Examination of 8-CI-cAMP genotoxicity by two in vivo test in BALB/c strain mice
Ispitivanje genotoksičnosti 8-CI-cAMP u dva in vivo testa na miševima soja BALB/c
Apstrakt
The antitumor agent 8-CI-cAMP (8-chloro-cyclic adenosine monophosphate) is the most potent site-selective analogue of cAMP. It acts primarily by selective down-regulation of regulatory sub-units of cAMP-dependent protein kinases. This results in reversion of the neoplastic predominance of PK-I type over PK-II type protein kinase back to the ratio more typical to of the normal phenotype. The differential activity of 8-CI-cAMP towards protein kinase isozymes leads to inhibition of cell growth, differentiation and neoplastic reversion of a wide variety of cancer cell lines. Since 8-CI-cAMP has been investigated as a new potential anticancer drug with no previous studies of its mutagenic and clastogenic effects, we have investigated the genotoxicity of 8-CI-cAMP. Genotoxic effects were estimated by the bone marrow micronucleus assay and the occurrence of morphological chromosome lesions in adult mice (BALB/c strain). 8-CI-cAMP was administered intraperitoneally (i.p) in three doses, 10 mg/...kg b.w.; 90 mg/kg b.w. and 160 mg/kg b.w., with saline solution as a negative control and cyclophosphamide, a known mutagen and clastogen as a positive control at twenty four hour intervals during a seven day period. Micronucleus test results showed a consistent dose-dependent pattern. Thus, with increase of the dose (10 mg/kg b.w., 90 mg/kg b. w. and 160 mg/kg b.w.) there was an increase in the frequency of micronuclei in polychromatic erythrocytes (4.88 ± 0.35; 8.32 ± 0.57; 11.75 ± 0.37) compared to the negative control (2.04 ±0.28). Using chromosome aberrations as an indicator of genotoxic potential, 8-CI-cAMP in all three doses (10 mg/kg b.w.; 90 mg/kg b.w. and 160 mg/kg b.w.) produced karyotype transformation of mouse bone marrow cells. 8-CI-cAMP induced structural chromosome aberrations as lesions (2.87 0.14; 4,37 0.14 i 5.25 0.35), interruptions (9±0.1; 12.37±0.26 i 13.37±0,33), ring chromosomes (3.62 0.21; 2.5±0,07 i 2.5±0.07), accentrics (10±0.49; 16.5±0.45 i 18.37±0.54) and Robertsonian translocations (7.12±0.26 ;9 0.1 i 11.24 ±0.18) as well as numerical chromosome aberrations of the aneuploidal type (36 5± 0.74; 60.25±0.24 i 85.62±0.5) and polyploidy (7±0.24; 5.5+0.27 / 5.87±0.14). These results demonstrate the genotoxic potential of the investigated substance.
Antitumorski preparat 8-CI-cAMP (8-hloro-ciklični adenozin monofosfat) je najpotentniji analog AMP koji deluje primamo na modulaciju cAMP - zavisne protein kinaze dovodeći do inhibicije regulatornih subjedinica. Rezultat takvog dejstva je smanjenje dominantnog tipa PK-I protein kinaze u kanceroznim ćelijama nad drugim tipom PK-II protein kinaze, u odnosu na međusobni nivo PK-I I PK-II koji se nalaze u normalnim ćelijama. Ciklični 8-CI-AMP je analog koji ima izuzetnu anti-neoplastičnu aktivnost sa efektom restauracije, diferencijacije i reverzne transformacije kanceroznih ćelija miša i čoveka. Sa stanovišta mogućeg mutagenog i genotoksičnog efekta 8-CI-cAMP nije dovoljno istražen. Zato je i cilj ovog rada bio da se primenom citogenetičkog i mikronukleus testa, na ćelijama kostne srži miša BALB/c soja, ispita genotoksični efekat 8-CI-cAMP u tri dozna režima (10 mg/kg t.m; 90 mg/kg t.m. i 160 mg/kg t.m.). Pored eksperimentalnih grupa životinja u eksperimentu su uspostavljene i negativna k...ontrola koju su činile jedinke tretirane sa fiziološkim rastvorom, kao i pozitivna kontrola životinja koje su tretirane sa poznatim klastogenom i mutagenom-ciklofosfamidom u dozi od 40 mg/kg t.m. Rezultati ispitivanja pokazuju konzistetni dozno-zavisni obrazac primenom mikronukleus testa. Sa rastom doze (10 mg/kg t.m ; 90 mg/kg t.m. i 160 mg/kg t.m.) raste i broj mikronukleusa u polihromatofilnim eritrocitima (4,88 ±0,35; 8,32±0,57; 11,75±0,37) u odnosu na kontrolnu grupu (2,04±0,28). Testirane rastuće doze 8-CI-cAMP u citogenetičkom testu in vivo pokazuju sposobnost transformacije kariotipa ćelija kostne srži BALB/c miševa u vidu struktumih hromozomskih aberacija tipa lezija (2,87±0,14; 4,37±0,14; 5,25±0,35), prekida (90,1; 12,37±0,26; 13,37±0,33), ring hromozoma (3,62+0,21; 2,5±0,07; 2,5±0,07), acentrika (100,49; 16,5±0,45; 18,37±0,54) i Robersonovih translokacija (7,12±0,26; 90,1; 11,24±0,18) i numeričkih hromozomskih aberacija tipa aneuploidija (36,5±0,74; 60,25±0,24; 85,62±0,5) i poliploidija (70,24; 5,5±0,21; 5,87±0,14) što ukazuje na postojanje genotoksičnog potencijala ispitivane supstance.
