Gynaecology Research Today is a free monthly online journal that collates and summarizes the latest research about Gynaecology, including details on pap smears, laparoscopy, ultrasound, hysteroscopy. | ||||||||
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GnRH analogues containing conformationally restricted amino acids in positions 3 and 6: differential impact on pituitary binding affinity and direct antiproliferative effect on breast cancer cells.Zompra AA, Magafa V, Lamari FN, Nikolopoulou A, Nock B, Maina T, Spyroulias GA, Karamanos NK, Cordopatis P Department of Pharmacy, University of Patras, 26500 Patras, Greece. Analogues of GnRH have been widely used in oncology and gynaecology to induce reversible chemical castration. In addition to the classic hypophysiotropic action of GnRH, it has been shown that many malignant cells, such as breast cancer cells, secrete GnRH and express the GnRH receptor/s. In order to study the effect of modifications in position 3 and 6 of GnRH on both pituitary binding affinity and breast cancer cell proliferation, we synthesized eight new GnRH analogues. All GnRH analogues lacked the carboxy-terminal Gly(10)-amide of GnRH and an ethylamide residue was added to Pro(9). Gly(6) was substituted by alpha,alpha-dialkyl amino acids (Aib: alpha-aminoisobutyric acid, Deg: diethylglycine) and Trp(3) by D-Trp, D- and L-1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid (Tic). During competition binding experiments in mouse anterior pituitary alphaT3-1 cells, [Aib(6),desGly(10)]GnRH-NHEt bound to the GnRH receptor with IC(50) values comparable to those of parent hormone in contrast to the analogues substituted at position 3. However, [L-Tic(3),Deg(6),desGly(10)]GnRH-NHEt had high pituitary binding affinity. With the exception of GnRH and [Aib(6),desGly(10)]GnRH-NHEt, all GnRH analogues significantly inhibited the proliferation of human breast cancer cells (MCF-7); higher inhibitory effect was observed for analogues modified at position 3. Results show differential impact of the modifications on the binding affinity to the GnRH receptor in mouse pituitary cells and on the inhibition of human breast cancer cell proliferation and provide insight into structure-activity relationship of GnRH in different biological systems. Published 2 May 2006 in J Pept Res, 66: 57-64.
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