Participation of lipids in the tumor response to photodynamic therapy and its exploitation for therapeutic gain

Hydroperoxides of unsaturated membrane lipids (LOOHs) are the most abundant non-radical intermediates generated by photodynamic therapy (PDT) of soft tissues such as tumors and have far longer average lifetimes than singlet oxygen or oxygen radicals formed during initial photodynamic action. LOOH-initiated post-irradiation damage to remaining membrane lipids (chain peroxidation) or to membrane-associated proteins remains largely unrecognized. Such after-light processes could occur during clinical oncological PDT, but this is not well-perceived by practitioners of this therapy. In general, the pivotal influence of lipids in tumor responses to PDT needs to be better appreciated. Of related importance is the fact that most malignant tumors have dramatically different lipid metabolism compared with healthy tissues, and this is often ignored. The response of tumors to PDT appears especially vulnerable to manipulations within the tumor lipid microenvironment. This can be exploited for therapeutic gain with oncological PDT, as exemplified here by the combined treatment with antitumor lipid edelfosine.