For tumors to grow and metastasize, they must induce the generation of new blood vessels, a process referred to as angiogenesis. Inhibition of angiogenesis thus provides an important new therapeutic target. The angiogenesis inhibitor angiostatin is a kringle-containing internal fragment of plasminogen, which has been shown to inhibit cancer growth in numerous animal models. In previous R01-supported work at Northwestern University, Soff et al. have demonstrated the mechanism of generation of native human angiostatin. Plasminogen is first converted to plasmin by a plasminogen activator, and in the presence of a free sulfhydryl donor, plasmin undergoes autoproteolysis within kringle 5 to yield Angiostatin 4.5(AS4.5), consisting of the first 4 kringles as well as 85 percent of kringle 5. AS4.5 is present in normal and malignant blood and other specimens and is a potent inhibitor of angiogenesis and cancer growth in vivo. Of particular interest, in initial experiments in mice and humans with cancer, administration of an antiangiogenesis cocktail, consisting of a plasminogen activator and a free sulfhydryl donor results in marked increases in AS4.5 levels and inhibition of tumor growth. While ongoing work continues in better understanding the nature in vitro of AS4.5 activity, we are interested in more rigorously studying the in vivo generation of AS4.5 in human patients with advanced malignancies. The focus of this quick trial grant application is to determine in Phase I fashion the safe dosage range of drugs in the """"""""cocktail,"""""""" namely tissue plasminogen activator (tPA) and mesna. In addition, we will determine the dose response relationship of the agents in the antiangiogenesis cocktail with the levels of AS4.5. This will allow a rigorous calculation of the half-life, volume of distribution and area under the curve of this uniquely in vivo-generated anti-neoplastic therapy.
| Soff, Gerald A; Wang, Hao; Cundiff, Deborah L et al. (2005) In vivo generation of angiostatin isoforms by administration of a plasminogen activator and a free sulfhydryl donor: a phase I study of an angiostatic cocktail of tissue plasminogen activator and mesna. Clin Cancer Res 11:6218-25 |
| Wang, Hao; Schultz, Ryan; Hong, Jerome et al. (2004) Cell surface-dependent generation of angiostatin4.5. Cancer Res 64:162-8 |
| Hanford, Holly Anne; Wong, Christie A; Kassan, Hallie et al. (2003) Angiostatin(4.5)-mediated apoptosis of vascular endothelial cells. Cancer Res 63:4275-80 |