Ključne reči:
antitumor agent 8-CI-cAMP / genotoxicity / apoptosis / micronucleus test / cytogenetic in vivo test / numerical and structural aberrationsIzvor:
Acta Veterinaria-Beograd, 2000, 50, 2-3, 177-190Izdavač:
- Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd
Kolekcije
Institucija/grupa
Fakultet veterinarske medicineTY - JOUR AU - Bajić, Vladan AU - Stanimirović, Zoran AU - Marković, Biljana PY - 2000 UR - https://vet-erinar.vet.bg.ac.rs/handle/123456789/147 AB - The antitumor agent 8-CI-cAMP (8-chloro-cyclic adenosine monophosphate) is the most potent site-selective analogue of cAMP. It acts primarily by selective down-regulation of regulatory sub-units of cAMP-dependent protein kinases. This results in reversion of the neoplastic predominance of PK-I type over PK-II type protein kinase back to the ratio more typical to of the normal phenotype. The differential activity of 8-CI-cAMP towards protein kinase isozymes leads to inhibition of cell growth, differentiation and neoplastic reversion of a wide variety of cancer cell lines. Since 8-CI-cAMP has been investigated as a new potential anticancer drug with no previous studies of its mutagenic and clastogenic effects, we have investigated the genotoxicity of 8-CI-cAMP. Genotoxic effects were estimated by the bone marrow micronucleus assay and the occurrence of morphological chromosome lesions in adult mice (BALB/c strain). 8-CI-cAMP was administered intraperitoneally (i.p) in three doses, 10 mg/kg b.w.; 90 mg/kg b.w. and 160 mg/kg b.w., with saline solution as a negative control and cyclophosphamide, a known mutagen and clastogen as a positive control at twenty four hour intervals during a seven day period. Micronucleus test results showed a consistent dose-dependent pattern. Thus, with increase of the dose (10 mg/kg b.w., 90 mg/kg b. w. and 160 mg/kg b.w.) there was an increase in the frequency of micronuclei in polychromatic erythrocytes (4.88 ± 0.35; 8.32 ± 0.57; 11.75 ± 0.37) compared to the negative control (2.04 ±0.28). Using chromosome aberrations as an indicator of genotoxic potential, 8-CI-cAMP in all three doses (10 mg/kg b.w.; 90 mg/kg b.w. and 160 mg/kg b.w.) produced karyotype transformation of mouse bone marrow cells. 8-CI-cAMP induced structural chromosome aberrations as lesions (2.87 0.14; 4,37 0.14 i 5.25 0.35), interruptions (9±0.1; 12.37±0.26 i 13.37±0,33), ring chromosomes (3.62 0.21; 2.5±0,07 i 2.5±0.07), accentrics (10±0.49; 16.5±0.45 i 18.37±0.54) and Robertsonian translocations (7.12±0.26 ;9 0.1 i 11.24 ±0.18) as well as numerical chromosome aberrations of the aneuploidal type (36 5± 0.74; 60.25±0.24 i 85.62±0.5) and polyploidy (7±0.24; 5.5+0.27 / 5.87±0.14). These results demonstrate the genotoxic potential of the investigated substance. AB - Antitumorski preparat 8-CI-cAMP (8-hloro-ciklični adenozin monofosfat) je najpotentniji analog AMP koji deluje primamo na modulaciju cAMP - zavisne protein kinaze dovodeći do inhibicije regulatornih subjedinica. Rezultat takvog dejstva je smanjenje dominantnog tipa PK-I protein kinaze u kanceroznim ćelijama nad drugim tipom PK-II protein kinaze, u odnosu na međusobni nivo PK-I I PK-II koji se nalaze u normalnim ćelijama. Ciklični 8-CI-AMP je analog koji ima izuzetnu anti-neoplastičnu aktivnost sa efektom restauracije, diferencijacije i reverzne transformacije kanceroznih ćelija miša i čoveka. Sa stanovišta mogućeg mutagenog i genotoksičnog efekta 8-CI-cAMP nije dovoljno istražen. Zato je i cilj ovog rada bio da se primenom citogenetičkog i mikronukleus testa, na ćelijama kostne srži miša BALB/c soja, ispita genotoksični efekat 8-CI-cAMP u tri dozna