• No results found

Chelation of lysosomal iron protects against ionizing radiation.

N/A
N/A
Protected

Academic year: 2021

Share "Chelation of lysosomal iron protects against ionizing radiation."

Copied!
24
0
0

Loading.... (view fulltext now)

Full text

(1)Linköping University Post Print. Chelation of lysosomal iron protects against ionizing radiation.. Carsten Berndt, Tino Kurz, Markus Selenius, Aristi P Fernandes, Margareta R Edgren and Ulf T Brunk. N.B.: When citing this work, cite the original article.. Original Publication: Carsten Berndt, Tino Kurz, Markus Selenius, Aristi P Fernandes, Margareta R Edgren and Ulf T Brunk, Chelation of lysosomal iron protects against ionizing radiation., 2010, Biochemical Journal, (432), 2, 295-301. http://dx.doi.org/10.1042/BJ20100996 Copyright: Portland Press -- London http://www.portlandpress.com/ Postprint available at: Linköping University Electronic Press http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-63266.

(2) Berndt et al., Iron and ionizing radiation. 1. 

(3)             .   

(4)           ! " # !$  %&  

(5). '( & )*+, '-+ &  ) )*+,  -*,)  . / // )*+0 2#'#3 '( & *+)!, ), & 4* )) 56 65 78-! %(,0 2#'#3 '( & *!, '-+ & 79,  )  . : 6; )*+0 2#'#3 $'( &  ) "  *,) '-+ & <)),=*!,  . / /; )*+0 2#'#30  . & ) ,9!,  ,-*!, *--=%(> ?5@?/ 9! A#"3B    !"  #$ .  !   . * * )9 C,  * D - ! *E    '( & )*+, '-+ &  ). )*+,  -*,)  . )* F>!  / // )*+ D  *E G:; 6 5: 6//5 HE G:; 6 5: 6:/;   I . %%&  !$ < )  !0 ' < &H+0 7 ,+ ++9 -+90 <' -) ,0  -) &)0 "< )( H,! -)0 .4 ), *,  ), *,  '( )$ !    ! )) ,+ H (   )*.

(6) Berndt et al., Iron and ionizing radiation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

(7) Berndt et al., Iron and ionizing radiation. 3.   *. 3=!) )) *-, ! )*+=   *-,  +, 9  *  ) & --) ) * &D! * - ) & )( H,! -) K"<L  )+9! H (  )*  ++9 & * * H &+, & - -H  +  )  & -!  + )  ) D* )  )* *- N=5O .  !, + * '3 +! +  9, * *, H,  ) K4<PL *  &+ 9,  ,) )(! & D  -9 & ) * ) 9, !   N;O . * -(, 9 -  *     '3 +!   -5?= +  ) * ,+ ++9 -+9 K7L  ) 9, H (    )9! &)  --) ) * ) 9, !   N/O )* 7  -   ,+  H=)(  * ) -H   &!+ & * ,+ ++9 ) ,  * H (  *    ) N/ 6O =,- ) 9D *, ! -H    H=)(    &+ & *, H,  )   * ,+ )+-+ . *& &D * * ,+ )) &  H=)(  D 9 ),   * H & 7 . * 9 & *  = ) 7 ) 9 9! 9, )* & ,+  H=)(  ! &H+ K' <L N/O ' < *D( , D* * ,+ )+-+ &D!   ),) - ) =( D* ! ) *   9(,   D=  )* . * ! ( H  ! +9 & +)-*! +, & D*)* *( !& ,*),  )C, ) =)* ,+ * +, 9   )C) & !    ) +)-*! *  )9  *  ) &   -+  -+, &9 *+ * -+, ) ,- +, *( =)* ,+  !, * -( -*!, *   9,   !, *) * + & ,+  H=)(  N/O "-( -*-*!,   D, & )  !  +! )  (( * 9 D & ) &! + )*  &  +)*     -*!,+ , 9)+ )*  D +  H=)(  *!*   (, -  & * ,+ )+-+  9   &  H-   (, & 9) -) D* +)*   * ), NQ @O 7! ))  -, *  ! ) & ))= * D D  NO , ) & ! )) C !    - & * +!+ & * )++ !- & (& +!) D*  !, - )+  +R -9+ * + *  &    *  &  )! -+, &9 D*)* +,    9 & *! NO C,   & ),  --,   & !   *   * -+ & &&)( *-, .+-(+ & *-) &&)),  *& 9(,    4 D !!  +D* * H D, & * ! *   !  + +  *) *   &&)),  + D* D * !! ! & * -) &  ! +   & ,   -) +& D*)* ) ,  *--  9  ,+-)  )* * 9 H-  ))  N?=5O 4 D *(  * &&) & ,+ =)* 9, * --*) )* ), *,  ), *,  K.4L  ) (( &D!     (, & ) ) ) .4 C),   ( ) 9!  C9+ D*  ))  *  ! + +  ) , 9  D,   )  ' < *  ! ! &&) N;O.

