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LIPOPHILIC PROBES FOR TUMOR CELL SURFACES

用于肿瘤细胞表面的亲脂性探针

基本信息

批准号：
3184255
负责人：
Fritz Sieber
金额：
$ 20.19万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-09-30 至 1991-07-31
项目状态：
已结题

项目摘要

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.)

对于许多患有白血病或播散性实体瘤的患者在标准治疗后复发的人，非常强化化疗/放疗后进行骨髓移植可提供长期无病生存的唯一现实机会。使用患者自己的（自体）骨髓移植不适合接受治疗的患者的频率越来越高由于年龄或因为同种异体骨髓移植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消除自体移植物的隐匿性克隆形成肿瘤细胞。该提案是围绕以下假设制定的：由亲脂性部花青染料介导的光敏作用，例如因为 MC 540 可用于选择性杀死体内残留的肿瘤细胞自体骨髓移植。虽然MC 540介导光敏作用降低了实验浓度白血病细胞大于100,000倍而不过量多能干细胞区室受损，可能不是对某些自发性肿瘤同样有效或无效足以清除具有非常高水平的骨髓肿瘤细胞。因此我们想确定是否使用 MC 540 与另一种净化剂（例如抗体、药物、热疗）可以增强其抗肿瘤作用，而无需增加干细胞毒性。第二组实验的目标识别细胞和分子机制调节 MC 540 与细胞的结合并介导 MC 540 和光使细胞失活。我们还将完成一个 MC 540介导的I期临床试验并启动II期临床试验用于净化自体骨髓移植物的光敏化。在本次试验中，我们将研究染料的影响介导造血干细胞的光敏作用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 及其交互产生新的见解具有核 DNA 和质膜脂质的光产物蛋白质、脂质过氧化和蛋白质交联的作用 MC 540 介导的细胞毒性及其临床用途部花青染料。（方法：正常和肿瘤细胞，骨髓移植，染料介导光敏化、热疗、流式细胞术、计算机膜脂的模拟、操作和分析蛋白质、紫外/可见光和荧光光谱、体细胞遗传学。）