PhD ceremony: Ms. A.A. Rybczynska, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen
Dissertation: Sigma receptor ligands: novel applications in cancer imaging and treatment
Promotor(s): prof. R.A.J.O. Dierckx, prof. P.H. Elsinga
Faculty: Medical Sciences
Sigma receptors (types 1 and 2) are unique binding sites showing a considerably higher expression in cancerous compared to non-cancerous tissues. Although the endogenous agonists have not been identified with certainty, many artificial ligands are available to study the function of sigma receptors in health and disease. Therapeutic doses of such compounds (particularly sigma-1 antagonists and sigma-2 agonists) are known to decrease proliferation and survival of cancer cells, but minimally affect non-cancer cells. The research in this thesis aimed at further development of sigma ligands as diagnostic imaging agents and therapeutic drugs in oncology.
Results indicate that competition by steroid hormones accounts for variability of sigma ligand uptake during PET imaging. It was also shown that sigma-1 receptors are over-expressed in spontaneous pituitary tumors and that 11C-SA4503-PET may be a suitable method for detection of such lesions.
Sigma receptor occupancy in cancer cells determined the observed anti-cancer effect of sigma ligands. Cytotoxicity was accompanied by striking, early changes of metabolism in such cells. Assessment of sigma-2 receptor occupancy in human tumors with PET may be employed for prediction of the therapeutic dose. A combination of sigma ligands and cytokine-based therapy was tested and found to display robust anti-cancer effects in melanoma cell lines and in patient-derived primary samples of ovarian carcinoma.
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