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.