režima (10 mg/kg t.m; 90 mg/kg t.m. i 160 mg/kg t.m.). Pored eksperimentalnih grupa životinja u eksperimentu su uspostavljene i negativna kontrola koju su činile jedinke tretirane sa fiziološkim rastvorom, kao i pozitivna kontrola životinja koje su tretirane sa poznatim klastogenom i mutagenom-ciklofosfamidom u dozi od 40 mg/kg t.m. Rezultati ispitivanja pokazuju konzistetni dozno-zavisni obrazac primenom mikronukleus testa. Sa rastom doze (10 mg/kg t.m ; 90 mg/kg t.m. i 160 mg/kg t.m.) raste i broj mikronukleusa u polihromatofilnim eritrocitima (4,88 ±0,35; 8,32±0,57; 11,75±0,37) u odnosu na kontrolnu grupu (2,04±0,28). Testirane rastuće doze 8-CI-cAMP u citogenetičkom testu in vivo pokazuju sposobnost transformacije kariotipa ćelija kostne srži BALB/c miševa u vidu struktumih hromozomskih aberacija tipa lezija (2,87±0,14; 4,37±0,14; 5,25±0,35), prekida (90,1; 12,37±0,26; 13,37±0,33), ring hromozoma (3,62+0,21; 2,5±0,07; 2,5±0,07), acentrika (100,49; 16,5±0,45; 18,37±0,54) i Robersonovih translokacija (7,12±0,26; 90,1; 11,24±0,18) i numeričkih hromozomskih aberacija tipa aneuploidija (36,5±0,74; 60,25±0,24; 85,62±0,5) i poliploidija (70,24; 5,5±0,21; 5,87±0,14) što ukazuje na postojanje genotoksičnog potencijala ispitivane supstance. PB - Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd T2 - Acta Veterinaria-Beograd T1 - Examination of 8-CI-cAMP genotoxicity by two in vivo test in BALB/c strain mice T1 - Ispitivanje genotoksičnosti 8-CI-cAMP u dva in vivo testa na miševima soja BALB/c VL - 50 IS - 2-3 SP - 177 EP - 190 UR - https://hdl.handle.net/21.15107/rcub_veterinar_147 ER -
@article{ author = "Bajić, Vladan and Stanimirović, Zoran and Marković, Biljana", year = "2000", abstract = "The antitumor agent 8-CI-cAMP (8-chloro-cyclic adenosine monophosphate) is the most potent site-selective analogue of cAMP. It acts primarily by selective down-regulation of regulatory sub-units of cAMP-dependent protein kinases. This results in reversion of the neoplastic predominance of PK-I type over PK-II type protein kinase back to the ratio more typical to of the normal phenotype. The differential activity of 8-CI-cAMP towards protein kinase isozymes leads to inhibition of cell growth, differentiation and neoplastic reversion of a wide variety of cancer cell lines. Since 8-CI-cAMP has been investigated as a new potential anticancer drug with no previous studies of its mutagenic and clastogenic effects, we have investigated the genotoxicity of 8-CI-cAMP. Genotoxic effects were estimated by the bone marrow micronucleus assay and the occurrence of morphological chromosome lesions in adult mice (BALB/c strain). 8-CI-cAMP was administered intraperitoneally (i.p) in three doses, 10 mg/kg b.w.; 90 mg/kg b.w. and 160 mg/kg b.w., with saline solution as a negative control and cyclophosphamide, a known mutagen and clastogen as a positive control at twenty four hour intervals during a seven day period. Micronucleus test results showed a consistent dose-dependent pattern. Thus, with increase of the dose (10 mg/kg b.w., 90 mg/kg b. w. and 160 mg/kg b.w.) there was an increase in the frequency of micronuclei in polychromatic erythrocytes (4.88 ± 0.35; 8.32 ± 0.57; 11.75 ± 0.37) compared to the negative control (2.04 ±0.28). Using chromosome aberrations as an indicator of genotoxic potential, 8-CI-cAMP in all three doses (10 mg/kg b.w.; 90 mg/kg b.w. and 160 mg/kg b.w.) produced karyotype transformation of mouse bone marrow cells. 