(8) Berndt et al., Iron and ionizing radiation. 4. +   )  ! K<L 9 D &+ A K %L .4 K  !& &+ & ' ")*  %(, & 3D * 2 , , L D (  '<  *   #<4  )*  D, * * & )  ) .4   )) & @ +   @T '<UQ@T #<4 (*) C & * )  D    ) ) + +  9 & )) & @=@@ V .4 ) '<   D=D )(! & *, H,  )  -) ! !   N/O  H-+ D )    * * D & )) & * '<U#<4 (*) *  &)  * ) (,     *, ! -H  K   *DL  * )*+) D &+ !+= )* K)*+ D L   

(9)    D !, &+   %-- %(, 47  W//: ) D !D  '# KA9) %L %;Q@ )  #  * )  %@@ %6@  %Q@;  ". KA9) %L  +  D --+ D* @T *=)( & )& + K L  + !+  @@ X+ Y -)U-+,) K )*! L  D !D  -) &  ?5 ++  * K! 3D B %L  ?/Z   Q@T *+ & +-* )! 5T <  *, D 9)( )  D)  D  

(10)  γ=  D -&+ D*  ?/ ) K) H %-- D L  *  . )*+   -*   & @5 A,X+= '+, D  D*   )*+9  D  D* & -* )) !  * (, & *  )   D  * ! & @=6 A,  D -   9H     + +- *   D   &* + + D*  D* .4 2* -- .4 D   ?@ + 9&   *   + + D -) 9, &* !D* + + KD* .4L D* ) D     ) )  

(11) 

(12)      --- ) +9 D - & (( ! * -(, )9 )!) , )*C N6O !=) - D -  ?5 ++ -)  *  ;=D -  -)  C -)   & + + (+ & ? +U *  D  * &  * )9 & ?=: *  )* 9&   D*)* D -&+  )9 9( D!   * ) D )9 & @=: , D*  )*! & + + & 5=/ , *& ) D &H   )  "  (( )( D )) &+   &  -  H-+           * 7[ +  NQO D   &  D* *  C +* D* * -99, & )!) ) ((       !( 9, N@OE S = exp (- D – D2) *  & @T (( ( D ))  + * =+ &,! &)  * ) * -) &) K L.

(13) Berndt et al., Iron and ionizing radiation. 5. 

(14) 

(15)    

(16)    (( & 47 ) D +  )9 9(  D --  +9 * D , )! & ? , &D!    ( +*  + ) (( &D!   D --  * )  %Q@;  %6@  * ) ,-    , &+ ) . * ) ) D    !D  5 )+  ) & & : * -    * D -&+   )  )9 9(  D * , 9=)   E:   ) * + !  - & :=; , &D!   #+ & ) +9 K)U+L D 9 9, ,! -) , K<'L  ;@@ +  ,- !=) - * <' D )+-     )( * D -(, )) 9, )!   &  ) -   ]=)*+9 , !D* )( D 9 9, )+-! ) +9   +9 & +=-    * ) +9  * -( 9)(     

