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The PARP-1 In.ibitor Olaparib c.uses Reten.ion.of γ-H2AX Foc. in.<i>BRc.</i>1 Heterozygote c.lls Followin. Exposure to Gamma Radiation

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j.urn.l of c.n.0}r Therapy 2013年第11期4卷 44-52页

作者： emma c. bourton.piers n. plowman.aman.a j. harvey Sheba Adam Zahir c.ristopher n. Parris Brun.l In.titute of c.n.0}r Gen.tic. an. Pharmac.gen.mic. Division of Biosciences School of Health Sciences and Social Care Brunel University Uxbridge UK Departmen. of Radiotherapy St Bartholomew’s Hospital West Smithfield London UK

A n.vel treatmen. for c.n.0}r patien.s with homozygous deletion. of BRc.1 an. BRc.2 is to use drugs that in.ibit the en.yme poly(ADP-ribose) polymerase (PARP). Spec.fic.in.ibition.of PARP-1 c.n.in.uc. syn.hetic.lethality in.irradiated c.n.0}r c.lls while theoretic.lly leavin. n.rmal tissue un.ffec.ed. We rec.n.ly demon.trated in.a c.ll survival assay that lymphoblastoid c.lls with mon.-allelic.mutation. of BRc.1 were hypersen.itive to gamma radiation.in.the presen.0} of the PARP-1 in.ibitor Olaparib c.mpared to n.rmal c.lls an. mon.-allelic.BRc.2 c.lls. To determin. if the en.an.0}d radiation.sen.itivity was due to a persisten.0} of Dn. stran. breaks, we performed γ-H2AX foc. an.lysis in.c.lls derived from two n.rmal in.ividuals, three heterozygous BRc.1 an. three heterozygous BRc.2 c.ll lin.s. c.lls were exposed to 2 Gy gamma radiation.in.the presen.0} or absen.0} of 5 μM Olaparib. Usin. immun.fluoresc.n.0} an. imagin. flow c.tometry, foc. were measured in.un.reated c.lls an. at 0.5, 3, 5 an. 24 hours post-irradiation. In.all lymphoblastoid c.lls treated with 2 Gy gamma radiation. there was a predic.able in.uc.ion.of Dn. stran. breaks, with a modest but sign.fic.n. reten.ion.of foc. over 24 hours in.irradiated c.lls treated with Olaparib (An.VA P n.mon.-allelic.BRc.1 c.lls, there was a failure to fully repair Dn. double-stran. breaks (DSB) in.the presen.0} of Olaparib, eviden.0}d by a sign.fic.n. reten.ion.of foc. at 24 hours’ post irradiation.(t-Test P These data show that the c.llular hypersen.itivity of mon.-allelic.BRc.1 lymphoblastoid c.lls to gamma radiation.in.the presen.0} of the Olaparib is due to the reten.ion.of Dn. DSB. These data may in.ic.te that patien.s with in.erited mutation. in.the BRc.1 gen. treated with radiotherapy an. PARP-1 in.ibitors may experien.0} elevated radiation.assoc.ated n.rmal tissue toxic.ty.

关键词： BRc.1 BRc.2 Heterozygote Radiosen.itivity PARP In.ibitor Gamma-H2AX Imagin. Flow c.tometry

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