Plastic Surgery Research Council
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GENE-DIRECTED ENZYME PRODRUG THERAPY (GDEPT) IN A HUMAN TUMOR XENOGRAFT MODEL USING GENE-MODIFIED MUSCLE TISSUES AND CHEMOTHERAPEUTIC PRODRUG MOLECULES.
Presenter: Ergun Kocak, MD
Co-Authors: Carruthers KH; Choi E; During MJ
The Ohio State University

Background: Local recurrence following resection of solid tumors remains an ongoing challenge in cancer therapy. Most chemotherapy regimens rely on systemic administration of drugs and affect not only the target region, but also distant organs leading to a wide array of toxicities. Using viral-vector mediated gene modification of muscle tissues, we have developed a method for gene directed enzyme prodrug therapy (GDEPT). In our model, an inactive prodrug of the potent chemotherapeutic Geldanamycin is activated by muscle tissues gene-modified to express the enzyme beta-galactosidase.

Methods: Recombinant adeno-associated viral vectors (recAAV) were used to gene-modify the pectoralis muscles of nude mice by direct surgical injection. In the treatment group, gene-modification was accomplished with recAAV-lacZ to express beta-galactosidase. In the control group, muscles were injected with recAAV-GFP to express green fluorescence protein. One week later, human colon cancer cells (SW620) were implanted into the muscle. All animals were simultaneously treated with intramuscular injection of Geldanamycin chemotherapeutic prodrug. Tumors were serially measured and tumor weights and histology were assessed.

Results: Tumor growth was significantly suppressed in animals whose muscles were gene-modified to express beta-galactosidase compared to those that were gene-modified to express green fluorescence protein. Host muscle tissues non-target organs were evaluated histologically and by measuring serum chemistries. Minimal damage to the non-target organs was seen.

Conclusion: Recombinant adeno-associated viral vectors, with high avidity for muscle tissues, can be used to gene-modify muscle tissues to express enzymes that can subsequently serve to activate chemotherapeutic prodrugs to provide local tumor suppression that has minimal effect on non-target organs. Such GDEPT methods might be used in muscle flaps that are used to reconstruct tumor reconstruction beds to provide therapeutic tumor control in addition to reconstructive coverage of the wound.


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