(17)       D    Q; D -  @: )UD & ; * * ) D )9 &  * D* && )) & 4< K@Y@@ +L  4  D*  D* @@ V .4 - + ) D )9 D* ?@ V  ? & 5 * 9& * 4< + KD*    ) + + K...L &+ 9 =-*-*U*, H  *   - 9,  ),  -  * ,+ )+-+L D!  * & 4 <= H- K ! * - & + + & * *, ! -H  D !  9, * )L ) D D*      ) )  * +9 & (9 ) D + : *  ! *  &  .. K")* -- )) A+,L * ,  9  &+ &  ) &+ &D! +)*  H  & * +  ^ 9, +9), )( ) * , D C& !  +)-   K-)H ?:@ ) '()  %L  :Q@  ;5@ +     

(18) 

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

(20) Berndt et al., Iron and ionizing radiation. 6. *   

(21)   

(22) 

(23)  

(24) 

(25)    

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

(27)   

(28) 

(29)  

(30)       

(31)  )   9( * * &&) & !   -, -   ) &+ & *, ! -H  N5O D* ! 7 N/O D (! -) 9, .4 ! 4<= ) ) * * +=) ! ))  %@@ N;O  %;Q@ D H-  ( )) & 4< D*  D* @@ V .4 - K ! ?  L  ) (( D )) : *   %@@ ) * #)5@ 4< ( ) &+ @ +  /65 + K ! ? L  & * %;Q@ ) &+ Q? V  56@ V K ! ? L  D  & & !   K !  L (( ) & ) D H-    -*-* )+-H -  *  ) & H (  K ! ? L * #) 5@ ( & %;Q@ ) --  5? V &D! )9 D* ?@ V ? & &( * 9& ! 4< + . * 9 -  * *   & ?  ) + +   &+ &   -*-*U*, H  -)- *   ), 9, * ) * ,+ )+-+  *9, )* D* .

(32) Berndt et al., Iron and ionizing radiation. 7. %! ! * )!) )=(( , D )) *D +, %;Q@ ) (( H-  && )) & 4< )+-   ) 2 & * D* .4 -)  %;Q@ ) (( * =* - & 4<=H-  , 5@=5@ V D* 5@=@@T & * ) * D -) 9, @ V .4   K ! ? L   

(33)      

(34) 

(35)   

(36)   

(37) 

(38)   9 &* !*  * -) +)*+ &&  9, * =)* .4 D , 7 !( * &) *  H=)(   +, &   ,+ N /=?@O %;Q@ ) D 9R)  * <=)  D! <= ! ) D H- & ?@ +  @@ V 4 < GU= @@ V .4  4   ! &)) D , 9, &D ),&+, K L & * ?@ + K ! : L +-  * ) ) * + ! &)) ) -  5;T &D! H-  4 < , D* ) H-  @@ V 4<   * -) & @@ V .4 *D ,  + ) & * + ! &))0 -  @T & * ) ) K ! : L.

(39) Berndt et al., Iron and ionizing radiation. 8. *. - &+  ,) )(! & D  !  &+ & *, H,  ) K4<PL * + - ) & *, ! -H    D=D &&) & !     N/ 5O 4D( * -9 &) & *, ! -H    = ) ) +!   , +  9 &,   )) *  +D* -! )   -- &+ Q; < 29! -  * * ) &&) & H-  !     *, ! -H  *D 9 + N?O H2O + ionizing radiation → HO• + H+ + eO2 + e- → O2•O2•- + O2•- + 2H+→ H2O2 + O2 D!    * +!! &&) &  +, &+ 4<P  * 9 - * * *=( K@=Q )L  H+, !!(  ) ) D* ) '3  * (, - D* *,  &+ )!  ) +  !  9  9 D* ! ) +! #( &    &(, -( * 4< P= ) '3 +!  * + ) & ) R, &D!   *   (D*+! + &  ) ( ) * *    * )  * +  9    C * !+ 4D( - &+  ,) )(! & D 4< P )  9 - ) 9, =,- K +=+  L ) D*)* !( )(  H+ * ))) & )* ) ! !   Fe2+ + H2O2 → Fe3+ + HO• + OHFe3+ + O2•- → Fe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

(40) Berndt et al., Iron and ionizing radiation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

(41) Berndt et al., Iron and ionizing radiation. 10.  -  )*    D D H-   *!*=*=+=  =   +, ) * (( )*) & ! )) - D*)* D *D * *!* +, &  )) - NO 9, -)! +,   *& ))9    !  9  *  +!), D* D,.

