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Enhanced Photodynamic
Therapy Efficacy With Inducible Suicide Gene Therapy Controlled By the
grp Promoter
Luna, Marian1,
Wong, Sam 1, Chen, Xinke2,
Tsui, Janet1, Lee, Amy2
and Gomer, Charles 1,2
Childrens Hospital Los Angeles1
University of Southern California2
Abstract-
Photodynamic therapy (PDT) elicits strong transcriptional activation
of a variety of genes including stress response genes belonging to the
heat shock protein (hsp) and glucose regulated protein (grp) families.
We previously demonstrated that both hyperthermia and PDT could function
as efficient molecular switches for temporal and spatial expression
of heterologous genes ligated to hsp promoters (Cancer Res., 60: 1637-1644,
2000). Oxidative stress and hypoxia can activate the grp promoter and
both physiological environments occur during and/or after PDT. In the
current study we evaluated the grp promoter as a PDT inducible molecular
switch for controlled expression of the herpes simplex virus-thymidine
kinase (HSV-tk) suicide gene product in a mouse (TSA) mammary carcinoma
cell line stably transduced with a G1NaGrpTk retroviral expression vector.
We also examined whether grp inducible expression of HSV-tk together
with systemic administration of ganciclovir could enhance the tumoricidal
responsiveness of PDT. Selective and temporal expression of HSV-tk was
observed after PDT in transduced TSA cells grown either in culture or
subcutaneously transplanted into BALB-c mice. We also demonstrated enhanced
tumoricidal activity when mice with TSA tumors containing the G1NaGrpTk
expression vector were treated with PDT and ganciclovir when compared
to either treatment alone. This is the first in-vivo PDT inducible gene
therapy study and the results confirm that PDT can efficiently function
as an inducible molecular switch for effective expression of the therapeutic
HSV-tk gene.
Keywords: photodynamic
therapy, gene therapy, stress protein , grp
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