INHIBITION OF HEPARIN-BINDING GROWTH FACTORS

抑制肝素结合生长因子。持续性前列腺癌

Inhibition of Heparin-Binding Growth Factors. Sustained prostate cancer growth and metastasis requires paracrine signals between the tumor cells and the normal surrounding host tissue. One crucial function of these signals is to recruit endothelial cells and thus new blood vessels for the nourishment of the expanding tumor mass. This proliferation and migration of endothelial cells in the vicinity of progressing tumors con- trasts with the extremely low turn-over rate of endothelial cells in the healthy adult. Thus, a selective blockade of the tumor-induced endothelial cell proliferation should inhibit tumor growth and potentially metastasis with only few adverse effects. We found that the most effective endothelial cell growth factors released from prostate cancer cells in vitro are heparin-binding growth factors (HBGFs) and we have therefore focused our search for inhibitors on heparin-like polysulfates. We have demonstrated that HBGF action in vitro can be blocked by a structural analogue of heparin: pentosanpolysulfate (PPS). Furthermore, the growth of human prostate cancer cell lines into tumors in athymic nude mice can be inhibited by the treatment of the animals with PPS. PPS was effective against tumors derived from in vitro PPS-sensitive and from in vitro PPS-resistant tumor cell lines. This data suggests that PPS blocks the hosts' reaction to the HBGF(s) released from the tumor cells. We propose the following studies: 1. To study the efficacy of PPS in a Phase II trial with prostate cancer patients. In an ongoing Phase I trial with PPS in patients with advanced cancer, we will determine a dose schedule that is safe and maintains continuously high concentrations of biologically active drug in the patients. 2. To develop new synthetic heparinoids as HBGF-inhibitors in vitro and in vivo. In particular, to find analogues with improved therapeutic index. 3. To determine to what extent endothelial cell proliferation in normal, hypertrophic and cancerous prostate tissue can serve as an indicator of the disease state, prognosis of the patient and responsiveness to therapy. 4. To probe for expression of known HBGF genes in normal, hypertrophic and cancerous prostate tissue as potential markers of the progression and prognosis of the disease as well as therapeutic response to the HBGF-targeted therapy. An important aspect of our studies is to analyze the results according to the ethnic origin of the patients. This should enable us to detect differences in the biological and molecular markers and thus understand differences in the prognosis and therapeutic responsiveness of prostate cancer.