Breast Cancer Gene Therapy: Development of Novel Non-Invasive Magnetic Resonance Assay to Optimize Efficacy

摘要

Gene therapy holds great promise for treatment of breast cancer. In particular clinical trials are underway to apply therapeutic genes related to pro-drug activation or to modulate the activity of oncogenes by blocking promoter sites. However, there are major problems in terms of assessing the delivery to target tissue, assessing the uniformity (versus heterogeneity) of biodistribution, and determining whether the genes are expressed. We designed, evaluated and tested a novel approach to gene activity detection- specifically, using fluorinated substrates of beta-galactosidase to reveal gene activity. Our prototype molecule PFONPG (p-fluoro-o-nitro-phenyl beta-D-galactopyranoside) is a direct analog of the traditional yellow biochemical indicator ONPG (o- nitro- phenyl beta-D-galactopyranoside). Analogs of this prototype were developed to optimize MR and biological characteristics and explore the feasibility of tailoring the reporter to specific applications, e.g., exploiting -gal activity to deliver specific physiological reporter molecules such as pH and potentially specific cytotoxic agents. The agents have been tested in solution, applied to cultured breast cancer cells, and used to examine beta-gal activity in vivo in transfected breast tumors.