Control of Gemcitabine Activity With Blue and Red Light.

Treating cancer with chemotherapy is generally associated with many side effects. This problem can be addressed by selectively releasing the desired drugs with light. In a screening approach, we modified known antimetabolite cytostatics with photoremovable protecting groups (PPGs). Sixteen new light-activatable cytostatics with a blue light-activatable diethylaminocoumarin group (DEACM) were synthesized, and their (photo-)chemical properties were tested. The most promising compounds were subjected to cytotoxicity studies with HT-29 colon cancer cells. In our experiments, the DEACM-gemcitabine derivative showed the best properties with full recovery of gemcitabine activity after irradiation. In the absence of blue light, this compound was 29 times less toxic. In the next step, based on these results, we designed a red-light activatable derivative of gemcitabine, featuring a heptamethine (Cy7) PPG. We were able to confirm the photorelease of gemcitabine with tissue-penetrating red light in HT-29 cells. Our "gem-Cy-tabine" was almost inactive in the absence of light, but its activity increased >33 fold after irradiation with red light. It is, therefore, an interesting candidate for more specific cancer therapy by photopharmacology.