New Enzyme Prodrug and Methionine-Depletion Combination Therapy of Breast Cancer Designed for Effective Delivery to the Tumor
Annual rept. 15 Sep 2010-14 Sep 2011
OKLAHOMA UNIV NORMAN
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Recombinant L-methioninase-annexin V and cytosine deaminase-annexin V fusion proteins have been produced in good purity and yield from E. coli, with both FP genes of the correct sequence. As indicated by measuring the dissociation constant Kd, both purified FPs bind strongly to human endothelial cells, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells grown in vitro. In vitro tests of both enzyme prodrug systems showed that significant killing of endothelial cells, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells 80 confluent was obtained with very little or no effect of the prodrug when the FP was not present. The Lmethioninaseannexin VSeMet enzyme prodrug system was tested in vivo in nude mice with implanted MDA-MB- 231GFP cancer cells using i.p. injection of the FP and the prodrug. The result was that the tumors were nearly completely eliminated. These results provide strong support for the idea that this enzyme prodrug system will lead to the elimination of breast tumors wherever they occur in the body.
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