ENHANCEMENT OF PDT USING BIOLOGICAL RESPONSE MODIFIERS

精心设计的辅助或组合疗法可导致维持或增加抗肿瘤作用的效力，同时消除毒性。 我们以前已经证明，通过将光动力疗法（POT）与TNF-α相结合，治疗效力增加而不增加毒性。 然而，佐剂TNF-α的优化可能是不可行的，因为TNF的全身应用已经显示在人类患者中具有显著的毒性。 我们建议在这里检查POT和胃肠外给药的化合物5，6-二甲基咕吨酮-4-乙酸（5，6-MeXAA）的组合，其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降低了直接或全身应用TNF时观察到的毒性。 在初步实验中，我们发现PDT和5，6-MeXAA的组合导致鼠RIF-1肿瘤应答的显著增强，而不增加正常组织损伤，在两种模式单独都无效的条件下。 组合PDT/5，6-MeXAA以两种不同的方式操作：i）在某些条件下，联合治疗产生急性反应，肿瘤体积立即减小至不可测量的质量，最终导致治愈或长时间的再生长延迟，和ii）在其他条件下，联合治疗导致弱的早期反应，随后是延迟的肿瘤反应，其中指数（re）生长中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。 在以下建议中，我们将）优化PDT和5，6-MeXAA组合的治疗参数，2）阐明负责由PDT和5，6-MeXAA诱导的即时抗肿瘤效应的机制，和3）确定导致由PDT和5，6-MeXAA诱导的延迟肿瘤反应的机制。 我们进一步假设，延迟反应将提供更有效的长期肿瘤控制，并将打击隐匿性转移。

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.