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T o m a s z O b t u Bo w i c z a , A l i c j a W i n c z u r a a , E l |b i e t a S p e i n a a , M a j a S w o b o d a a , J u s t y n a J a n i k a , B e a t a J a n o w s k a a , J a r o s Ba w M . C i e [l a a , P a w e B K o w a l c z y k b , A r k a d i usz Jawien c, Daniel Gackowski d, Zbigniew Banaszkiewicz c, Ireneusz Krasnodebski e, Andrzej Chaber e, Ryszard Olinski d, Jagadesaan Nair f, Helmut Bartsch f, Thierry Douki g, Jean Cadet g, Barbara Tudek a,h,*
a Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
b Interdisciplinary Centre for Mathematical and Computational Modeling, Warsaw University,
Warsaw, Poland
c Department of Surgery, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
d Department of Clinical Biochemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland,
e Public Central Teaching Hospital, Medical University of Warsaw, Warsaw, Poland
f German Cancer Research Center hi, Heidelberg, Germany
g Laboratoire Lsions des Acides Nucliques, Service de Chimie Inorganique et Biologique
UMR-E 3 CEA-UJF, CNRS FRE 3200, CEA/DSM/INAC, CEA-Grenoble, France.
h Institute of Genetics and Biotechnology, Warsaw University, Warsaw, Poland
JN has deceased
* Corresponding author: Barbara Tudek,
Institute of Biochemistry and Biophysics,
Polish Academy of Sciences,
Pawinskiego 5a,
02-106 Warsaw, Poland
tel: (+4822) 592-3334; fax: (+4822) 592-2190
e-mail: HYPERLINK "mailto:tudek@ibb.waw.pl"tudek@ibb.waw.pl
Running title: Repair of etheno DNA adducts in colorectal cancer patients
A B S T R A C T
T o a s s e s s t h e r o l e o f l i p i d p e r o x i d a t i o n ( L P O ) - i n d u c e d D N A d a m a g e a n d r e p a i r i n c o l o n c a r c i n o g e n e s i s , e x c i s i o n r a t e a n d t h e l e v e l o f 1 , N 6 - e t h e n o - 2 - d e o x y a d e n o s i n e ( d A ) , 3 , N 4 - e t h e n o - 2 - d e o x y c y t i d i n e ( d C ) a n d 1 , N 2 - e t h e n o - 2 - d e o x y g u a n o s i n e ( 1 , N 2 - d G ) w e r e a n a l y z e d i n p o l y m o r p h i c b l o o d l e u k o c y t e s ( P B L ) a n d r e s e c t e d c o l o n t i s s u e s o f 5 4 c o l o r e c t a l c a r c i n o m a ( C R C ) p a t i e n t s a n d P B L o f 5 6 h e a l t h y i n d i v i d u a l s . I n P B L t h e e x c i s i o n r a t e o f 1 , N 6 - e t h e n o a d e n i n e ( A d e ) a n d 3 , N 4 - e t h e n o c y t o s i n e ( C y t ) , m e a s u r e d b y t h e n i c k i n g o f o l i g o d e o x y n u c l e o t i d e d u p l e x e s w i t h s i n g l e l e s i o n s , a n d u n e x p e c t e d l y a l s o t h e l e v e l o f d A a n d 1 , N 2 - d G , m e a s u r e d b y L C / M S / M S , w e r e l o w e r i n C R C p a t i e n t s t h a n i n c o n t r o l s . I n c o n t r a s t m R N A l e v e l s o f r e p a i r e n z y m e s , a l k y l p u r i n e - ( A N P G ) a n d t h y m i n e - D N A g l y c o s y l a s e s ( T D G ) a n d a b a s i c s i t e e n d o n u c l e a s e ( A P E 1 ) w e r e h i g h e r i n P B L o f C R C p a t i e n t s t h a n o f c o n t r o l s , a s m e a s u r e d b y Q P C R . I n t h e t a r g e t c o l o n t i s s u e s A d e a n d C y t e x c i s i o n r a t e w a s h i g h e r , w h i l e d A a n d d C l e v e l i n D N A , m e a s u r e d b y 32P-postlabeling method, was lower in tumor than in adjacent colon tissue, although the higher mRNA level was observed only for APE1. This suggests that during onset of carcinogenesis, etheno adducts repair in the colon seems to be under complex transcriptional and post-transcriptional control, whereby deregulation may act as a driving force to malignancy.
Keywords: Oxidative Stress; Colon Cancer; Base Excision Repair; 1,N6-Ethenoadenine; 3,N4-Ethenocytosine
Colorectal cancer is a frequent cause of death in developed countries ADDIN EN.CITE ADDIN EN.CITE.DATA [1, 2]. Important etiological risk factors of sporadic colorectal tumors are inflammatory bowel diseases, excess consumption of animal fat and meat, alcohol drinking, and tobacco smoking ADDIN EN.CITE Levi199933317Levi, F.Pasche, C.La Vecchia, C.Lucchini, F.Franceschi, S.Registre Vaudois des Tumeurs, Institut universitaire de medecine sociale et preventive, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.Food groups and colorectal cancer riskBritish journal of cancer1283-7797-8AdultAgedCase-Control StudiesColonic Neoplasms/*etiologyDairy ProductsDiet/adverse effectsFemaleFood/*classificationFruitHumansMaleMeatMiddle AgedOdds RatioRectal Neoplasms/*etiologyVegetables1999Mar0007-0920 (Print)10098773http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10098773 eng[3]. Chronic inflammation is associated with the large release of reactive oxygen and nitrogen species ADDIN EN.CITE Dizdaroglu199344417Dizdaroglu, M.Olinski, R.Doroshow, J. H.Akman, S. A.Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899.Modification of DNA bases in chromatin of intact target human cells by activated human polymorphonuclear leukocytesCancer research1269-72536Cell LineChromatin/*metabolismDNA/*metabolismHumansHydrogen Peroxide/toxicityHydroxidesHydroxyl RadicalNeutrophils/drug effects/*physiologyTetradecanoylphorbol Acetate/pharmacology1993Mar 150008-5472 (Print)8383005http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8383005