Zbornik - Društvo genetičara Srbije

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198 ZBORNIK ABSTRAKATA III KONGRESA GENETIÈARA SRBIJE V-Usm-15 Subotica, 30. novembar - 4. decembar 2004. ISTOVREMENA METILACIJA p16 INK4A I MGMT GENA JE POVEZANA SA POVOLJNIJIM TOKOM BOLESTI KOD OBOLELIH OD KOLOREKTALNOG KARCINOMA Milena Krajnoviæ 1 , Koviljka Krtolica 1 , Slavica Kneeviæ-Ušaj 2 i B. Dimitrijeviæ 1 1 Laboratorija za radiobiologiju i molekularnu genetiku, Institut za nuklearne nauke «Vinèa», Beograd 2 Institut za patologiju, VMA, Beograd Da bismo ispitali eventualnu povezanost izmeðu navedenih parametara, analizirali smo 37 iseèaka tkiva tumora obolelih od kolorektalnog karcinoma. Za utvrðivanje metilacionog statusa p16 INK4A i MGMT gena je primenjena metoda bisulfitne modifikacije DNK, kojom se pod odgovarajuæim uslovima svi nemetilovani, ali ne i metilovani citozini prevode u uracil, a eljeni fragmenti ovako modifikovane DNK su zatim amplifikovani posebno dizajniranom, za metilaciju specifiènom PCR tehnikom-MSP. Istovremena metilacija p16 INK4A i MGMT gena je u našem radu detektovana kod 27% (10 od 37) ispitanika, a korelacija izmeðu ovog dogaðaja i klinièko-patoloških karakteristika, kao što su pol, starost, Ðukovi stadijumi, histološki tip, diferenciranost i lokacija tumora, nije uoèena. Meðutim, u analizi klinièkog toka i ishoda bolesti u dvogodišnjem periodu, istovremena metilacija navedenih gena je statistièki znaèajno (p < 0.05) korelirala sa manje agresivnim postoperativnim tokom bolesti i duim preivljavanjem obolelih od kolorektalnog karcinoma. Utvrðeno je da je do pojave metastaza i smrtnog ishoda u toku dve godine došlo kod svega 30% (3 od 10) ispitanika sa istovremenom metilacijom oba gena, dok je to bio sluèaj kod 72% (18 od 25), odnosno, 68% (17 od 25) obolelih bez istovremene metilacije analiziranih gena. Dobijeni rezultati sugerišu da bi istovremena metilacija p16 INK4A i MGMT gena mogla da predstavlja povoljniji prognostièki parametar kod obolelih od kolorektalnog karcinoma, a identifikacija ovih molekularnih markera bi omoguæila dizajniranje specifiènih terapijskih pristupa. SIMULTANEOUS METHYLATION OF p16 INK4A AND MGMT GENES IS ASSOCIATED WITH LESS AGGRESSIVENESS OF THE DISEASE AND LONGER SURVIVAL IN COLORECTAL CANCER To explore the possible association between these parameters we analysed tumour tissue samples from 37 patients with colorectal cancer. DNA methylation patterns were determined by chemical bisulphite modification of unmethylated, but not methylated cytosines to uracil and subsequent PCR amplification, using primers specific for either methylated or the unmethylated DNA. Simultaneous methylation of p16 INK4A tumour suppressor and MGMT genes was found in 27% (10 of 37) of samples and there was no correlation between this event and any clinicopathological characteristics including age, gender, Dukes' stage, histological type, differentiation and tumour location. However, in the two-years survival analysis, simultaneous methylation of these two genes was significantly associated (p < 0.05) with less aggressiveness of the disease and longer survival in patients with colorectal cancer who underwent curative surgery. In this period, the progression of the disease and the death occurred in only 30% (3 of 10) patients with simultaneous methylation of two examined genes, while that was the case with 72% (18 of 25) and 68% (17 of 25) patients without simultaneous methylation of analysed genes, respectively. Our results suggest that simultaneous methylation of p16 INK4A and MGMT genes could be the factor of better prognosis in patients with colorectal cancer and that identification of these molecular markers may be of use for the patient specific design of antitumour therapy.
V-Usm-16 ZBORNIK ABSTRAKATA III KONGRESA GENETIÈARA SRBIJE 199 Subotica, 30. novembar - 4. decembar 2004. IN VITRO ANALIZA MIKRONUKLEUSA I ÆELIJSKE KINETIKE U HUMANIM LIMFOCITIMA POD DEJSTVOM ADRENALINA Biljana Markoviæ i N. Ðeliæ Katedra za biologiju, Fakultet veterinarske medicine, Univerzitet u Beogradu, Beograd Upotrebljeno je osam razlièitih koncentracija adrenalina (opseg 5×10-10 M do 5×10-5 M), od one koja odgovara fiziološkom nivou ovog hormona u plazmi, preko koncentracija uporedljivih sa minimalnim, srednjim i maksimalnim terapijskim dozama u humanoj medicini, sve to 10, 30 i 100 puta jaèih koncentracija od terapijskih doza u humanoj medicini. Eksperimentalna procedura u potpunosti je odgovarala smernicama OECD za in vitro mikronukleus test. Upotrebljena je krv tri zdrave muške osobe mlaðe od 35 god. Statistièka analiza dobijenih rezultata uraðena je Studentovim t-testom i 2 testom. Dobijeni rezultati ukazuju da adrenalin znaèajno smanjuje kinetiku proliferacije humanih limfocita praæenu CBPI indeksom (engl. cytochalasine block proliferation index) pri koncentraciji uporedljivoj sa maksimalnom terapijskom dozom, kao i pri svim višim koncentracijama adrenalina. Smanjena æelijska kinetika pod uticajem adrenalina u skladu je sa literaturnim podacima da poveæana kolièina cAMP moe da uspori deobu æelija. S druge strane, u svim primenjenim koncentracijama adrenalin nije doveo do statistièki znaèajnog porasta uèestalosti mikronukleusa u humanim limfocitima. Odsustvo aneugenih i klastogenih efekata moguæe je objasniti ili nedovoljnim metabolièkim kapacitetom limfocita za konverziju kateholamina, ili nedovoljnom senzitivnošæu samog mikronukleus testa. IN VITRO ANALYSIS OF MICRONUCLEI AND CELL CYCLE KINETICS IN HUMAN LYMPHOCYTES EXPOSED TO EPINEPRHINE We used eight experimental concentrations of epinephrine in a range from 5×10 -10 Mto 5×10 -5 M, starting with a concentration which corresponds to physiological level of this hormone in human plasma, through concentrations corresponding to minimal, average and maxmial therapeutic doses in human medicine, and finally 10-, 30- and 100-fold max. therapeutic doses. The experimental procedure was entirely according to OECD in vitro micronucleus assay guiedlines. Three healthy men under 35 donated blood for these experiments. Statistical analysis was performed by Student´s t-test and 2 test. Epinephrine significantly decreased progression through the cell cycle measured by CBPI (cytochalasine block proliferation index) at the concentration comparable to maximal therapeutic dose, as well as all higher concentrations. Cell cycle delay is consistent to literature data that increased level of cAMP can supress mitotic activity. On the other hand, there is no significant change in micronucleus frequencies at all concentrations analysed. The abscence of aneugenic and clastogenic effects may have resulted from poor metabolic capacity of human lymphocytes, or undersensitivity of micronucleus assay itself.
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Zbornik - Društvo genetičara Srbije

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