(42) Berndt et al., Iron and ionizing radiation. 11. ' ,  2 * & W* # %(, & 7( B % & (9 !! * * )  )&) & .

(43) Berndt et al., Iron and ionizing radiation. 12.

(44) *  . 2 * * ')* )*!!+)*& K #?5Q=  L *  . K  L ) )* !&  K L " +*++ &!&  K L  4R>= 7!&  KL & &) --.

(45) Berndt et al., Iron and ionizing radiation. 13. REFERENCES 1 Arner, E. S. and Holmgren, A. (2006) The thioredoxin system in cancer. Semin. Cancer. Biol. 16, 420-426 2 Kinnula, V. L., Paakko, P. and Soini, Y. (2004) Antioxidant enzymes and redox regulating thiol proteins in malignancies of human lung. FEBS Lett. 569, 1-6 3 Cunnea, P., Fernandes, A. P., Capitanio, A., Eken, S., Spyrou, G. and Bjornstedt, M. (2007) Increased expression of specific thioredoxin family proteins; a pilot immunohistochemical study on human hepatocellular carcinoma. Int. J. Immunopathol. Pharmacol. 20, 17-24 4 Fernandes, A. P., Capitanio, A., Selenius, M., Brodin, O., Rundlof, A. K. and Bjornstedt, M. (2009) Expression profiles of thioredoxin family proteins in human lung cancer tissue: correlation with proliferation and differentiation. Histopathology. 55, 313-320 5 Soini, Y., Kahlos, K., Napankangas, U., Kaarteenaho-Wiik, R., Saily, M., Koistinen, P., Paaakko, P., Holmgren, A. and Kinnula, V. L. (2001) Widespread expression of thioredoxin and thioredoxin reductase in non-small cell lung carcinoma. Clin. Cancer Res. 7, 1750-1757 6 Roots, R. and Okada, S. (1975) Estimation of life times and diffusion distances of radicals involved in x-ray-induced DNA strand breaks of killing of mammalian cells. Radiat. Res. 64, 306-320 7 Persson, H. L., Kurz, T., Eaton, J. W. and Brunk, U. T. (2005) Radiation-induced cell death: importance of lysosomal destabilization. Biochem. J. 389, 877-884 8 Kurz, T., Eaton, J. and Brunk, U. (2010) Redox activity within the lysosomal compartment: Implications for aging and apoptosis. Antioxid. Redox Signal. 13, 511-523 9 Kurz, T., Terman, A., Gustafsson, B. and Brunk, U. T. (2008) Lysosomes in iron metabolism, ageing and apoptosis. Histochem. Cell Biol. 129, 389-406 10 Kurz, T., Terman, A., Gustafsson, B. and Brunk, U. T. (2008) Lysosomes and oxidative stress in aging and apoptosis. Biochim. Biophys. Acta. 1780, 1291-1303 11 Parkin, D. M., Bray, F., Ferlay, J. and Pisani, P. (2005) Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74-108 12 Beinert, T., Binder, D., Stuschke, M., Jorres, R. A., Oehm, C., Fleischhacker, M., Sezer, O., Mergenthaler, H. G., Werner, T. and Possinger, K. (1999) Oxidant-induced lung injury in anticancer therapy. Eur. J. Med. Res. 4, 43-53 13 Andreassen, C. N., Grau, C. and Lindegaard, J. C. (2003) Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin. Radiat. Oncol. 13, 62-72 14 Werner-Wasik, M., Langer, C. and Movsas, B. (2005) Amifostine in chemoradiation therapy for non-small cell lung cancer: review of experience and design of a phase II trial assessing subcutaneous and intravenous bolus administration. Semin. Oncol. 32, S105-108 15 Yu, Z., Eaton, J. W. and Persson, H. L. (2003) The radioprotective agent, amifostine, suppresses the reactivity of intralysosomal iron. Redox Rep. 8, 347-355 16 Kurz, T., Gustafsson, B. and Brunk, U. T. (2006) Intralysosomal iron chelation protects against oxidative stress-induced cellular damage. FEBS J. 273, 3106-3117 17 Abok, K., Rundquist, I., Forsberg, B. and Brunk, U. (1984) Dimethylsulfoxide increases the survival and lysosomal stability of mouse peritoneal macrophages exposed to low-LET ionizing radiation and/or ionic iron in culture. Virchows Arch. B Cell. Pathol. Incl. Mol. Pathol. 46, 307-320 18 Puck, T. T. and Marcus, P. I. (1956) Action of x-rays on mammalian cells. J. Exp. Med. 103, 653-666 19 Sinclair, W. K. (1966) The shape of radiation survival curves of mammalian cells cultured in vitro. In In: Biophysical Aspects of Radiation Quality, Technical Report Series No. 58. pp. 21-.

