Bimolane induces multiple types of chromosomal aberrations in human lymphocytes in vitro

• Published in: Mutation research. Genetic toxicology and environmental mutagenesis 2011-12, Vol.726 (2), p.181-187
• Main Authors: Roy, Shambhu K., Eastmond, David A.
• Format: Article
• Language: English
• Subjects: Aneuploidy; Antibodies; Bimolane; Binucleated cells; Biological and medical sciences; Chemical compounds; Chromosome aberrations; Chromosomes; Dicentric chromosome; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Leukemia; Lymphocytes; Medical genetics; Medical sciences; Micronucleus; Polyploidy; Therapy-related leukemia; Toxicity; Toxicology
• ISSN: 1383-5718; 1879-3592
• DOI: 10.1016/j.mrgentox.2011.09.006

► Bimolane, a leukemia-inducing agent, was genotoxic to human lymphocytes in vitro. ► Both the synthesized and commercially available drug induced the following. ► Chromosomal breakage resulting in micronuclei and dicentric chromosomes. ► Aneuploidy as manifested by chromosome loss and non-disjunction. ► Polyploidy due to mitotic slippage, endoreduplication and binucleation. Bimolane has been commonly used in China for the treatment of psoriasis and various types of cancer. Patients treated with bimolane have been reported to have an increased risk of developing therapy-related leukemias. Although bimolane has been identified as a human leukemia-inducing agent, little is known about its genotoxic effects, and a systematic study of the types of chromosomal alterations induced by this compound has not been performed. In this study, a combination of immunochemical, molecular and conventional cytogenetic techniques has been used to study the chromosomal alterations induced by bimolane in cultured human lymphocytes. Immunochemical staining with the CREST antibody indicated that bimolane induces micronuclei (MN) originating primarily from chromosome breakage. Interestingly fluorescence in situ hybridization (FISH) with differentially labeled chromosomes 1 and 9 centromeric probes indicated that bimolane also caused non-disjunction and polyploidy. Consistent with this, an expedited analysis of Giemsa-stained metaphase chromosomes in bimolane-treated lymphocytes revealed a high frequency of polyploidy/hyperdiploidy as well as dicentric chromosomes, and premature centromeric division (PCD). In addition, bimolane was also found to produce binucleated cells, possibly through an interference with normal functioning of intermediate filaments. As a follow-up to these studies, three different types of commercially available bimolane formulations obtained from different Chinese manufacturers were also evaluated. The effects seen with the formulated bimolane were similar to those seen with the synthesized compound. Our studies indicate that bimolane effectively induces a variety of cellular and chromosomal changes in cultured lymphocytes and that similar alterations occurring in bone marrow stem cells could contribute to the development of the secondary cancers seen in bimolane-treated patients.