LIPOPHILIC PROBES FOR TUMOR CELL SURFACES

对于许多白血病或播散性实体瘤患者 他们在标准治疗后复发，非常密集 化疗/放疗后再进行骨髓移植可以提供 只有长期无病生存的现实机会。 使用患者自己的(自体)骨髓移植 随着不是候选的患者的频率增加 异基因骨髓移植，因为他们的年龄或因为 他们缺乏组织相容的骨髓捐赠者。然而，完整的 自体骨髓移植的潜力无法实现 除非我们找到方法去除自体移植物中的隐匿性克隆 肿瘤细胞。这项提议是围绕这样一种假设提出的 亲脂性花菁染料等的光敏化 AS MC 540可选择性杀伤体内残留肿瘤细胞 自体骨髓移植。尽管MC 540介导的 光敏化降低了实验中的浓度 白血病细胞超过100,000倍而不过量 对多能干细胞室的损害，它可能不是 对一些自发性肿瘤是否同样有效 足以净化具有很高水平的骨髓 肿瘤细胞。因此，我们希望确定是否使用MC 540 与另一种清除剂(例如抗体、药物、 热疗)可以增强其抗肿瘤作用，而无需 增加干细胞的毒性。第二组实验的目的 在确定细胞和分子机制方面 调节MC 540与细胞的结合并介导 MC 540和LIGH对细胞的灭活作用。我们还将完成一个 MC 540介导的I期和II期临床试验 用于清除自体骨髓移植物的光敏化。 在这项试验中，我们将研究染料的影响- 介导型光敏化对造血干细胞的影响 移植物中的辅助细胞及其对植入和移植的影响 免疫功能的恢复。提案工作将 对MC 540与其相互作用产生新的见解 含有核DNA和质膜脂质的照相产品和 蛋白质中脂质过氧化和蛋白质交联的作用 MC 540介导的细胞毒作用及其临床应用 花菁染料。方法：正常对照和正常对照的克隆试验 染料介导的骨髓移植肿瘤细胞 光敏、热疗、流式细胞术、计算机 膜脂和膜脂的模拟、操作和分析 蛋白质，UV/Vis和荧光光谱，体细胞 遗传学。)

For many patients with leukemia or disseminated solid tumors who have relapsed after standard therapy, very intensive chemo/radiotherapy followed by a marrow transplant offers the only realistic chance of long-term disease-free survival. Transplantation of the patient's own (autologous) marrow is used with increasing frequency in patients who are not candidates for allogeneic marrow transplants because of their age or because they lack histocompatible marrow donors. However, the full potential of autologous marrow transplantation cannot be realized unless we find ways to rid autologous grafts of occult clonogenic tumor cells. This proposal is molded around the hypothesis that photosensitization mediated by lipophilic merocyanine dyes such as MC 540 can be used to selectively kill residual tumor cells in autologous bone marrow grafts. Although MC 540-mediated photosensitization reduces the concentration of experimental leukemia cells greater than 100,000-fold without excessive damage to the pluripotent stem cell compartment, it may not be equally effective against some spontaneous tumors or not be sufficient for the purging of marrows with very high levels of neoplastic cells. We therefore want to determine if using MC 540 in combination with another purging agent (e.g. antibody, drug, hyperthermia) can augment its antineoplastic effect without increasing stem cells toxicity. A second set of experiments aims at identifying the cellular and molecular mechanisms that regulate the binding of MC 540 to cells and mediate the inactivation of cells by MC 540 and light. We will also complete a phase I and initiate a phase II clinical trial of MC 540-mediated photosensitization for the purging of autologous marrow grafts. In the context of this trial we will study the effects of dye- mediated photosensitization on hematopoietic stem cells and accessory cells in the graft, and its effects on engraftment and the recovery of immune function. The proposal work will generate new insights into the interactions of MC 540 and its photoproducts with nuclear DNA and plasma membrane lipids and proteins, the role of lipid peroxidation and protein crosslinking in MC 540-mediated cytotoxicity, and the clinical usefulness of merocyanine dyes. (Methods: Clonal assays of normal and neoplastic cells, marrow transplantation, dye-mediated photosensitization, hyperthermia, flow cytometry, computer simulation, manipulation and analysis of membrane lipids and proteins, UV/VIS- and fluorescence spectroscopy, somatic cell genetics.)