Recent progress in prostaglandin F2α ethanolamide (prostamide F2α) research and therapeutics.

Prostamide (prostaglandin ethanolamide) research emerged from two distinct lines of research: 1) the unique pharmacology of the antiglaucoma drug bimatoprost and 2) the discovery that endocannabinoid anandamide was converted by COX-2 to a series of electrochemically neutral prostaglandin (PG) ethanolamides. Bimatoprost pharmacology was found to be virtually identical to that of prostamide F2α. The earliest studies relied on comparison of agonist potencies compared with PGF2α and synthetic prostaglandin F2α (FP) receptor agonists. The subsequent discovery of selective and potent prostamide receptor antagonists (AGN 211334-6, as shown in Fig. 3) was critical for distinguishing between prostamide and FP receptor-mediated effects. The prostamide F2α receptor was then modeled by cotransfecting the wild-type FP receptor with an mRNA splicing variant (altFP4).Bimatoprost is now used therapeutically for treating both glaucoma and eyelash hypotrichosis. Bimatoprost also stimulates hair growth in isolated human scalp hair follicles. A strong effect is also seen in mouse pelage hair, where bimatoprost essentially halves the onset of hair regrowth and the time to achieve full hair regrowth in shaved mice. Beyond glaucoma and hair growth, bimatoprost has potential for reducing fat deposition. Studies to date suggest that preadipocytes are the cellular target for bimatoprost. The discovery of the enzyme prostamide/PGF synthase was invaluable in elucidating the anatomic distribution of prostamide F2α. High expression in the central nervous system provided the impetus for later studies that described prostamide F2α as a nociceptive mediator in the spinal cord. At the translational level, bimatoprost has already provided therapeutics in two distinct areas and the use of both prostamide agonists and antagonists may provide other useful medicaments.

Development of therapeutic vaccines by direct modification of cell membranes from surgically removed human tumor tissue with immunostimulatory molecules.

The addition of immunostimulatory molecules to tumor cells has been proposed as a potentially useful strategy to induce anti-tumor immunity. In this report we have investigated the application of using isolated tumor membranes modified by transfer of a glycosyl-phosphatidylinositol (GPI)-anchored form of the costimulatory molecule, B7-1 (CD80), as a cell free cancer vaccine for clinical use. Isolated tumor cell membranes were prepared from established tumor cell lines and the optimum conditions necessary for modification and clinical application were determined. GPI-B7-1 transferred optimally onto isolated human tumor membranes at physiological temperature (37 degrees C) in a dose dependent manner. Transfer of GPI-B7-1 to isolated membranes resulted in stable expression and costimulatory function. These modified membranes could be stored for repeated immunizations while retaining expression of GPI-B7-1. Critically, isolated tumor membranes, prepared directly from surgically removed human tumor tissue, could be modified by GPI-B7-1 and costimulate T cells. Finally, membranes isolated from tumor tissue expressed MHC class II, unlike the cell line established in vitro from the same patient. This novel approach to express immunostimulatory molecules on isolated membranes derived from a patient's tumor tissue will make the preparation of autologous therapeutic cancer vaccines available to patients from which tumor cell lines can not be established.