mTHPC-mediated photodynamic therapy; from bed to bench and back again

Abstract

Photodynamic therapy (PDT) is a relatively new treatment option in oncology. When it is used for the proper indication and appropriate protocols are followed, efficacy is high and no severe long-term side effects are encountered. Therefore PDT is slowly gaining acceptance as an alternative for conventional cancer therapy. Meso-tetra-hydroxyphenyl-chlorin (mTHPC) is a second-generation photosensitizer that is more powerful than the first-generation photosensitizer Photofrin and administration results in a shorter period of generalized photosensitivity. The aim of this thesis was to determine whether drug uptake and distribution influence tumor response to mTHPC-mediated PDT. We also wanted to test the hypothesis that for a good tumor response after PDT, vascular mediated damage is more important than direct tumor cell toxicity. To reach this goal determination of PDT efficacy, mTHPC pharmacokinetics and cellular distribution was studied in vitro, in vivo and in cancer patients. Although mTHPC-mediated PDT is already very effective with the present treatment protocols, both pre-clinical and clinical data in this thesis suggest that treatment can be improved by taking into account the importance of induced vascular damage and shortening the drug-light interval. However, because of the unusual pharmacokinetics of mTHPC in humans as shown, care must be taken before further reduction of drug-light interval to less than 1 day. This should go hand in hand with experiments for understanding the influence of and pharmacokinetic behavior of mTHPC during the first 12 hours. Clinical trials are already underway for further optimization of drug-light interval used for mTHPC-PDT. Together with these studies new dose finding studies for mTHPC should also be performed, since drug dose reduction could shorten the photosensitivity interval.