ENHANCEMENT OF PDT USING BIOLOGICAL RESPONSE MODIFIERS

设计良好的辅助或联合治疗可以维持或增加抗肿瘤作用的效力，同时消除毒性。我们之前已经证明，光动力疗法（POT）与tnf - α联合使用可以提高治疗效力，但不会增加毒性。然而，优化辅助TNF- α可能是不可行的，因为TNF的全身应用已被证明对人类患者具有显着的毒性。我们在此建议研究POT与一种非肠外给药化合物5,6-二甲基黄酮- 4-乙酸（5,6- mexaa）的联合使用，该化合物可选择性地诱导肿瘤组织中的tnf - α。5,6- mexaa在肿瘤组织中选择性诱导TNF降低了直接或系统应用TNF的毒性。在初步实验中，我们发现PDT和5,6- mexaa联合使用在单独使用两种方式都无效的情况下，可显著增强小鼠的rif - 1肿瘤反应，而不会增加正常组织损伤。联合PDT/5,6- mexaa以两种不同的方式起作用：i)在某些条件下，联合治疗产生急性反应，肿瘤体积立即减少到不可测量的质量，最终导致治愈或长时间的再生延迟；ii)在其他条件下，联合治疗导致早期反应弱，随后是肿瘤反应延迟，指数（重新）生长的肿瘤迅速完全消退。我们假设急性反应是PDT和5,6- mexaa诱导的直接肿瘤细胞杀伤和抗血管生成作用的结果，而延迟反应是诱导抗肿瘤特异性免疫反应的结果。在接下来的研究中，我们将优化PDT与5,6- mexaa联合治疗的治疗参数，2)阐明PDT与5,6- mexaa联合抗肿瘤的即时作用机制，3)确定PDT与5,6- mexaa联合诱导肿瘤延迟反应的机制。我们进一步假设，延迟反应将提供更有效的长期肿瘤控制，并将打击隐匿转移。

Well designed adjuvant or combination therapies can result in maintaining or increasing the potency of the anti- tumor effect while abrogating toxicity. We have previously demonstrated increased therapeutic potency without increasing toxicity by combining photodynamic therapy (POT) with TNF-alpha. However, the optimization of adjuvant TNF- alpha may be unfeasible because the systemic application of TNF has been shown to have significant toxicity in human patients. We propose here to examine the combination of POT and a parenterally administered compound, 5,6- dimethylxanthenone- 4-acetic acid (5,6-MeXAA), which selectively induces TNF-alpha in tumor tissue. The selective induction of TNF in tumor tissue by 5,6-MeXAA reduces the toxicity seen in direct or systemic application of TNF. In preliminary experiments we have found that the combination of PDT and 5,6-MeXAA results in a marked potentiation of murine RIF-l tumor response, without increasing normal tissue damage, under conditions where neither modality alone is effective. Combined PDT/5,6-MeXAA operates in two different ways: i) under certain conditions, combination therapy produces an acute response with an immediate reduction of tumor volume to an unmeasurable mass, eventually leading to either cures or long regrowth delays, and ii) under other conditions, combination therapy results in a weak early response followed by a delayed tumor response where the exponentially (re)growing tumors rapidly and completely regress. We hypothesize that the acute response is a result of PDT and 5,6-MeXAA induced direct tumor cell kill and anti-angiogenic effects, while the delayed response is the result of an induction in an anti- tumor specific immune response. In the following proposal we willl) optimize the treatment parameters of combined PDT and 5,6-MeXAA, 2) elucidate the mechanisms responsible for the immediate antitumor effect induced by PDT and 5,6-MeXAA, and 3) determine the mechanisms leading to the delayed tumor response induced by PDT and 5,6-MeXAA. We further hypothesize that the delayed response will provide more effective long-term tumor control and will combat occult metastases.