8-CI-cAMP induced structural chromosome aberrations as lesions (2.87 0.14; 4,37 0.14 i 5.25 0.35), interruptions (9±0.1; 12.37±0.26 i 13.37±0,33), ring chromosomes (3.62 0.21; 2.5±0,07 i 2.5±0.07), accentrics (10±0.49; 16.5±0.45 i 18.37±0.54) and Robertsonian translocations (7.12±0.26 ;9 0.1 i 11.24 ±0.18) as well as numerical chromosome aberrations of the aneuploidal type (36 5± 0.74; 60.25±0.24 i 85.62±0.5) and polyploidy (7±0.24; 5.5+0.27 / 5.87±0.14). These results demonstrate the genotoxic potential of the investigated substance., Antitumorski preparat 8-CI-cAMP (8-hloro-ciklični adenozin monofosfat) je najpotentniji analog AMP koji deluje primamo na modulaciju cAMP - zavisne protein kinaze dovodeći do inhibicije regulatornih subjedinica. Rezultat takvog dejstva je smanjenje dominantnog tipa PK-I protein kinaze u kanceroznim ćelijama nad drugim tipom PK-II protein kinaze, u odnosu na međusobni nivo PK-I I PK-II koji se nalaze u normalnim ćelijama. Ciklični 8-CI-AMP je analog koji ima izuzetnu anti-neoplastičnu aktivnost sa efektom restauracije, diferencijacije i reverzne transformacije kanceroznih ćelija miša i čoveka. Sa stanovišta mogućeg mutagenog i genotoksičnog efekta 8-CI-cAMP nije dovoljno istražen. Zato je i cilj ovog rada bio da se primenom citogenetičkog i mikronukleus testa, na ćelijama kostne srži miša BALB/c soja, ispita genotoksični efekat 8-CI-cAMP u tri dozna režima (10 mg/kg t.m; 90 mg/kg t.m. i 160 mg/kg t.m.). Pored eksperimentalnih grupa životinja u eksperimentu su uspostavljene i negativna kontrola koju su činile jedinke tretirane sa fiziološkim rastvorom, kao i pozitivna kontrola životinja koje su tretirane sa poznatim klastogenom i mutagenom-ciklofosfamidom u dozi od 40 mg/kg t.m. Rezultati ispitivanja pokazuju konzistetni dozno-zavisni obrazac primenom mikronukleus testa. Sa rastom doze (10 mg/kg t.m ; 90 mg/kg t.m. i 160 mg/kg t.m.) raste i broj mikronukleusa u polihromatofilnim eritrocitima (4,88 ±0,35; 8,32±0,57; 11,75±0,37) u odnosu na kontrolnu grupu (2,04±0,28). Testirane rastuće doze 8-CI-cAMP u citogenetičkom testu in vivo pokazuju sposobnost transformacije kariotipa ćelija kostne srži BALB/c miševa u vidu struktumih hromozomskih aberacija tipa lezija (2,87±0,14; 4,37±0,14; 5,25±0,35), prekida (90,1; 12,37±0,26; 13,37±0,33), ring hromozoma (3,62+0,21; 2,5±0,07; 2,5±0,07), acentrika (100,49; 16,5±0,45; 18,37±0,54) i Robersonovih translokacija (7,12±0,26; 90,1; 11,24±0,18) i numeričkih hromozomskih aberacija tipa aneuploidija (36,5±0,74; 60,25±0,24; 85,62±0,5) i poliploidija (70,24; 5,5±0,21; 5,87±0,14) što ukazuje na postojanje genotoksičnog potencijala ispitivane supstance.", publisher = "Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd", journal = "Acta Veterinaria-Beograd", title = "Examination of 8-CI-cAMP genotoxicity by two in vivo test in BALB/c strain mice, Ispitivanje genotoksičnosti 8-CI-cAMP u dva in vivo testa na miševima soja BALB/c", volume = "50", number = "2-3", pages = "177-190", url = "https://hdl.handle.net/21.15107/rcub_veterinar_147" }
Bajić, V., Stanimirović, Z.,& Marković, B.. (2000). Examination of 8-CI-cAMP genotoxicity by two in vivo test in BALB/c strain mice. in Acta Veterinaria-Beograd Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd., 50(2-3), 177-190. https://hdl.handle.net/21.15107/rcub_veterinar_147
Bajić V, Stanimirović Z, Marković B. Examination of 8-CI-cAMP genotoxicity by two in vivo test in BALB/c strain mice. in Acta Veterinaria-Beograd. 2000;50(2-3):177-190. https://hdl.handle.net/21.15107/rcub_veterinar_147 .
Bajić, Vladan, Stanimirović, Zoran, Marković, Biljana, "Examination of 8-CI-cAMP genotoxicity by two in vivo test in BALB/c strain mice" in Acta Veterinaria-Beograd, 50, no. 2-3 (2000):177-190, https://hdl.handle.net/21.15107/rcub_veterinar_147 .