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Deregulated sequential motion of centromeres induced by antitumor agents may lead to genome instability in human peripheral blood lymphocytes

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Authors
Bajić, Vladan
Potparević, Biljana
Milicević, Z.
Živković, Lada
Article (Published version)
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Abstract
Purpose: Segregation of chromosomes in anaphase is preceded by a sequential order of centromere separation. Alteration of the sequence of centromere separation or premature centromere division (PCD) has been found to be significantly higher in populations exposed to various xenobiotics. The purpose of this study was to investigate if PCD induced by various cytostatics can alter the stability of chromosomes and lead to aneuploidy. Materials and methods: Peripheral blood lymphocytes of 10 healthy, non smoking subjects were exposed to 8-Cl-cAMP at a dose of 1, 5 and 15 mu M, paclitaxel at a dose of 0.01, 0.05 and 0.2 mu M, and cycloheximide (CX) at a dose of 5, 10 and 25 mu g/ml. By using the cytohalasin B (CB)-micronucleus (MN) test in vitro, in combination with fluorescent in situ hybridization (FISH), the presence of MN was analyzed in 1000 binuclear cells for each experimental and negative control group. For analysis of MN content we used the a-centromeric probe for chromosome 18. Res...ults: 8-Cl-cAMP and paclitaxel induced an increase in the frequency of MN in peripheral blood lymphocytes. 8-Cl-cAMP and paclitaxel proved clastogenic, i.e. they increased the frequency of MN and induced PCD in all respective doses. CX proved no clastogenic in the respected doses when using the CB-AM test in vitro, although CX is a specific PCD inducer No correlation of PCD and aneuploidy of chromosome 18 was found in cells exposed to 8-Cl-cAmp and paclitaxel by using FISH. In cells exposed to CX we found PCD of chromosome 18 in binuclear cells and single signals in scarce AN. These findings were not statistically significant compared to the negative control group. Conclusion: Our results show that the properties of the investigated antitumor agents to induce PCD in peripheral blood lymphocytes and, therefore, aneuploidy and genome instability, is highly based on the nature of the alteration of centromere function, i.e. the temporal order of centromere kinetics are more regulated through the sequence of centromere separation than by the segregation processes. We suggest that PCD induced by novel antitumor agents could be included in preclinical and clinical genetic risk assessment analysis.

Keywords:
aneuploidy / 8-Cl-cAMP / fluorescent in situ hybridization / paclitaxel / premature centromere division
Source:
Journal of BUON, 2007, 12, 1, 77-83
Publisher:
  • Balkan Union of Oncology (B.U.ON.)

