Since the first angiogenesis inhibitors were discovered in our laboratory in the early 1980s, at leat 8 angiogenesis inhibitors are currently in clinical trial for advance cancer. These can slow, but not regress tumor growth in animals. We have recently discovered two angiogenesis inhibitors capable of complete or nearly complete inhibition of tumor angiogenesis, angiostatin a 38 kD fragment of plasminogen and endostatin an 18kD fragment of collagen XVIII. They regress tumors that are 1% of mouse body weight to a microscopic dormat state.
In Aim 1 we will produce recombinant endostatin from E.Coli and from baculovirus; isolate the receptor for endostatin on endothelial cells; determine the minimal structure for antiangiogenic activity; and, determine the enzyme(s) which release endostatin from collagen XVIII.
In Aim 2 we will develop animal models of long-term tumor dormancy due to blocked angiogenesis by: (I) endostatin therapy for 2 to 24 months; (ii) gene transfection of angiostatin into tumor cells; and (iii) selection of metastatic tumor cell clones that are not angiogenic in the target organ.
In Aim 3 we will show that the antiangiogenic activity of certain cytotoxic chemotherapeutic agents (e.g, cyclophosphamide) can be enhanced by changing the dose and schedule of administration. We will determine if this strategy can produce stable disease even in tumor cells that are already drug resistant. These studies have immediate clinical application. They show that """"""""dormancy therapy"""""""" by blocked angigenesis could potentiate chemotherapy, radiotherapy or immunotherapy. They provide a strategy to treat drug-resistant tumors. They provide the first mouse model for long-term dormancy similar to human tumors.
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