Enhancing photodynamic therapy by utilizing combination approaches with small molecule inhibitors

Photodynamic therapy (PDT) is increasingly being used as a treatment method for precancerous lesions and superficial non-melanoma skin cancers. The photodynamic effect leads to tumor damage via several complementary mechanisms: direct damage to tumor cells, vascular injury and generation of immune responses. Photosensitizers can be delivered via many routes, including as a topical application as with prodrug aminolevulinic acid (ALA) and its esters. ALA is a precursor in the heme biosynthetic pathway to endogenous photosensitizer protoporphyrin IX (PpIX). Malignant and premalignant cells are known to have altered activity of key heme synthesis enzymes and lower levels of iron, therefore these cells can accumulate PpIX at a greater rate compared to nonmalignant cells. ALA-PDT treatment is beneficial as it causes negligible damage to connective tissue and thus minimal scarring. However, while ALA-PDT is efficacious in many dermatologic applications it has to date had limited success in the treatment of nodular and invasive lesions of the skin.;Published studies have shown that many signal transduction cascades are altered by the PDT induced photoreaction. This includes activation of signaling events which may be counterproductive to the intended PDT-induced cell toxicity. The Met pathway was shown to play a significant role in cancer progression and it therefore stands to reason that interference with this pathway may increase sensitivity to PpIX and HPPH PDT. These studies with Met kinase inhibitors provided interesting data which led to the hypothesis that inhibition of Met and the downstream signaling cascade caused a specific increase in PpIX production which correlated to an enhanced photodynamic effect.;Most photosensitizers cause damage to the tumor vascular supply. However, studies using laser Doppler perfusion imaging demonstrated a minimal decrease in blood flow following topical ALA-PDT, suggesting that the main tumor damaging effect of topical ALA is direct cytotoxicity to the tumor cells. Thus, it is hypothesized that the addition of a tumor-specific vascular damaging agent will improve the response to topical ALA-PDT. 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA) was shown to increase vascular permeability and decrease blood flow in murine and human tumors. Previous data reported a marked enhancement of antitumor activity when PDT (Photofrin, HPPH) was combined with low-dose i.p. DMXAA. This thesis describes the first attempt to combine topically applied DMXAA with ALA-PDT. The combination approach resulted in a significant decrease in tumor volume compared to tumors treated with ALA-PDT alone. This preliminary study suggests a potential role for topical DMXAA in combination with ALA-PDT in the dermatologic setting.