PARENT SESSION
9:00 AM to 11:00 AM
Sunday, April 21, 2002
NAHS Symposium 7
NAHS Defining Thermal Goals for Hyperthermia
Room: Nevada 4-5
Chair: Roti Roti, Joseph²², St. Louis, MO, Co-Chair: Prosnitz, Leonard³³, Durham, NC
Speakers: Roti Roti, Joseph⁴; Wust, Peter⁵; Corry, Peter⁶; Dewhirst, Mark⁷⁴, St. Louis, MO⁵Charite Medical Center, Campus Virchow-Klinikum, Berlin, GERMANY⁶, Royal Oak, MI⁷, Durham, NC

(S07-4) Thermal Goals for Gene Therapy.

Corry, Peter^*,1, Borrelli, Michael¹, Armour, Elwood¹, ¹ Radiation Oncology Research Laboratories, Royal Oak, MI

ABSTRACT-
Effective gene therapy is one of the most sought after goals of modern medical research. At the present time most forms of gene therapy introduce the desired transgene on a constitutive, always on to some degree, promoter with the hope that other physiological factors will modulate expression of the transgene's gene product. One of the most exquisitely controlled promoters available is the human HSP70 promoter which is virtually silent in the absence of heat shock. After even mild thermal exposure (41 deg. C for 30 minutes) high levels of transcription of transgenes can be detected, will persist for a few hours and then spontaneously shut down as the production of heat shock factor (HSF) decreases at physiologically normal temperatures. The thermal target for controlling heat activated gene therapy depends on the target cell type, the desired level of gene expression and the desired length of time for transgene expression. To some extent these parameters are altered by cell cycle position at the time of thermal exposure which may have important implications in clinical application to tumor therapy. Another important influence on thermal goals in the context is other agents, such as ionizing radiation, with which gene therapy is being combined in human applications. Elevated temperatures are known to enhance ionizing radiation by at least two distinct mechanisms, repair inhibition and reoxygenation, which themselves have differing thermal goals. Higher temperatures or longer times being required for repair inhibition. Hyperthermia may also be desirable in enhancing the effects of the transgene's gene product and those thermal goals may be different than for the activation of transgene transcription. Other factors which will be discussed are the incorporation of reporter genes that might be picked up as tracers with MRI of PET procedures to dynamically assess efficacy of transgene activation on three dimensions and methods for conformal delivery of the activation heat shock. Other factors may be the combination with other promoters such as those activated by ionizing radiation and hypoxia.

KEYWORDS: Thermally, Activated, Gene, Therapy