PORPHYRIN-MEDIATED PHOTOSENSITIZATION HAS A WEAK TUMOR-PROMOTING ACTIVITY IN MOUSE SKIN - POSSIBLE ROLE OF IN SITU-GENERATED REACTIVE OXYGEN SPECIES

Reactive oxygen species (ROS) have been implicated in skin tumor promo tion, Earlier, we showed that porphyrin-mediated cutaneous photosensit ization results in the in situ generation of ROS, Recently, we have pr ovided the first in situ evidence for the involvement of ROS in stage I tumor promotion, In this study we further show that in situ-generate d ROS act as weak complete tumor promoters in 7,12-dimethylbenz[a]anth racene (DMBA)-initiated mouse skin, Papillomas were induced in Swiss a lbino mice by a single topical application of DMBA as initiator, The p romotion was achieved in these mice by the sustained generation of ROS through dihematoporphyrin ether (DHE)-mediated cutaneous photosensiti zation, which was done once every day (six times a week) for 24 weeks, The first appearance of visible papillomas could be recorded 24 weeks after the initiation, The highest tumor incidence of 60% occurred at a dose of 2.5 mg/kg body wt DHE. Increasing the dose of DHE produced a decrease in the incidence as well as in the number of papillomas, In contrast, the number of carcinomas/mouse increased with increasing dos e of DHE, Histopathology of the tumor samples indicated the formation of in situ carcinoma also in skin, ROS generated through DHE-mediated photosensitization resulted in a similar to 3 fold induction of ODC ac tivity 9 h after photosensitization, DHE-mediated photosensitization e nhanced [H-3]thymidine incorporation in cutaneous DNA in a dose-depend ent manner, A maximum 5-fold induction of [H-3]thymidine incorporation was observed at a dose of 10 mg/kg body wt DHE. The longer latency pe riod, low incidence of tumor induction, low tumor yield and low induct ion of ODC activity as compared,vith TPA represent the weak but comple te tumor promoting potential of in situ-generated ROS, The low tumor i ncidence and tumor yield observed at higher doses of DHE may be due to the ablation of tumors at early stages due to the strong photodynamic action of DHE. Our data indicate that porphyrin-mediated photosensiti zation has a weak tumor promoting effect in mouse skin and in situ-gen erated ROS may play an important role in the development of this respo nse.