Photodynamic Therapy Oxidative Stress as a Molecular Switch Controlling Therapeutic Gene Expression for the Treatment of Locally Recurrent Breast Carcinoma

摘要

Photodynamic Therapy (PDT) is a developing therapeutic modality which continues to show promise in the clinical treatment of cancer, including locally recurrent breast carcinoma. Our application is directly related to using novel molecular technologies to improve the effectiveness of PDT for treating locally recurrent breast cancers. In PDT, properties of photosensitizer localization in tumor tissue and photochemical generation of reactive oxygen species are combined with precise delivery of laser-generated light to produce a procedure offering local tumoricidal activity. We have demonstrated that PDT-mediated oxidative stress is a strong transcriptional inducer of stress proteins belonging to the heat shock protein (hsp) and glucose regulated protein (grp) families. We have also shown that the hsp and grp promoters can drive inducible expression of heterologous genes following PDT mediated oxidative stress. Inducible expression and function of p53 as well as inducible expression, secretion and biological activity of TNF-a have been demonstrated in human tumor cells. We have also demonstrated PDT inducible expression of the suicide gene HSV-thymidine kinase and enhanced tumoricidal action when PDT is combined with inducible HSV-TX gene therapy. These studies address a critical problem associated with improving treatments for locally recurrent breast cancer using new approaches which will minimize systemic toxicity and maximize a patient's quality of life.