Angiogenesis of solid tumors is an important target of cancer therapy. It has been well recognized that growth and metastasis of solid tumors require persistent angiogenesis and that induction of angiogenesis is a discrete component of the tumor phenotype. Vascular endothelial growth factor and its cognate receptors (VEGFR1 and 2) are critical factors in promoting tumor angiogenesis. Our laboratory has recently identified a catalytic oligodeoxynucleotide (DNAzyme) that targets the VEGFR2 mRNA transcript. With intratumoral injections of subcutaneous implanted breast cancer, the VEGFR2 DNAzyme was found to inhibit tumor growth markedly in vivo. One objective of this proposal is to extend this therapy to a clinically relevant model, C6 gliomas. Our laboratory has also synthesized a polymer composed of histidine and lysine (HK polymer) that significantly increases transfection and oligonucleotide delivery. The linear and branched HK polymers offer the potential for effective delivery of therapeutic oligonucleotides including DNAzymes. Our overall aim and long term goal is to develop an effective antiangiogenic oligonucleotide approach to reduce tumor growth in vivo.
Aim 1 is designed to improve the bioactivity efficiency of the DNAzyme targeting the mRNA of the VEGF 2 receptor. Although the DNAzyme targeting VEGFR2 developed by our laboratory effectively reduced tumor growth, modification of the annealing arms by the addition ofphosphorothioate linkages is expected to augment the potency of the DNAzyme. Therefore, the current VEGFR2 DNAzyme will be modified to augment its resistance to enzymatic degradation and thus increase its bioactivity. To transport the DNAzyme more effectively to tumor endothelial cells, Aim 2 will determine a more effective branched HK cartier of the DNAzyme. Several HK polymers that vary in the degree of branching and the histidine/lysine ratio will be tested for their ability to increase the efficacy of the DNAzyme. The most effective HK carrier will then be modified with a ligand to further augment the uptake of the complex into tumor endothelial cells. With improved design of HK-containing complexes, it is anticipated that this cartier in complex with the VEGFR DNAzyme will have more anfitumor efficacy toward an orthotopically implanted glioma.
| Leng, Qixin; Mixson, Archibald James (2005) Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo. Cancer Gene Ther 12:682-90 |
