TARGETS OF PHOTODYNAMIC THERAPY

本研究计划旨在提供有关模式(S)的信息 与光动力疗法治疗癌症相关的光毒性 控制力。长期目标是设计具有以下特点的敏化方案 提高了疗效。我们将专注于肿瘤与肿瘤之间的作用 作为PDT靶点的血管系统使用阳离子光敏剂和 FANFT诱导的大鼠尿路上皮移植瘤。在体外和体内。 这种肿瘤表达多药耐药基因产物，即多药转运蛋白。这 向外运输系统。由P-糖蛋白介导，识别为 具有适当疏水性的底物阳离子试剂。肿瘤细胞 从而保护表达MDR不受底物的光损伤 被传送者识别。但对肿瘤血管的光损伤是 由于血管MDR表达仅限于中枢神经系统，因此不能预防。我们 已经确定了两种阳离子光敏剂，它们是 多药传输者和非传毒者。这些代理是 由艾伦·摩根博士开发的系列苯甲酰亚胺盐，世界卫生组织 将提供增敏剂并对光动力疗法进行有选择的体内研究 功效。后者将涉及顺序照射方案，该方案 可以选择性地激活每一种安息香。维克多·芬格博士将成为 负责评估直接细胞毒性与 在这些实体瘤中，血管损伤是肿瘤反应的因素。 将在韦恩州立大学进行的研究将提供 肿瘤光毒性增敏剂药代动力学模式的研究进展 和致敏剂定位，然后可以与血管和 非血管PDT反应。光损伤对P-2的影响研究 糖蛋白也可以提供结合位点的信息。 这种运输蛋白的底物。细胞凋亡性与坏死性的作用 直接杀伤肿瘤细胞与血管关闭导致的细胞死亡 还将接受检查。

This research program is designed to provide information on the mode(s) of phototoxicity associated with the use of photodynamic therapy for cancer control. The long-range goal is the design of sensitizer protocols with improved efficacy. We will focus on the role of tumor vs. tumor vasculature as targets for PDT using cationic photosensitizers and the transplantable FANFT-induced urothelial rat tumor. In vitro and in vivo. This tumor expresses the mdr gene product, the multidrug transporter. This outward transport system. mediated by P-glycoprotein, recognizes as substrates cationic agents of appropriate hydrophobicity. Neoplastic cells which express MDR are thereby protected from photodamage by substrates recognized by the transporter. but photodamage to the tumor vasculature is not prevented since vascular MDR expression is confined to the CNS. We have identified two cationic photosensitizers which are substrates for the multidrug transporter and one which is not. These agents are members of a series of benzochlorin iminium salts developed by Dr. Alan Morgan, who will provide the sensitizers and carry out selected in vivo studies on PDT efficacy. The latter will involve sequential irradiation protocols which can selectively activate each benzochlorin. Dr. Victor Fingar will be responsible for experiments designed to assess direct cytotoxicity vs. vascular damage as factors in tumor response in these solid tumors. Studies to be carried out at Wayne State University, will provide information on sensitizer pharmacokinetics modes of tumor phototoxicity and sensitizer localization, which can then be compared with vascular and non-vascular PDT responses. Studies on effects of photodamage to the P- glycoprotein may also provide information on sites of binding of substrates to this transport protein. The role of apoptotic vs. necrotic cell death resulting from direct tumor cell kill vs. vascular shut-down will also be examined.