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。癌细胞通常释放与肝素结合的生长 因子(HBGFs)，有效的血管生成刺激物。聚硫代戊聚糖 (PPS)是一种结构上与肝素相关的硫化多糖，与 HBGFs，并抑制其活动。PPS预防裸鼠肿瘤生长的实验研究 注射致癌人类癌细胞的小鼠，可以延缓或预防 化学致癌在Huggins大鼠乳腺癌模型中的应用。 PPS是非常有效的，如果长期给动物之前， 肿瘤的出现，但不会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 较大的肿瘤会释放HBGFs。PPS在欧洲临床上用作一种 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，评估临床安全性和证据 抗癌活性。我们还在评估(A)抗凝效果 PPS水平；(B)血浆PPS水平(用酶联免疫吸附试验)；和(C)血浆能力 使用一种新的治疗方法来阻断HBGF介导的细胞增殖 隆巴迪中心开发了新的生物检测方法。初步结果 证明循环中的高水平的“抗HBGF”活动可能是 维持在患者血浆中，剂量为PPS，产生最小 抗凝剂。 我们现建议：(1)完成现正进行的私人参建计划第一阶段研究；(2) 进行口服液的I期临床药理及生物利用度研究 PPS；(3)对以下患者进行PPS辅助治疗的试点研究 在接受III期或较差的治疗后临床上没有疾病 预后II期乳腺癌。虽然临床上没有疾病， 这些患者中的大多数最终会复发并死于癌症。 这些患者的肿瘤负担较低，可能是戊聚糖治疗的理想对象。 治疗。这项先导研究将产生安全性数据和先导疗效。 经验，用于规划未来PPS的第三阶段试验，并可能 未来的化学预防研究。该计划的未来目标包括 其他抗凝剂较少的肝素类药物的临床评价 活性，但保留抗HBGF活性，以及其他 抗血管生成药物(如成纤维细胞生长因子相关肽和AGM-1470)和新的 来自其他孢子程序或其他来源的药物(例如，我们的U01药物 发现计划)。

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).