This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is extensive literature supporting the paradigm that cancer development, invasiveness, metastatic potential, and response to therapy are related to tumor-associated angiogenic potential. This includes direct correlation of tumor-associated vascular density, as well as levels of vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) and other markers, with clinical course. Recent studies of women with breast cancer, using non-invasive Doppler sonography, offer the promise that tumor-associated vasculature and angiogenesis may be assessed without direct pathological analysis. Angiostatin is a compound which appears to act as a potent anti-angiogenic agent. Dr. Gerald Soff (Northwestern University) has shown that angiostatin can be generated in vivo. A series of studies have shown that the normal activation of plasminogen to plasmin was followed by an autoproteolytic process whereby plasmin was cleaved to form angiostatin 4.5, which can be mediated by a free sulfhydryl donor. tPA is clinically available and has been administered to humans in a variety of clinical scenarios for a number of years. In addition, a number of drugs are available which can serve as potential free sulfhydryl donors. It is thus reasonable to assume that angiostatin can be generated in vivo in humans, and that its generation will be associated with clinical activity. The purpose of this clinical trial is 1) to assess the toxicity of combining captopril with continuous infusion tPA in patients with progressive, metastatic cancer, 2) to measure the in vivo generation of angiostatin by Western analysis, and 3) to assess the anti-tumor effect of combining captopril with continuous infusion tPA in patients with progressive, metastatic cancer.
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