Sustained tumor growth 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. Abundant neovascularization is a characteristic of highly malignant glioblastoma multiforme. This tumor-induced proliferation and migration of endothelial cells contrasts with the extremely low turn-over rate of endothelial cells in the healthy adult. It is thus conceivable that a selective blockade of endothelial cell proliferation should inhibit tumor growth with only few adverse effects. We found that the most effective endothelial cell growth factors released from cancer cells in vitro are heparin-binding growth factors (HBGFs) and we have therefore focused our search for inhibitors of HBGFs 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 cancer cell lines into subcutaneous 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. These data suggest that PPS blocks the hosts' reaction to the HBGF(s) released from the tumor cells. A phase I trial in cancer patients was prompted by these preclinical studies. In an independent approach, we show that the endothelial cell inhibitor AGM 1470 can prevent angiogenesis induced by benign tumors (e.g. schwannomas) as well as by glioblastomas and inhibit tumor progression in vivo. We propose the following studies: 1. To probe for expression of known HBGF genes in normal and cancerous brain tissues as potential molecular markers of the progression and prognosis of the disease as well as markers of a potential therapeutic response to an HBGF-targeted therapy. 2. To determine to what extent endothelial cell proliferation in normal and cancerous brain tissues can serve as a biological indicator of the disease state, prognosis of the patient and responsiveness to therapy. 3. To study PPS and new synthetic heparinoids as HBGF-inhibitors. In particular, to find analogues with improved therapeutic index that act on brain tumors in vivo. 4. To study the novel endothelial cell inhibitor AGM 1470 for its ability to inhibit growth of brain tumors alone and combined with PPS.
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