“Delayed death” phenomenon: A synergistic action of cyclophosphamide and exogenous DNA

• Published in: Gene Vol. 495; no. 2; pp. 134 - 145
• Main 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.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10-03-2012
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Bone marrow cells; Bone Marrow Cells - drug effects; cyclophosphamide; Cyclophosphamide - pharmacology; death; DNA; DNA - pharmacology; DNA Breaks, Double-Stranded; DNA damage; DNA repair; DNA Repair - drug effects; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - immunology; histopathology; Humans; Interspersed Repetitive Sequences; Involution of lymphoid organs; Leukosialin - immunology; Lymphoid Tissue - drug effects; Lymphoid Tissue - pathology; Mice; Mice, Inbred CBA; Morbidity; Mortality; Mouse short interspersed elements; pretreatment; stem cells; Systemic inflammation; DSB; ICL; HSC; BMC; Mouse short interspersed elements; Involution of lymphoid organs; Bone marrow cells; CP; Systemic inflammation; Apoptosis
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2011.12.032

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 1800kb of exogenous DNA ex vivo. The 18–24h 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.
► Administration of exogenous DNA 18–30h after CP results in mortality of mice. ► This DNA reaches bone marrow cells and interferes with correct DNA repair process. ► CD34+ cells abrogate the possibility to differentiate into lymphoid progenitors. ► Nonrecoverable involution of peripheral lymphoid organs occurs. ► Mice die due to systemic inflammatory response.