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The Quarterly Journal of Nuclear Medicine 1999 June;43(2):170-6


language: English

Dying a thousand deaths. Radionuclide imaging of apoptosis

Blankenberg F., Ohtsuki K., Strauss H. W.

From the Department of Radiology and Division of Nuclear Medicine Stanford University School of Medicine, Stanford, CA, USA


Programmed ­cell ­death, apop­to­sis, is an indu­cible, orga­nized, ener­gy requir­ing ­form of ­demise ­that ­results in the dis­ap­pear­ance of a ­cell with­out the induc­tion of an inflam­ma­to­ry ­response. Apoptotic ­cell ­death is strik­ing­ly dif­fer­ent ­than necrot­ic ­death, ­which is dis­or­der­ly, ­does not ­require ener­gy and ­results in ­local inflam­ma­tion, usu­al­ly sec­on­dary to sud­den ­release of intra­cel­lu­lar con­tents. Apoptosis is ­induced ­when ­cells under­go ­severe inju­ry to ­their nucle­us, as ­occurs fol­low­ing expo­sure to gam­ma or X-radi­a­tion, or mit­co­chon­dria, as ­occurs in a varie­ty of ­viral ill­ness­es. Apoptosis can ­also be ­induced by exter­nal sig­nals, ­such as inter­ac­tion of fas ­ligand ­with fas recep­tors. Once the ­cell is com­mit­ted to apop­to­sis, the cas­pase ­enzyme cas­cade is acti­vat­ed. An ear­ly ­effect of cas­pase acti­va­tion is the rap­id expres­sion of phos­phat­i­dyl­se­rine on the exter­nal leaf­let of the ­cell mem­brane. Membrane ­bound phos­phat­i­dyl­se­rine expres­sion ­serves as a sig­nal to sur­round­ing ­cells, iden­ti­fy­ing the express­ing ­cell as under­go­ing apop­to­sis. A defi­cien­cy or an ­excess of pro­grammed ­cell ­death is an inte­gral com­po­nent of auto­im­mune dis­or­ders, trans­plant rejec­tion and can­cer. A tech­nique to ­image pro­grammed ­cell ­death ­would be use­ful to ­assist in the devel­op­ment of ­drugs ­designed to ­treat ­these dis­eas­es, and to mon­i­tor the effec­tive­ness of ther­a­py. The sud­den expres­sion of phos­phat­i­dyl­se­rine on the ­cell mem­brane is a tar­get ­that ­could be ­used for ­this pur­pose. A 35 kD phys­io­log­ic pro­tein, Annexin V lip­o­cor­tin, ­binds ­with nano­mo­lar affin­ity to mem­brane ­bound phos­phat­i­dyl­se­rine. Annexin V has ­been radio­lab­eled ­with Technetium-99m by ­direct ­coupling to ­free sulf­hy­dryl ­groups, and ­through the hydra­zin­o­nic­a­tin­a­mide and N2S2 link­ing ­agents. The bio­dis­trib­u­tion of the ­agents ­labeled ­with ­each of the meth­ods is slight­ly dif­fer­ent. In all cas­es the radio­phar­ma­ceu­ti­cal ­binds to ­cells under­go­ing apop­to­sis in vitro, and per­mits imag­ing of the pro­cess in experi­men­tal ani­mals.

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