Angiogenesis (the formation of new blood vessels) is required for growth of neoplastic tissues. Cancer cells commonly release heparin-binding growth factors (HBGFs), potent stimulants of angiogenesis. Pentosan polysulfate (PPS), a sulfated polysaccharide structurally related to heparin, binds to HBGFs and inhibits their activities. PPS prevents tumor growth in athymic mice injected with tumorigenic human cancer cells, and can delay or prevent chemical carcinogenesis in the Huggins rat mammary carcinogenesis model. PPS is very effective when given chronically to animals prior to the appearance of tumors, but does not block growth of most established tumors, probably because PPS cannot effectively inhibit the high quantities of HBGFs released by larger tumors. PPS is used clinically in Europe as an anticoagulant, and has few clinical adverse effects. We are currently conducting a phase I clinical trial of subcutaneous PPS in patients with advanced cancer, evaluating clinical safety and evidence of anticancer activity. We are also evaluating (a) the anticoagulant effects of PPS; (b) plasma levels of PPS (by ELISA); and (c) the ability of plasma of treated patients to block HBGF-mediated cellular proliferation, using a novel bioassay developed at the Lombardi Center. Preliminary results document that high circulating levels of """"""""anti-HBGF"""""""" activity can be maintained in patient plasma, at PPS doses which produce minimal anticoagulation. We now propose to (1) complete our ongoing Phase I study of PPS; (2) conduct a Phase I clinical pharmacology and bioavailability study of oral PPS; (3) conduct a pilot study of adjuvant PPS treatment in patients who are clinically disease-free following treatment for stage III or poor prognosis stage II breast cancer. Although clinically free of disease, most of these patients will eventually relapse and die with their cancer. These patients, with a low tumor burden, may be ideal subjects for pentosan treatment. This pilot study will yield safety data and pilot efficacy experience, for planning of future Phase III trials of PPS and, possibly, future chemoprevention studies. Future aims of this program include clinical evaluation of other heparinoids which have lesser anticoagulant activity but retain anti-HBGF activity, and clinical studies of other antiangiogenic agents (e.g., FGF-related peptide and AGM-1470) and novel agents from other SPORE programs or other sources (e.g., our U01 drug discovery program).
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