such attenuated strains, the tumor:liver ratios ranged between 250:1 and 9000:1. When these auxotrophs were inoculated i.p. into C57B6 mice bearing B16F10 melanomas, they suppressed tumor growth and prolonged average survival to as much as twice that of untreated mice. A plasmid containing the HSV TK gene with a ß-lactamase secretion signal was constructed that, when expressed, resulted in translocation to the periplasm and phosphorylation of the prodrug ganciclovir. Melanoma-bearing animals inoculated with HSV TK-expressing Salmonella showed ganciclovir-mediated, dose-dependent suppression of tumor growth and prolonged survival in addition to that seen with bacteria alone. The results demonstrate that attenuated Salmonella would be useful both for inherent antitumor activity and delivery of therapeutic proteins to cancer cells in vivo.
1 This work was supported by a grant from Vion Pharmaceuticals.
2 To whom requests for reprints should be addressed, at Department of Dermatology, 333 Cedar Street, P.O. Box 208059, New Haven, CT 06520. Phone: (203) 785-4411; Fax: (203) 785-7637; E-mail: sodi@biomed.med.yale.edu.
3 Present address: Vion Pharmaceuticals, Four Science Park, New Haven, CT 06511.
Received 3/ 6/97. Accepted 8/16/97.
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