CHAPTER 4:The Story of ALA Photodynamic Therapy: A Cancer Enigma

ALA photodynamic therapy (PDT) is an established clinical method of proven efficacy and safety using ALA as a prodrug applied for 4–24 hours prior to photosensitization. The intracellular levels of protoporphyrin IX (PpIX) produced during ALA treatment are dependent on the overall activity of the heme synthesis pathway, specifically the third enzyme porphobilinogen deaminase (PBGD), which is activated during the synthesis of porphobilinogen, and on the activity of the last enzyme ferrochelatase. The characteristic phenomenon of anomalous energy metabolism in tumors, using mostly glycolysis for ATP production, is further correlated with disturbed heme synthesis as manifested by PpIX production. In the future, improved ALA administration protocols adjusted in order to preactivate the key enzyme PBGD prior to photoactivation may improve PpIX accumulation in cancers and their corresponding stem cells. Furthermore, the use of multifunctional ALA prodrugs that maximize photosensitizer biosynthesis, targeting multiple subcellular targets, may increase PDT anticancer efficacy in additional disease settings. In conclusion, improved ALA delivery protocols, light irradiation regimes and novel ALA prodrugs may boost anticancer actions and drive ALA-PDT into becoming a front-line cancer therapy.