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19 The Logic of Anti-angiogenic Gene Therapy

Judah Folkman, Philip Hahnfeldt, Lynn Hlatky


Virtually all current strategies for gene therapy of cancer target the cancer cell. The goal is the destruction of cancer cells in the primary tumor and in its metastases. These approaches include, among others, the introduction of genes that (1) permit tumor cells to express toxic molecules; (2) prevent or correct genetic defects; (3) increase the immunogenicity of tumor cells; or (4) increase the sensitivity of tumor cells to drugs (Friedmann 1996; Blaese 1997; Lowenstein 1997; Roth and Cristiano 1997). Although gene therapy of cancer may be inherently less toxic than conventional chemotherapy, it may still have to overcome at least three other fundamental obstacles that hinder conventional chemotherapy, i.e., limited access to tumor cells, heterogeneity of tumor cells, and emergence of resistant tumor cells. Whereas conventional chemotherapy is directed mainly against tumor cells, anti-angiogenic therapy is directed specifically against microvascular endothelial cells that have been recruited into the tumor bed. In contrast to chemotherapy, specific anti-angiogenic therapy has little or no toxicity, does not require that the therapeutic agent enter any tumor cells nor cross the blood brain barrier, acts independent of tumor cell heterogeneity, and does not induce acquired drug resistance (Boehm et al. 1997). In addition, the effectiveness of anti-angiogenic therapy is independent of tumor type and growth fraction. Therefore, it may be fruitful to consider gene therapy of cancer that is optimized to the endothelial cell population of the tumor bed, e.g., anti-angiogenic gene therapy. We do not view anti-angiogenic gene therapy and anticancer cell gene...

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