Nonmelanoma skin carcinomas are the most common of all human cancers. Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) has been used to treat these tumors, but has shown variable results. We are pursuing a
multifaceted approach toward optimizing tumor responsiveness. First, a new paradigm is being developed in which
tumors are pretreated with differentiation-inducing agents, e.g. methotrexate or Vitamin D, to enhance synthesis of
protoporphyrin IX (PpIX) and improve tumor cell killing upon exposure to 635 nm light. This principle was first
elucidated in cell culture studies, and has now been shown to hold true for murine skin tumors, and for a human
subcutaneous tumor model (A431 cells injected in nude mice). Clinical trials to test methotrexate and Vitamin D as
augmenting agents for ALA-PDT of nonmelanoma skin cancer are being designed. Second, better methods to measure
PpIX in patients' skin tumors in real time are being developed. In a clinical study to measure PpIX in patients with
dysplastic skin lesions, in vivo fluorescence dosimetry was used to measure the accumulation of PpIX over time, and
revealed that intralesional PpIX may reach clinically-useful levels earlier than previously thought for the treatment of
actinic keratoses. In a second clinical study to examine depth of PpIX production in nonmelanoma skin cancer, the
depth of PpIX within BCC tumors was found at relatively deep levels (>1 mm) in some tumor nests, but not in others.
Production of PpIX in deep squamous cell carcinoma was very low. In summary, molecular approaches such as
differentiation therapy to enhance ALA-PDT for individual patients may ultimately be needed to help to improve skin
cancer responses to this modality.