SUBJECTS WITH ADVANCED IMAGEABLE MALIGNANCIES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。尽管通过放疗、化疗和手术治疗癌症取得了进展，但许多实体瘤仍然无法治愈。目前迫切需要具有新的作用机制的治疗方法，可以与化疗和放疗协同作用。肿瘤血管已成为最近癌症新疗法发展的一个目标，其重点主要针对防止新血管形成和生长的化合物（即抗血管生成疗法）。另一种治疗方法是使用血管破坏剂（vda）靶向肿瘤现有血管系统（即抗血管治疗）。通过这种方法，肿瘤血液流动受阻，导致广泛的肿瘤细胞死亡，这是氧气和营养剥夺的结果。几种药物在动物模型中显示可引起明显的肿瘤血管关闭，但剂量会引起禁毒性毒性。Combretastatin a -4 Phosphate （CA4P）是一种新型抗癌药物，对肿瘤血管具有强效和选择性的毒性。CA4P是天然产物combretastatin a -4 （CA4）的合成，水溶性磷酸化前药，最初从非洲灌木柳树Combretum caffrum的树皮中分离出来。在体外，母体CA4是一种强的微管蛋白结合剂，在阻止微管蛋白聚合方面具有有效的活性。尽管CA4P抗血管作用的确切机制仍在研究中，临床前证据表明它可能是内皮细胞损伤的结果。临床方面，截至2002年1月，CA4P在三个I期试验中进行了评估，其中包括96例晚期恶性肿瘤患者。由于这些I期试验推荐的II期剂量范围很大，因此选择化疗的最佳II期剂量仍然很困难。综上所述，解释的I期试验表明，真正的最大耐受剂量（MTD）约为67 mg/m2 （75 mg/m2盐形式），并且在患者亚群中可能更大。在剂量选择中需要进一步考虑的是CA4P和化疗的非重叠毒性。由于最佳生物剂量可能不一定与MTD一致，因此回顾了肿瘤灌注变化的I期数据。根据DCE（动态对比成像）-MRI， 47 mg/m2至61 mg/m2（分别为52和68 mg/m2盐形式）的剂量可有效减少肿瘤灌注20-50%，因此最佳生物剂量可能接近MTD。现有的PET数据表明，即使是更低的剂量也可能产生这种效应。由于这些原因，本研究正在评估45 mg/m2 （50 mg/m2盐形式）和63 mg/m2 （70 mg/m2盐形式）的剂量，以努力解决这些I期研究提出的不同建议。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite advances in the management of cancer with radiotherapy, chemotherapy and surgery, many solid tumors remain incurable. There is an urgent need for treatments with new mechanisms of action, which may act synergistically with chemotherapy and radiotherapy. Tumor vasculature has become a recent target in the development of new cancer therapies, with the focus aimed primarily on compounds that prevent the formation and growth of new blood vessels (i.e., anti-angiogenesis therapy). An alternative approach is therapy targeted against the existing vasculature of tumors (i.e., anti-vascular therapy) using vascular destructing agents (VDAs). Through this approach, tumor blood flow is impeded, leading to extensive tumor cell death as a consequence of oxygen and nutrient deprivation. Several agents have been shown in animal models to cause marked tumor vascular shutdown, but at doses that cause prohibitive toxicity. Combretastatin A-4 Phosphate (CA4P) is a novel anti-cancer agent that displays potent and selective toxicity towards tumor vasculature. CA4P is a synthetic, water soluble, phosphorylated prodrug of the natural product combretastatin A-4 (CA4), which was originally isolated from the bark of the African bush willow, Combretum caffrum. In vitro, the parent CA4 is a strong tubulin-binding agent that has potent activity in preventing tubulin polymerization. Although the exact mechanism for the anti-vascular effects of CA4P remain under investigation, preclinical evidence suggests that it may be a consequence of endothelial cell damage. Clinically, CA4P was evaluated in three Phase I trials as of January 2002, which included 96 patients with advanced malignancies. Due to the range of Phase II recommendations from these Phase I trials, it remains difficult to choose a best dose for Phase II studies with chemotherapy. Taken together, the interpreted Phase I trials suggests the real maximum tolerated dose (MTD) is approximately 67 mg/m2 (75 mg/m2 salt form) and may be even greater in subsets of patients. Points of further consideration involved in the choice of doses are the non-overlapping toxicities of CA4P and chemotherapy. Since the optimal biologic dose may not necessarily coincide with the MTD, Phase I data for changes in tumor perfusion were reviewed. It appears that doses between 47 mg/m2 and 61 mg/m2 (52 and 68 mg/m2 salt form, respectively) are effective in reducing tumor perfusion based on DCE (dynamic contrast imaging)-MRI from 20-50%, so the optimal biologic dose may be close to the MTD. There exist PET data that suggest the effects may occur at even lower doses. For these reasons, this study is evaluating doses of 45 mg/m2 (50 mg/m2 salt form) and 63 mg/m2 (70 mg/m2 salt form) in an effort to resolve the divergent recommendations made by these Phase I studies.