(46) Berndt et al., Iron and ionizing radiation. 14. 43, IAEA, Vienna 20 Curtis, S. B. (1976) The OER of mixed high- and low-LET radiation. Radiat. Res. 65, 566-572 21 Zdolsek, J., Zhang, H., Roberg, K. and Brunk, U. (1993) H 2O2-mediated damage to lysosomal membranes of J-774 cells. Free Radic. Res. Commun. 18, 71-85 22 Bergh, J., Nilsson, K., Ekman, R. and Giovanella, B. (1985) Establishment and characterization of cell lines from human small cell and large cell carcinomas of the lung. Acta Pathol. Microbiol. Immunol. Scand. A. 93, 133-147 23 Cedervall, B., Sirzea, F., Brodin, O. and Lewensohn, R. (1994) Less initial rejoining of Xray-induced DNA double-strand breaks in cells of a small cell (U-1285) compared to a large cell (U-1810) lung carcinoma cell line. Radiat. Res. 139, 34-39 24 Brodin, O., Arnberg, H., Bergh, J. and Nilsson, S. (1995) Increased radioresistance of an in vitro transformed human small cell lung cancer cell line. Lung Cancer. 12, 183-198 25 Halliwell, B. and Gutteridge, J. M. C. (1999) The chemistry of free radicals and other related "reactive species". In Free Radicals in Biology and Medicine. pp. 36-104, Oxford University Press, Oxford 26 Mellstrom, K., Bjelfman, C., Hammerling, U. and Pahlman, S. (1987) Expression of c-src in cultured human neuroblastoma and small-cell lung carcinoma cell lines correlates with neurocrine differentiation. Mol. Cell Biol. 7, 4178-4184 27 Brunk, U. T., Zhang, H., Roberg, K. and Öllinger, K. (1995) Lethal hydrogen-peroxide toxicity involves lysosomal iron-catalyzed reactions with membrane damage. Redox Report. 1, 267-277 28 Persson, H. L., Yu, Z., Tirosh, O., Eaton, J. W. and Brunk, U. T. (2003) Prevention of oxidant-induced cell death by lysosomotropic iron chelators. Free Radic. Biol. Med. 34, 12951305 29 Yu, Z., Persson, H. L., Eaton, J. W. and Brunk, U. T. (2003) Intralysosomal iron: a major determinant of oxidant-induced cell death. Free Radic. Biol. Med. 34, 1243-1252 30 Zdolsek, J. M., Roberg, K. and Brunk, U. T. (1993) Visualization of iron in cultured macrophages: a cytochemical light and electron microscopic study using autometallography. Free Radic. Biol. Med. 15, 1-11 31 Warburg, O. H. (1962) New Methods of Cell Physiology. Applied to Cancer, Photosynthesis, and Mechanism of X-Ray Action. Interscience Publishers, New York 32 Doulias, P. T., Christoforidis, S., Brunk, U. T. and Galaris, D. (2003) Endosomal and lysosomal effects of desferrioxamine: protection of HeLa cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest. Free Radic. Biol. Med. 35, 719-728 33 Kurz, T., Leake, A., Von Zglinicki, T. and Brunk, U. T. (2004) Relocalized redox-active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage. Biochem. J. 378, 1039-1045 34 Tenopoulou, M., Doulias, P. T., Barbouti, A., Brunk, U. and Galaris, D. (2005) Role of compartmentalized redox-active iron in hydrogen peroxide-induced DNA damage and apoptosis. Biochem. J. 387, 703-710 35 Schafer, F. Q. and Buettner, G. R. (2000) Acidic pH amplifies iron-mediated lipid peroxidation in cells. Free Radic. Biol. Med. 28, 1175-1181 36 Nilsson, E., Ghassemifar, R. and Brunk, U. T. (1997) Lysosomal heterogeneity between and within cells with respect to resistance against oxidative stress. Histochem. J. 29, 857-865 37 Terman, A., Kurz, T., Navratil, M., Arriaga, E. and Brunk, U. (2010) Mitochondrial turnover and aging of long-lived postmitotic cells: The mitochondrial-lysosomal axis theory of aging. Antioxid. Redox. Signal. 12, 503-535.

