"Delayed death" phenomenon: a synergistic action of cyclophosphamide and exogenous DNA.
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.
Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, Novosibirsk 630090, Russia.
Evgenia V
EV
Dolgova
Anastasia S
AS
Proskurina
Valeriy P
VP
Nikolin
Nelly A
NA
Popova
Ekaterina A
EA
Alyamkina
Konstantin E
KE
Orishchenko
Vladimir A
VA
Rogachev
Yaroslav R
YR
Efremov
Tatiana D
TD
Dubatolova
Anastasia V
AV
Prokopenko
Elena R
ER
Chernykh
Alexandr A
AA
Ostanin
Oleg S
OS
Taranov
Vladimir V
VV
Omigov
Stanislav N
SN
Zagrebelniy
Sergey S
SS
Bogachev
Mikhail A
MA
Shurdov
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D004247:DNA / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020071:Interspersed Repetitive Sequences; D051917:Leukosialin / Q000276:immunology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D009017:Morbidity; D009026:Mortality
D051917:Leukosialin; D003520:Cyclophosphamide; D004247:DNA