77,78 Suramin, a sulfonated naphthylurea, has multiple antitumor effects (including an ability to block heparanase activity) but causes relatively severe side-effects in humans.79 PI-88 is a yeast-derived phosphosulfomannan that performed well in phase I and II clinical trials, exhibiting efficacy against several cancers.80 In addition to blocking heparanase activity, it also interferes Inhibitors,research,lifescience,medical with growth factor interactions, leading to inhibition
of angiogenesis.81 However, because PI-88 is a complex mixture of oligosaccharides, characterization of its structure-activity relationships has been complicated, thereby necessitating attempts to generate analogs with desirable pharmacokinetic properties.82 A significant progress is represented by the PG500 series, a collection of new HS mimetics based on anomerically pure, fully sulfated, oligosaccharide glycosides modified by the addition of an aglycone at the reducing end Inhibitors,research,lifescience,medical of
the molecule.82 The aglycones are primarily lipophilic groups chosen specifically to improve the biological activities, primarily the efficacy and pharmacokinetic properties. PG500 series compounds are believed to interfere with two important processes in tumor development, namely angiogenesis via inhibition of VEGF, FGF-1, and FGF-2, and metastasis via inhibition of heparanase activity. Inhibitors,research,lifescience,medical Compound PG545 was tested in a HT29 colon xenograft model and found to inhibit markedly tumor development comparable with the standard of care chemotherapeutic agent Inhibitors,research,lifescience,medical 5-fluorouracil (5-FU).
The fact that administration of these agents to tumor-bearing animals led to significant tumor growth inhibition strongly supports further development of these HS mimetics for the treatment of cancer. Heparin is a Inhibitors,research,lifescience,medical potent inhibitor of heparanase, but its use at high doses is impossible due to the potential for anticoagulant activity.83 Interestingly, low-molecular-weight heparin (LMWH), being more bioavailable and less anticoagulant than heparin, appears to prolong survival of patients with cancer. In several randomized controlled trials, four selleck kinase inhibitor different types of LMWH increased the survival of patients with advanced cancer.84 Indeed, rather than just preventing fatal pulmonary emboli in cancer patients, it seems more likely that LMWH has direct effects on tumor growth and metastasis. This until may be due, at least in part, to inhibition of heparanase enzyme activity by LMWH. On the basis of the structure-activity relationship emerging from our heparanase inhibition studies and in view of clinical data on the anticancerous and anti-inflammatory effect of heparin,84 we initiated a systematic study aimed at obtaining heparanase-inhibiting species of heparin devoid of anticoagulant and proangiogenic activities.