"Delayed death" phenomenon: a synergistic action of cyclophosphamide and exogenous DNA |
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Authors: | Dolgova Evgenia V Proskurina Anastasia S Nikolin Valeriy P Popova Nelly A Alyamkina Ekaterina A Orishchenko Konstantin E Rogachev Vladimir A Efremov Yaroslav R Dubatolova Tatiana D Prokopenko Anastasia V Chernykh Elena R Ostanin Alexandr A Taranov Oleg S Omigov Vladimir V Zagrebelniy Stanislav N Bogachev Sergey S Shurdov Mikhail A |
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Institution: | Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, Novosibirsk 630090, Russia. |
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Abstract: | Morbidity and mortality in mice were observed upon administration of exogenous DNA following their pre-treatment with a cytostatic agent cyclophosphamide. Upon intraperitoneal injections, the fragments of exogenous DNA reached bone marrow cells. These cells were also found to internalize up to 1800 kb of exogenous DNA ex vivo. The 18-24 h time frame represents a final stage in the repair of DNA double-strand breaks, so when exogenous DNA was administered within this critical period of time, pathological changes were observed in many target organs. Namely, bone marrow cells underwent a sustained increase in apoptosis. Copy number of B1 and B2 DNA repeats in bone marrow cells remained unchanged, whereas in the control group of animals their levels were significantly decreased. Finally, the bone marrow cells of moribund animals completely lacked lymphoid progenitors, yet the CD34+ hematopoietic stem cell counts were normal. Histopathology analysis suggested that mice died due to accidental involution of lymphoid organs combined with a systemic inflammatory process induced by massive administration of exogenous DNA and depletion of lymphoid lineage. |
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Keywords: | CP cyclophosphamide ICL interstrand cross-link HSC hematopoietic stem cell DSB double-strand break BMC bone marrow cell |
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