Combination Antiangiogenic and Inmmunomodulatory Gene Therapy for Breast Cancer
Annual rept. 1 May 1999-1 May 2000
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may he resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro as determined in endothelial cell proliferation assays as well as in vivo by suppression of angiogenesis induced by VEGF165. Persistent high serum levels of endostatin 605- 1740 ngml mean 936 ngml was achieved after systemic administration of the vector to nude mice which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma p0.001 and p0.05, respectively. In addition, the endostatin vector treatment completely prevented the formation of pulmonary micro-metastases in Lewis lung carcinoma p0.0001. lmmunohistochemical staining of the tumors demonstrated a decreased vascularity in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy in cancer treatment. Changes in vector design, however, resulting in higher transgene expression levels, may even lead to stronger anti-tumor activity.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research