ENHANCEMENT OF PDT USING BIOLOGICAL RESPONSE MODIFIERS

设计良好的辅助剂或联合疗法可以在消除毒性的同时保持或增加抗肿瘤作用的效力。我们以前已经证明，通过将光动力疗法(POT)与肿瘤坏死因子-α相结合，在不增加毒性的情况下提高了治疗效率。然而，佐剂的优化可能是不可行的，因为全身应用的肿瘤坏死因子已被证明对人类患者具有显著的毒性。在这里，我们建议研究POT和肠外给药化合物5，6-二甲基黄原酮-4-醋酸(5，6-MeXAA)的结合，后者选择性地诱导肿瘤组织中的肿瘤坏死因子-α。5，6-MeXAA选择性诱导肿瘤组织中的肿瘤坏死因子可降低直接或全身应用肿瘤坏死因子的毒性。在初步实验中，我们发现，光动力疗法和5，6-甲氧基丙烯酸的联合使用在不增加正常组织损伤的情况下，在两种方法都不有效的情况下，可以显著增强小鼠RIF-L肿瘤反应。PDT/5，6-MeXAA联合治疗有两种不同的作用方式：i)在某些情况下，联合治疗会产生急性反应，肿瘤体积立即缩小到无法测量的肿块，最终导致治愈或长时间的再生长延迟；ii)在其他情况下，联合治疗会导致微弱的早期反应和延迟的肿瘤反应，其中呈指数级增长的肿瘤迅速而完全消退。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。在下面的建议中，我们将优化PDT和5，6-MeXAA的联合治疗参数，2)阐明PDT和5，6-MeXAA诱导的即时抗肿瘤作用的机制，3)确定导致PDT和5，6-MeXAA诱导的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，并将对抗隐匿性转移。

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.