ASSESSMENT OF GENOTOXICITY OF VINCRISTINE, VINBLASTINE AND VINORELBINE IN HUMAN CULTURED LYMPHOCYTES: A COMPARATIVE STUDY
Mhaidat NM, Alzoubi KH, Khabour OF, Alawneh KZ, Raffee LA, Alsatari ES, Hussein EI, Bani-Hani KE
*Corresponding Author: Nizar M. Mhaidat, Ph.D., Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Amman-Ramtha Hwy, Irbid 22110, Jordan. Tel: +962- 2-720-100. Fax: +962-2-720-1075. E-mail: nizarm@just.edu.jo
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DISCUSSION

The current study indicated that VCR, VBL and VRL, at concentrations of 0.01 and 0.1 μg/mL, induced oxidative DNA damage as shown using 8-OHdG biomarker. The magnitude of the increase in 8-OHdG was higher in cells treated with VBL as compared to VCR and VRL. The VCR, VBL and VRL have been reported to induce reactive oxygen and nitrogen species. For example, VRL has been shown to cause oxidative injury to cultured human endothelial cells [33]. In addition, treatment of human bronchial epithelial cell with VCR was associated with oxidative DNA damage as measured using normal alkaline and formamidopyrimidine- DNA-glycosylase (FPG) modified comet assays [10,33,34]. It was recently reported that chronic treatment with antioxidant agents prevented che-motherapies, including VBL, induced oxidative damage and restores normal mitochondrial function in hepatic cells [35]. In this study, a significant increase in the level of 8-OHdG, which is a standard biomarker for oxidative DNA damage [36,37], was shown when cultured human lymphocytes were treated with VCR, VBL and VRL. This variation could be due to the unique properties of these Vinca alkaloids (see Introduction). However, this point requires further investigation. Current results show that at both tested doses, VBL induced increases in the levels of 8-OHdG that were larger in magnitude than those induced by both VCR and VRL. The exact mechanism for such amplified effect of VBL on the levels of 8-OHdG is unknown. However, previous studies have shown a differential effect for VBL on bone marrow cell as compared to fetal liver cells [17]. Additionally, VBL was shown to alter calcium homeostasis via mitochondrial membranes leading to substantiated cyto-toxicity as compared to VCR [38]. 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]. Vincristine was also shown to increase the number of micronucleated cells, indicating its possible genotoxcicity [39,40]. All three agents, VCR, VBL and VRL, showed signs of genotoxicity in the Drosophila model [17]. On the other hand, VBL was recently shown to induce chromosomal aberrations and increase mitotic index in vitro in bone marrow cells, which was prevented by pretreatment with various doses of caffeine [41]. However, using the mouse lymphoma assay, VCR pretreatment for 3 hours did not show positive results for genotoxicity [42]. Additionally, increasing doses of VCR or VBL treatments were found to decrease the numbers of chromosomal aberrations along with an increase in number of micronucleated cells [11,43]. In another in vivo study in pregnant mice, a 2-week treatment with VCR did not induce an increase in SCEs in both maternal and fetal tissues, although it was capable of increasing the frequency of micronuclei [44]. Thus, it seems that Vinca alkaloids are able to induce certain types of DNA alterations such as oxidative and micronuclei but not others (i.e., SCEs). This could be due to their mechanism of action that is associated with activation of apoptosis through interference with spindle fiber formation and mitochondrial function. Moreover, the aberrant variations in the genotoxicity results for VCR in in vitro cultured cell techniques and mammalian models could be related to variation in models, doses and duration of drug treatment. The current results showed increased mitotic index in cells treated with VCR, VBL and VRL, indicating an antimitotic activity of these compounds. This is consistent with previous results showing that VCR increased apoptotic cell numbers and ratios and decreased the nuclear division in a dose-dependent manner, thus, showing the cytotoxicity of VCR [10,40]. In fact, Vinca alkaloids including VCR, VBL and VRL, are known to exert their cytoxicity via arresting mitosis and going into interphase [45,46], which is consistent with the current results. Based on the these results, we concluded that VCR, VBL and VRL induce oxidative DNA damage in whole blood lymphocytes. Declaration of Interest. This project was supported by a grant from the Deanship of Research at Jordan University of Science and Technology. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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