SELECTIVE ACTIVATION OF AN APOPTOTIC RETINOID PRECURSOR IN MACROPHAGECELL-LINES

Advances in the understanding of the retinoid signaling mechanism has allowed the discovery of highly selective retinoids that activate only one specific receptor class, subtype, or signaling pathway. These nov el compounds lack certain of the common retinoid toxicities and theref ore suggest promising new approaches for therapeutic applications. We describe here a new compound, 6-[3-(l-adamantyl)-4-hydroxyphenyl]-2-na phthalene carboxylic acid methyl ester (MX84), that is selectively act ivated in macrophages, leading to killing of only macrophage monocyte type cells in vitro. We provide evidence that MX84 is an inactive prec ursor that is converted into an active apoptosis-inducing retinoid in macrophages. The macrophage activity is also secreted, and our data su ggest that the secreted activity is a phospholipase D type activity. O ur observation may lead to the development of molecules that are highl y macrophage-selective apoptosis inducers in vivo and that could repre sent important novel therapeutics against diseases caused by excessive macrophage activity.