TARGETS OF PHOTODYNAMIC THERAPY

本研究计划旨在提供有关以下模式的信息： 光动力疗法治疗癌症的光毒性 控制长期目标是设计致敏剂方案， 提高功效。我们将重点讨论肿瘤与肿瘤 使用阳离子光敏剂作为PDT的靶点， 可移植FANFT诱导的大鼠尿路上皮肿瘤。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 对外运输系统。由P-糖蛋白介导，识别为 底物阳离子试剂具有适当的疏水性。赘生性细胞 从而保护其免受底物的光损伤 被传送者识别但是光损伤肿瘤血管 由于血管MDR表达仅限于CNS，因此未被阻止。 我们 已经鉴定了两种阳离子光敏剂，它们是 一种是多药转运蛋白，另一种不是。这些特工是一个 由艾伦·摩根博士开发的一系列苯并二氢卟酚亚胺盐， 将提供致敏剂并进行选定的PDT体内研究 功效后者将涉及顺序照射方案， 可以选择性地激活每一种苯并二氢卟酚。维克托芬戈博士将 负责设计用于评估直接细胞毒性与 血管损伤作为这些实体瘤中肿瘤反应的因素。 研究将在韦恩州立大学进行，将提供 肿瘤光毒性的敏化剂药代动力学模式信息 和敏化剂定位，然后可以与血管和 非血管PDT反应。光损伤对P- 糖蛋白还可以提供关于结合位点的信息， 这种转运蛋白的底物。凋亡与坏死的作用 由直接肿瘤细胞杀死与血管关闭引起的细胞死亡 也将被审查。

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.