(47) Berndt et al., Iron and ionizing radiation. 15. 38 Li, W., Yuan, X., Nordgren, G., Dalen, H., Dubowchik, G. M., Firestone, R. A. and Brunk, U. T. (2000) Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett. 470, 35-39 39 Cable, H. and Lloyd, J. B. (1999) Cellular uptake and release of two contrasting iron chelators. J. Pharm. Pharmacol. 51, 131-134 40 Lloyd, J. B., Cable, H. and Rice-Evans, C. (1991) Evidence that desferrioxamine cannot enter cells by passive diffusion. Biochem. Pharmacol. 41, 1361-1363 41 Grdina, D. J. and Sigdestad, C. P. (1989) Radiation protectors: the unexpected benefits. Drug Metab. Rev. 20, 13-42 42 Held, K. D. (1985) Interactions of radioprotectors and oxygen in cultured mammalian cells. I. Dithiothreitol effects on radiation-induced cell killing. Radiat. Res. 101, 424-433 43 Murray, D., vanAnkeren, S. C., Milas, L. and Meyn, R. E. (1988) Radioprotective action of aminothiols in vitro and in vivo: comparison between effects on DNA damage and cell survival. Pharmacol. Ther. 39, 151-153 44 Patt, H. M., Tyree, E. B., Straube, R. L. and Smith, D. E. (1949) Cysteine protection against x irradiation. Science. 110, 213-214 45 Vos, O., Budke, L. and Vergroesen, A. J. (1962) Protection of tissueculture cells against ionizing radiation. I. The effect of biological amines, disulphide compounds and thiols. Int. J. Radiat. Biol. 5, 543-557 46 Weiss, J. F. (1997) Pharmacologic approaches to protection against radiation-induced lethality and other damage. Environ. Health Perspect. 105 Suppl 6, 1473-1478 47 Weiss, J. F. and Landauer, M. R. (2003) Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology. 189, 1-20.

(48) Berndt et al., Iron and ionizing radiation. 16. . %# / : ! ;: 

(49)  <& &# ! :" ; & < :## # ! ;##) ! ! = !   ! !  !: ;  !>:# ?   D )) 9  )!) ) (( , K ! L  *  & *  D*  D* .4 !( @ T ((  ,-. .4 )). .      D* )*!  ) ((. 47. @ V. @. @ T. 47. @ V. /6. /6 T. W//:. @ V. ?@. ?@ T. %;Q@. @ V. @. @ T.

(50) Berndt et al., Iron and ionizing radiation. 17.   

(51) *

(52) < /  !>:#  & :## ) ;##) ! ! = !   ! 47 KL %Q@; K.L  %6@ K    L ) D   9 : * 9& 9! H- & ?@Y;@ +  @ V .4 K + L   K))L &D 9,   K& ,+9  L D*  K.L ? KL  5 A, K@ L  D*   K+-, ,+9  L   *D (( & %6@ ) D D &D!     * -) & @ V .4 K& 9L  D* )* -) K+-, 9L )+-  =   ) ), !&) &&) 9D   .4=-) )    ) ) D )) !  ¥ = K

(53)

(54)

(55) ¦ @@@

(56)

(57) ¦ @@

(58) ¦ @@5L

(59) < A  !>:#  : :##  ! ! = !   !> !<: :##  47 K    .L W//: KL  %;Q@ KL ) D   9 : * 9& 9! )9 D* K))L  D* @ V K + L  @ V .4 KCL & ?@Y;@ +  *   D*  9D   6 A, * ((! &) 9  * +9 & ) & @=: , &D! *   D +  - ! *     . + * *) ( & ,+  K  &  ),) - & =-*-*U*, H L ) * +!! &&) & !  

