Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2591664 | Neurotoxicology and Teratology | 2009 | 6 Pages |
Abstract
6-Mercaptopurine (6-MP), an analogue of hypoxanthine, is used in the therapy of acute lymphoblastic leukemia and causes fetal neurotoxicity. To clarify the mechanisms of 6-MP-induced fetal neurotoxicity leading to the cell cycle arrest and apoptosis of neural progenitor cells, pregnant rats were treated with 50Â mg/kg 6-MP on embryonic day (E) 13, and the fetal telencephalons were examined at 12 to 72Â h (h) after treatment. Flow-cytometric analysis confirmed an accumulation of cells at G2/M, S, and sub-G1 (apoptotic cells) phases from 24 to 72Â h. The number of phosphorylated histone H3-positive cells (mitotic cells) decreased from 36 to 72Â h, and the phosphorylated (active) form of p53 protein, which is a mediator of apoptosis and cell cycle arrest, increased from 24 to 48Â h. An executor of p53-mediated cell cycle arrest, p21, showed intense overexpression at both the mRNA and protein levels from 24 to 72Â h. Cdc25A protein, which is needed for the progression of S phase, decreased at 36 and 48Â h. In addition, phosphorylated cdc2 protein, which is an inactive form of cdc2 necessary for G2/M progression, increased from 24 to 48Â h. These results suggest that 6-MP induced G2/M arrest, delayed S-phase progression, and finally induced apoptosis of neural progenitor cells mediated by p53 in the fetal rat telencephalon.
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Authors
H. Kanemitsu, H. Yamauchi, M. Komatsu, S. Yamamoto, S. Okazaki, K. Uchida, H. Nakayama,