CLINICAL EVALUATION OF PENTOSAN POLYSULFATE

血管生成（新血管的形成）是生长所必需的。 肿瘤组织 癌细胞通常释放肝素结合生长 因子（HBGFs），血管生成的有效刺激剂。 戊聚糖多硫酸 (PPS)，一种结构上与肝素相关的硫酸化多糖， HBGF并抑制其活性。 PPS预防无胸腺肿瘤生长 注射致瘤人类癌细胞的小鼠，并可以延迟或预防 Huggins大鼠乳腺癌发生模型中的化学致癌作用。 PPS在给药前长期给予动物时非常有效， 肿瘤的外观，但不阻止大多数已建立的肿瘤的生长， 可能是因为PPS不能有效地抑制大量的 由较大肿瘤释放的HBGF。 PPS在欧洲临床上用作 抗凝剂，临床不良反应少。 我们目前正在进行皮下PPS的I期临床试验， 晚期癌症患者，评估临床安全性和 抗癌活性。 我们还在评估（a）抗凝作用 （B）PPS的血浆水平（通过ELISA）;和（c）PPS的血浆浓度（通过ELISA）。 治疗患者阻断HBGF介导的细胞增殖，使用 Lombardi中心开发的新型生物测定法。 初步结果 证明高循环水平的“抗HBGF”活性可以 在患者血浆中维持，PPS剂量产生最小 抗凝 我们现在建议（1）完成正在进行的PPS I期研究;（2） 进行口服的I期临床药理学和生物利用度研究 PPS;（3）在以下患者中进行辅助PPS治疗的初步研究： 在III期或较差的治疗后临床上无疾病 II期乳腺癌的预后。 虽然临床上没有疾病， 这些病人大多数最终会复发并死于癌症。 这些患者的肿瘤负荷较低，可能是戊聚糖的理想受试者 治疗 这项初步研究将产生安全性数据和初步疗效 经验，用于规划未来的PPS III期试验，可能的话， 未来的化学预防研究 该计划的未来目标包括 其他抗凝剂较少的类肝素的临床评价 活性，但保留抗HBGF活性，和其他临床研究 抗血管生成剂（例如，FGF相关肽和AGM-1470）和新的 来自其它SPORE程序或其它源的代理（例如，我们的U 01药物 发现程序）。

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).