(60) < B  !>:#  : *ADAD ! */GHD :##  ! (! I > !<: :##  %@@ KL  %;Q@ K.L ) D    Q;=D=- K@: )UDL D* %;Q@ ) D     ;=D=-   , & @@=6@@ )UD KL * ) D * H- &  *  4< K,  @=@@ +L D* K+-, CL  !* D* K& ))L @@ V .4  (9, K .L  )!) ) (( KL D )) : *  @=: , &     ) )  *  ) ) (( &D! *   & ?@ V ?  * + + &( * 9& H-  4 <  *D 9, * *  D* & +  K.L * 4!+ KL  ) (( & ) H-  *, ! -H   * -) K& 9L & @ V .4   K+-, 9L 3 * -) )   (( * 4< H- ' - * (! & &  H -  D  -  H-+

(61) < J >: !  !  ;;: ; (! I    ;<!: ! ; #(K# % # = ! KL %;Q@ ) D -=  D* < ; * &  !  D * H- & ?@ +  , @@ V 4 <  4¥ 9&&  * -) & K9) *!+L  D* K+-, *!+L @@ V .4  R -  4¥ 9&& K!, *!+L & * ?@ +    ) )  * ) D ,-  ! 7 &)) 9!   ) & < )  * ),    & ,+ - D , 9, &D ),&+, K L K." * -) 9, .4 & ,+ ! 4< D )) K ¥ =

(62)

(63)

(64) ¦ @@@L * +-, 9 - ) H-  @@ V 4< , D* * & 9 - ) H-  @@ V 4<  * -) & @@ V .4.

(65) Berndt et al., Iron and ionizing radiation. 18.

(66) < L :K : ! ! ; < K:! K % ! >K  : !  !   !> !<: :##  * )  9  * ! +  =  *&  )* 9, * .4 D* + !     H-  .4 C, * +  D 9 -) ! ) *  ) 9, =+   ,- ) &D! !   .&   9, !  &   ) 9 -- (  -+, & D*  ) & ! &9 K&   HL.

(67) Berndt et al., Iron and ionizing radiation

(68) < /. 19.

(69) Berndt et al., Iron and ionizing radiation

(70) < A. 20.

(71) Berndt et al., Iron and ionizing radiation

(72) < B. 21.

(73) Berndt et al., Iron and ionizing radiation

(74) < J. 22.

(75) Berndt et al., Iron and ionizing radiation

(76) < L. 23.

(77)

References

Related documents

Repair of DSB and clustered damage: A study on influence of direct hits, chromatin acetylation and radiation quality.. Elmroth, Biological consequences of formation and repair of

We have investigated the formation and repair of complex lesions, including double strand breaks (DSB) and clustered damages (two or more lesions within 10-20 base pairs) after

When investigating the colony formation ability of the two HNSCC cell lines LK0412 and SqCC/Y1, both were found to give rise to holoclones, indicating the presence of cells

Genom att studera normala orala keratinocyter och jämföra dessa mot fem olika cellinjer etablerade från skivepitelcancer från munhåla har vi också funnit ett samband mellan

 Investigate if there was any benefit in terms of transfusion dependency, S-ferritin and overall survival in the chelated patients compared to the patients that did not receive

Immediate and late effects of delayed chronic lithium treatment on neurogenesis after irradiation of the developing mouse brain... 3 MATERIAL

We also characterized and compared the radiation-induced reactions in the hippocampus of the juvenile and adult rat brain, as well as evaluated the modulating effect of

Deltagarna måste även trycka på vilka svårigheter som finns hos personen, dels för att personen ska få ersättning, men även för att få möjlighet till rätt rehabilitering..