Kinetics of micronucleus induction and cytotoxicity caused by distinct antineoplastics and alkylating agents in vivo

Transmissible venereal tumour (TVT) generally presents different degrees of aggressiveness, which makes them unresponsive to conventional treatment protocols. This implies a progressive alteration of their biological profile. This study aimed to evaluate the cytotoxicity, cell survival, apoptosis and cell cycle alterations in TVT cell cultures subjected to treatment with vincristine. Similarly, it assessed possible implications of MDR-1, TP53, BCL-2, and BAX gene expressions in eight TVT primary cultures for both resistance to chemotherapy and biological behaviour. When comparing TVT cells receiving vincristine to those untreated, a statistical difference related to increased cytotoxicity and decreased survival rates, and alterations in G1 and S cell cycle phases were found but without detectable differences in apoptosis. Increased MDR-1 gene expression was observed after treatment. The groups did not differ statistically in relation to the TP53, BAX and BCL-2 genes. Although preliminary, the findings suggest that such augmented expression is related to tumour malignancy and chemotherapy resistance.

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“…Authors describe response rates ranging from 8 to 100% when vincristine is used for the treatment of tumours in vitro , corroborating this work …”

Section: Discussionsupporting

confidence: 72%

Cell cycle kinetics, apoptosis rates and gene expressions of MDR‐1, TP53, BCL‐2 and BAX in transmissible venereal tumour cells and their association with therapy response

Flórez

Fêo

Silva

et al. 2016

Vet Comparative Oncology

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“…Results of this study showed no significant increase in SCEs frequency in the VCR-, VBL- and VRL-treated groups. Previous studies indicated the possible genotoxicity of VCR and VBL [ 12 ]. For example, VCR was shown to induce DNA misrepair, telomere end fusions, nuclear buds, and increased frequency of gene mutations, all of which points to the possible genotoxicity of VCR [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Assessment of genotoxicity of vincristine, vinblastine and vinorelbine in human cultured lymphocytes: a comparative study

Mhaidat

Al-Zoubi

Khabour

et al. 2016

Balkan Journal of Medical Genetics

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Vincristine (VCR), vinblastine (VBL) and vinorelbine (VRL) are anticancer agents from the Vinca alkaloid family that have the potential to induce genotoxic effect. The aim of the present study was to compare the genotoxic effect of VCR, VBL and VRL. Levels of 8-hydroxy-2-deoxy guanosine (8-OHdG) and sister chromatid exchanges (SCEs) were measured in cultured human blood lymphocytes treated with VCR, VBL and VRL at concentrations of 0.01 and 0.1 μg/mL. Results showed that VCR, VBL and VRL significantly increased the 8-OHdG levels (p <0.05), whereas it did not cause a significant increase in the frequencies of SCEs in human blood lymphocytes as compared to controls. On the other hand, all three agents significantly increased cells mitotic index (p <0.05). At both tested concentrations, the magnitude of the increase in 8-OHdG was VBL>VCR>VRL. In conclusion, VCR, VBL and VRL induce DNA damage as indicated by the increase in the 8-OHdG biomarker but with different magnitude.

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“…The micronucleus assay allowed the determination of the long‐term consequences of DNA break production. The kinetic analysis of MN induction allowed us to establish whether different processes participated in MN induction based on the hypothesis that different mechanisms of DNA breaks occur at different times [Morales‐Ramírez et al ].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the possibility of crosslinks induced by radiation in BrdU‐substituted DNA, in the present study, radiation significantly increased the third peak of MN induction in BrdU‐substituted cells with respect to unsubstituted cells. To discern the timing of micronucleus induction, we proposed using the time of relative maximal induction (Trmi) [Morales‐Ramírez et al ], which represents the difference in the time of maximal induction by some agents with respect to the maximal induction by ionizing radiation because radiation acts directly without requiring pharmacokinetic processes, in contrast to chemical agents. In the present study, the third peak showed a Trmi of 18 h. In a previous study, higher doses of cisplatinum, busulfan, and bis‐chloroethyl nitrosourea showed a later peak of MN induction between 46 and 48 h [Morales‐Ramírez et al ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to considering that biological processes are very dynamic, it is important to establish strategies that allow us to observe responses over time to approach the complexity of the post‐treatment process. We proposed to use the kinetics of micronucleus induction in normoblasts in vivo as a strategy to establish the genotoxic profiles by measuring the increment of micronuclei in polychromatic erythrocytes or reticulocytes as a function of time after treatment [Morales‐Ramírez et al ]. This procedure can be accomplished by collecting small samples of blood from the tails of mice.…”

Section: Introductionmentioning

confidence: 99%

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In vivo Characterization of the Radiosensitizing Effect of a Very Low Dose of BrdU in Murine Cells Exposed to Low‐Dose Radiation

Cruz-Vallejo

Ortiz-Muñiz

Vallarino-Kelly

et al. 2019

Environ and Mol Mutagen

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The aim of the present study was to characterize the in vivo radiosensitizing effect of a very low dose of bromodeoxyuridine (BrdU) in mice exposed to low‐dose radiation by establishing the following: (1) the radiosensitizing effect during DNA synthesis using single‐cell gel electrophoresis (SCGE) in murine bone marrow cells, and (2) the number and timing of the mechanisms of genotoxicity and cytotoxicity, as well as the correlation of both end points, using flow cytometry analysis of the kinetics of micronucleus induction in reticulocytes. Groups of mice received intraperitoneal injections of 0.125 mg/g of BrdU 24 h prior to irradiation with 0.5 Gy of 60Co gamma rays. DNA breaks measured using SCGE were determined at 30 min after exposure to radiation. The kinetics of micronucleated reticulocyte (MN‐RET) induction was determined every 8 h after irradiation up to 72 h. The results from both experimental models indicated that low‐level BrdU incorporation into DNA increased the sensitivity to 0.5 Gy of radiation, particularly in the S phase. The formation of micronuclei by gamma rays was produced at three different times using two main mechanisms. In the BrdU‐substituted cells, the second mechanism was associated with a high cytotoxic effect that was absent in the irradiated BrdU‐unsubstituted cells. The third mechanism, in which micronucleus formation was increased in irradiated substituted cells compared with the irradiated nonsubstituted control cells, was also related to an increase in cytotoxicity. Environ. Mol. Mutagen. 60:534–545, 2019. © 2019 Wiley Periodicals, Inc.

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Kinetics of micronucleus induction and cytotoxicity caused by distinct antineoplastics and alkylating agents in vivo

Cited by 12 publications

References 45 publications

Cell cycle kinetics, apoptosis rates and gene expressions of MDR‐1, TP53, BCL‐2 and BAX in transmissible venereal tumour cells and their association with therapy response

Cell cycle kinetics, apoptosis rates and gene expressions of MDR‐1, TP53, BCL‐2 and BAX in transmissible venereal tumour cells and their association with therapy response

Assessment of genotoxicity of vincristine, vinblastine and vinorelbine in human cultured lymphocytes: a comparative study

In vivo Characterization of the Radiosensitizing Effect of a Very Low Dose of BrdU in Murine Cells Exposed to Low‐Dose Radiation

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