OXIGENE CA4P-212 FOR SUBJECTS WITH ADVANCED IMAGEABLE MALIGNANCIES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 尽管放射治疗、化疗和手术在治疗癌症方面取得了进展，但许多实体肿瘤仍然无法治愈。迫切需要具有新的作用机制的治疗方法，这种机制可能与化疗和放射治疗协同作用。肿瘤血管形成已成为肿瘤新疗法发展的一个新靶点，主要针对阻止新血管形成和生长的化合物(即抗血管生成治疗)。另一种方法是使用血管破坏剂(VDA)针对现有的肿瘤血管系统进行治疗(即抗血管治疗)。通过这种方法，肿瘤血流受阻，由于氧气和营养物质的缺乏，导致肿瘤细胞广泛死亡。在动物模型中，有几种药物被证明可以导致显著的肿瘤血管关闭，但剂量会导致令人望而却步的毒性。 复方苦参素A-4磷酸(CA4P)是一种新型抗癌药物，对肿瘤血管具有较强的选择性毒性。CA4P是一种合成的、水溶性的、磷酸化的前体药物，是天然产物comretasteatin A-4(CA4)的产物，最初从非洲灌木柳树的树皮中分离出来。在体外，母体CA4是一种强大的微管蛋白结合剂，具有很强的阻止微管蛋白聚合的活性。尽管CA4P抗血管作用的确切机制仍在研究中，但临床前证据表明，它可能是内皮细胞损伤的结果。 在临床上，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名晚期恶性肿瘤患者。由于这些I期试验的II期建议范围很广，仍然很难为化疗的II期研究选择最佳剂量。总而言之，解释的I期试验表明，实际最大耐受量(MTD)约为67毫克/平方米(75毫克/平方米盐分形式)，在部分患者中可能更高。 在选择剂量时需要进一步考虑的是CA4P和化疗的毒性不重叠。由于最佳生物剂量不一定与MTD一致，因此回顾了肿瘤血流灌注变化的I期数据。结果表明，47~61 mg/m2的剂量(盐型分别为52 mg/m2和68 mg/m2)能有效地降低DCE-MRI的肿瘤血流灌注率20-50%，因此最佳的生物剂量可能接近MTD。现有的PET数据表明，这种影响可能会在更低的剂量下发生。 出于这些原因，本研究正在评估45毫克/平方米(50毫克/平方米盐分)和63毫克/平方米(70毫克/平方米盐分形式)的剂量，以努力解决这些第一阶段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.