Balkan Journal of Medical Genetics

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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INTRODUCTION

Vinca alkaloids are a subset of drugs derived from the Madagascar periwinkle plant (Catharanthus roseus) [1]. They include the natural products vincristine (VCR) and vinblastine (VBL) and the semi-synthetic derivative vin-orelbine (VRL). Vinca alkaloids have been used for cancer management [2]. Chemically, vinca alkaloids have dimeric chemical structures composed of two basic multi-ringed units, an indole nucleus (catharanthine) and a dihydroindole nucleus (vindoline), joined together with other complex systems [2,3]. Different Vinca alkaloids have their own unique properties. The VBL inhibits angiogenesis [4]. It is also associated with anti-diuretic hormone secretion and angina, and applied to treat Hodgkin’s disease, non-Hodgkin’s lymphoma and breast cancer [5]. The VRL showed a significant anti-tumor activity in patients with breast cancer and induces anti-proliferative activity in osteosarcoma [6]. Moreover, VCR has been shown to have a mild myelo-suppressive action [7,8]. It is also widely used to treat pediatric leukemias, solid tumors, and hematological malignancies [2]. During cell division, Vinca alkaloids bind to the building blocks of a protein called tubulin, inhibiting its formation, which normally works in cells to create mitotic spindle [9]. Previous studies have shown that Vinca alkaloids have the potential to induce genotoxic effects in different biological systems. The VCR and VBL have been shown to increase the frequency of micronuclei in experimental animals and in cultured human lymphocytes [10-13]. In addition, they have also been shown to cause chromosomal mutations in vivo and in cultured cancer cells [14,15]. In cultured human lymphocytes, VRB and VCR increased the rate of micronucleus formation [16]. In Drosophila, VCR and VBL induced a significant genotoxic effect as measured using wing somatic mutation and the recombination test [17]. However, some other studies have shown lack of mutagenic effect for Vinca alkaloids in vivo and in cultured cells [18-20]. Thus, the genotoxicity of Vinca alkaloids is still controversial. In addition, oxidative DNA damage induced by these compounds has still not been investigated. The aim of the present study was to compare the genotoxic effect of VCR, VBL and VRL on human cultured lymphocytes using 8-hydroxy-2-deoxy guanosine (8-OHdG) and sister chromatid exchanges (SCEs) assays. The 8-OHdG is a marker that reflects oxidative DNA damage, while the SCEs assay reflects genotoxicity induced as a result of breaks in DNA during DNA recombination.

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