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THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING

Rivista di Medicina Nucleare e Imaging Molecolare


A Journal on Nuclear Medicine and Molecular Imaging
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  RADIOPHARMACOLOGY


The Quarterly Journal of Nuclear Medicine 2000 Settembre;44(3):256-67

lingua: Inglese

Development of DNA-based radiopharmaceuticals carrying Auger-electron emitters for anti-gene radiotherapy

Panyutin I. G., Winters T. A., Feinendegen L. E., Neumann R. D.

From the Department of Nuclear Medicine National Institutes of Health, Bethesda, MD, USA


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Targeting of radi­a­tion dam­age to spe­cif­ic DNA sequenc­es is the ­essence of anti­gene radio­ther­a­py. This tech­nique ­also pro­vides a ­tool to ­study molec­u­lar mech­a­nisms of DNA ­repair on a ­defined, sin­gle radio­dam­aged ­site. We ­achieved ­such ­sequence-spe­cif­ic radio­dam­age by com­bin­ing the high­ly local­ized DNA dam­age pro­duced by the ­decay of Auger-elec­tron-emit­ters ­such as 125I ­with the ­sequence-spe­cif­ic ­action of trip­lex-form­ing oli­go­nu­cleo­tides (TFO). TFO com­ple­men­tary to poly­pu­rine-poly­py­rim­i­dine ­regions of ­human ­genes ­were syn­the­sized and ­labeled ­with 125I-dCTP by the prim­er exten­sion meth­od. 125I-TFO ­were deliv­ered ­into ­cells ­with sev­er­al deliv­ery ­systems. In addi­tion, ­human ­enzymes ­capable of sup­port­ing DNA sin­gle-­strand-­break ­repair ­were iso­lat­ed and ­assessed for ­their ­role in the ­repair of ­this ­lesion. Also, the mutag­e­nic­ity and repair­abil­ity of 125I-TFO-­induced dou­ble ­strand ­breaks (DSB) ­were ­assessed by ­repair of a plas­mid pos­sess­ing a ­site-spe­cif­ic DSB ­lesion. Using plas­mids con­tain­ing tar­get poly­pu­rine-poly­py­rim­i­dine ­tracts, we ­obtained the ­fine struc­ture of ­sequence-spe­cif­ic DNA ­breaks pro­duced by ­decay of 125I ­with sin­gle-nucle­o­tide res­o­lu­tion. We ­showed ­that the ­designed 125I-TFO in nano­mo­lar con­cen­tra­tions ­could ­bind to and intro­duce dou­ble-­strand ­breaks ­into the tar­get sequenc­es in ­situ, i.e., with­in iso­lat­ed ­nuclei and ­intact digit­o­nin-per­mea­bi­lized ­cells. We ­also ­showed 125I-TFO-­induced DSB to be high­ly muta­gen­ic ­lesions result­ing in a muta­tion fre­quen­cy of near­ly 80%, ­with dele­tions com­pris­ing the major­ity of muta­tions. The ­results ­obtained dem­on­strate the abil­ity of 125I-TFO to tar­get spe­cif­ic sequenc­es in ­their nat­u­ral envi­ron­ment – with­in eucar­yot­ic nucle­us. Repair of 125I-TFO-­induced DNA dam­age ­should typ­i­cal­ly ­result in muta­gen­ic ­gene inac­ti­va­tion.

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