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Proceedings Paper

Nuclear transcription factors: a new approach to enhancing cellular responses to ALA-mediated photodynamic therapy
Author(s): Edward V. Maytin; Sanjay Anand; Nobuyuki Sato; Brian Moore; Judith Mack; Christopher Gasbarre; Samantha Keevey; Bernhard Ortel; Alok Sinha; Amor Khachemoune
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Paper Abstract

Photodynamic therapy (PDT) using aminolevulinic acid (ALA) relies upon the uptake of ALA into cancer cells, where it is converted into a porphyrin intermediate, protoporphyrin IX (PpIX) that is highly photosensitizing. For large or resistant tumors, however, ALA/PDT is often not completely effective due to inadequate PpIX levels. Therefore, new approaches to enhance the intracellular production of PpIX are sought. Here, we describe a general approach to improve intracellular PpIX accumulation via manipulations that increase the expression of an enzyme, coproporphyrinogen oxidase (CPO), that is rate-determining for PpIX production. We show that nuclear hormones that promote terminal differentiation, e.g. vitamin D or androgens, can also increase the accumulation of PpIX and the amount of killing of the target cells upon exposure to light. These hormones bind to intracellular hormone receptors that translocate to the nucleus, where they act as transcription factors to increase the expression of target genes. We have found that several other transcription factors associated with terminal differentiation, including members of the CCAAT enhancer binding (C/EBP) family, and a homeobox protein named Hoxb13, are also capable of enhancing PpIX accumulation. These latter transcription factors appear to interact directly with the CPO gene promoter, resulting in enhanced CPO transcriptional activity. Our data in several different cell systems, including epithelial cells of the skin and prostate cancer cells, indicate that enhancement of CPO expression and PpIX accumulation represents a viable new approach toward improving the efficacy of ALA/PDT.

Paper Details

Date Published: 6 March 2006
PDF: 10 pages
Proc. SPIE 6139, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XV, 613909 (6 March 2006); doi: 10.1117/12.646880
Show Author Affiliations
Edward V. Maytin, Cleveland Clinic Foundation (United States)
Massachusetts General Hospital (United States)
Sanjay Anand, Cleveland Clinic Foundation (United States)
Nobuyuki Sato, Cleveland Clinic Foundation (United States)
Brian Moore, Cleveland Clinic Foundation (United States)
Judith Mack, Cleveland Clinic Foundation (United States)
Christopher Gasbarre, Cleveland Clinic Foundation (United States)
Samantha Keevey, Cleveland Clinic Foundation (United States)
Bernhard Ortel, Massachusetts General Hospital (United States)
Alok Sinha, Massachusetts General Hospital (United States)
Amor Khachemoune, Massachusetts General Hospital (United States)

Published in SPIE Proceedings Vol. 6139:
Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XV
David Kessel, Editor(s)

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