טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShoukrun Rami
SubjectThe Involvement of the Peripheral Benzodiazepine Receptor
in Colorectal Cancer
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moshe Gavish


Abstract

Benzodiazepines are a group of drugs used clinically as anxiolytics, sedatives and anticonvulsants. Their therapeutic effects have been correlated with their potency in binding to central benzodiazepine receptors in the central nervous system (CNS). It has been suggested that the effects of benzodiazepines in the CNS is mediated via the γ-aminobutyric acid (GABA) receptor. In addition to central-type benzodiazepine receptors (CBR), benzodiazepines also bind to receptors located in various peripheral organs as well as in brain glial cells. These receptors are called "peripheral-type benzodiazepine receptors" (PBR).

PBR have been found to be involved in apoptosis, regulation of steroid production, cell growth and differentiation, mitochondrial respiratory chain and immunomodulation. Yet the relative importance of these functions is still unclear.

The aim of this study was to examine any putative involvement of PBR in colorectal cancer, using the HT29 cell line as a model. We stably transfected HT29 cells with over and under-expressing vectors and subjected them to various tumorigenity determining assays. We found that under-expressing IBP clones displayed a more aggressive tumorigenic phenotype. However, over-expressing IBP clones did not show significant differences in comparison to controls.

We also grafted HT29 cells into SCID mice and followed tumor progression with and without PBR ligand treatment. FGIN-1-27, a specific PBR ligand demonstrated a significant ability to lower the rate at which the grafted tumors progressed.

These studies suggest a direct association between PBR density and tumorgenicity. Moreovrer, PBR knock down transformed the HT29 cancer cell line into a more malignant type.