ISSN: 1107-0625

PubMed: 17436406

WoS: 000256496200013

Scopus: 2-s2.0-34249676748
[ Google Scholar ]
8
6
Handle
https://hdl.handle.net/21.15107/rcub_vinar_3462
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/906
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Bajić, Vladan
AU  - Potparević, Biljana
AU  - Milicević, Z.
AU  - Živković, Lada
PY  - 2007
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/906
AB  - Purpose: Segregation of chromosomes in anaphase is preceded by a sequential order of centromere separation. Alteration of the sequence of centromere separation or premature centromere division (PCD) has been found to be significantly higher in populations exposed to various xenobiotics. The purpose of this study was to investigate if PCD induced by various cytostatics can alter the stability of chromosomes and lead to aneuploidy. Materials and methods: Peripheral blood lymphocytes of 10 healthy, non smoking subjects were exposed to 8-Cl-cAMP at a dose of 1, 5 and 15 mu M, paclitaxel at a dose of 0.01, 0.05 and 0.2 mu M, and cycloheximide (CX) at a dose of 5, 10 and 25 mu g/ml. By using the cytohalasin B (CB)-micronucleus (MN) test in vitro, in combination with fluorescent in situ hybridization (FISH), the presence of MN was analyzed in 1000 binuclear cells for each experimental and negative control group. For analysis of MN content we used the a-centromeric probe for chromosome 18. Results: 8-Cl-cAMP and paclitaxel induced an increase in the frequency of MN in peripheral blood lymphocytes. 8-Cl-cAMP and paclitaxel proved clastogenic, i.e. they increased the frequency of MN and induced PCD in all respective doses. CX proved no clastogenic in the respected doses when using the CB-AM test in vitro, although CX is a specific PCD inducer No correlation of PCD and aneuploidy of chromosome 18 was found in cells exposed to 8-Cl-cAmp and paclitaxel by using FISH. In cells exposed to CX we found PCD of chromosome 18 in binuclear cells and single signals in scarce AN. These findings were not statistically significant compared to the negative control group. Conclusion: Our results show that the properties of the investigated antitumor agents to induce PCD in peripheral blood lymphocytes and, therefore, aneuploidy and genome instability, is highly based on the nature of the alteration of centromere function, i.e. the temporal order of centromere kinetics are more regulated through the sequence of centromere separation than by the segregation processes. We suggest that PCD induced by novel antitumor agents could be included in preclinical and clinical genetic risk assessment analysis.
PB  - Balkan Union of Oncology (B.U.ON.)
T2  - Journal of BUON
T1  - Deregulated sequential motion of centromeres induced by antitumor agents may lead to genome instability in human peripheral blood lymphocytes
VL  - 12
IS  - 1
SP  - 77
EP  - 83
UR  - https://hdl.handle.net/21.15107/rcub_vinar_3462
ER  - 
@article{
author = "Bajić, Vladan and Potparević, Biljana and Milicević, Z. and Živković, Lada",
year = "2007",
abstract = "Purpose: Segregation of chromosomes in anaphase is preceded by a sequential order of centromere separation. Alteration of the sequence of centromere separation or premature centromere division (PCD) has been found to be significantly higher in populations exposed to various xenobiotics. The purpose of this study was to investigate if PCD induced by various cytostatics can alter the stability of chromosomes and lead to aneuploidy. Materials and methods: Peripheral blood lymphocytes of 10 healthy, non smoking subjects were exposed to 8-Cl-cAMP at a dose of 1, 5 and 15 mu M, paclitaxel at a dose of 0.01, 0.05 and 0.2 mu M, and cycloheximide (CX) at a dose of 5, 10 and 25 mu g/ml. By using the cytohalasin B (CB)-micronucleus (MN) test in vitro, in combination with fluorescent in situ hybridization (FISH), the presence of MN was analyzed in 1000 binuclear cells for each experimental and negative control group. For analysis of MN content we used the a-centromeric probe for chromosome 18. Results: 8-Cl-cAMP and paclitaxel induced an increase in the frequency of MN in peripheral blood lymphocytes. 8-Cl-cAMP and paclitaxel proved clastogenic, i.e. they increased the frequency of MN and induced PCD in all respective doses. CX proved no clastogenic in the respected doses when using the CB-AM test in vitro, although CX is a specific PCD inducer No correlation of PCD and aneuploidy of chromosome 18 was found in cells exposed to 8-Cl-cAmp and paclitaxel by using FISH. In cells exposed to CX we found PCD of chromosome 18 in binuclear cells and single signals in scarce AN. These findings were not statistically significant compared to the negative control group. Conclusion: Our results show that the properties of the investigated antitumor agents to induce PCD in peripheral blood lymphocytes and, therefore, aneuploidy and genome instability, is highly based on the nature of the alteration of centromere function, i.e. the temporal order of centromere kinetics are more regulated through the sequence of centromere separation than by the segregation processes. We suggest that PCD induced by novel antitumor agents could be included in preclinical and clinical genetic risk assessment analysis.",
publisher = "Balkan Union of Oncology (B.U.ON.)",
journal = "Journal of BUON",
title = "Deregulated sequential motion of centromeres induced by antitumor agents may lead to genome instability in human peripheral blood lymphocytes",
volume = "12",
number = "1",
pages = "77-83",
url = "https://hdl.handle.net/21.15107/rcub_vinar_3462"
}
Bajić, V., Potparević, B., Milicević, Z.,& Živković, L.. (2007). Deregulated sequential motion of centromeres induced by antitumor agents may lead to genome instability in human peripheral blood lymphocytes. in Journal of BUON
Balkan Union of Oncology (B.U.ON.)., 12(1), 77-83.
https://hdl.handle.net/21.15107/rcub_vinar_3462
Bajić V, Potparević B, Milicević Z, Živković L. Deregulated sequential motion of centromeres induced by antitumor agents may lead to genome instability in human peripheral blood lymphocytes. in Journal of BUON. 2007;12(1):77-83.
https://hdl.handle.net/21.15107/rcub_vinar_3462 .
Bajić, Vladan, Potparević, Biljana, Milicević, Z., Živković, Lada, "Deregulated sequential motion of centromeres induced by antitumor agents may lead to genome instability in human peripheral blood lymphocytes" in Journal of BUON, 12, no. 1 (2007):77-83,
https://hdl.handle.net/21.15107/rcub_vinar_3462 .

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