RhG-CSF Improves Radiation-induced Myelosuppression and Survival in the Canine Exposed to Fission Neutron Irradiation
Zu-Yin YU
Ming LI
A-Ru-Na HAN
Shuang XING
Hong-Ling OU
Guo-Lin XIONG
Ling XIE
Yan-Fang ZHAO
He XIAO
Ya-Jun SHAN
Zhen-Hu ZHAO
Xiao-Lan LIU
Yu-Wen CONG
Qing-Liang LUO
Neutron irradiation/rhG-CSF/Myelosuppression. Fission-neutron radiation damage is hard to treat due to its critical injuries to hematopoietic and gastrointestinal systems, and so far few data are available on the therapeutic measures for neutron-radiation syndrome. This study was designed to test the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in dogs which had received 2.3 Gy mixed fission-neutron- irradiation with a high ratio of neutrons (~90%). Following irradiation, rhG-CSF treatment induced 100% survival versus 60% in controls. Only two of five rhG-CSF-treated dogs experienced leukopenia (white blood cells [WBC] count < 1.0 109/L) and neutropenia (neutrophil [ANC] count < 0.5 109/L), whereas all irradiated controls displayed a profound period of leukopenia and neutropenia. Furthermore, administration of rhG-CSF significantly delayed the onset of leukopenia and reduced the duration of leucopenia as compared with controls. In addition, individual dogs in the rhG-CSF-treated group exhibited evident differences in rhG-CSF responsiveness after neutron-irradiation. Finally, histopathological evaluation of the surviving dogs revealed that the incidence and severity of bone marrow, thymus and spleen damage decreased in rhGCSF-treated dogs as compared with surviving controls. Thus, these results demonstrated that rhG-CSF administration enhanced recovery of myelopoiesis and survival after neutron-irradiation.
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Neutrons are non-charged particles, and classified as high
linear energy transfer (LET) radiation. Extensive studies
have shown the biological effect of fission-neutron
irradiation and confirmed that the relative biological effectiveness
(RBE) of fission-neutron irradiation for different animal
models is greater than that observed with either X rays or
rays.14) Based on these studies, it was proposed that neutron
irradiation caused more severe injuries to hematopoietic and
gastrointestinal (GI) system as compared with the low-LET
ray and X ray irradiation.4,5) For instance, after neutron
irradiation, the incidence and severity of the early signs of
GI syndrome as well as early death increased, and the
leucocyte count decreased very rapidly with much lower nadirs,
which led to grave early infection and death.5) Thus, it is
especially difficult to treat the neutron-irradiation syndrome
in view of these critical injuries, and so far few data are
available on the therapeutic measures for neutron-radiation
damage. Previous studies demonstrated that clinical support
regimens4) and bone marrow transplantation3,68) effectively
improved the survival and increased the LD50/30 after mixed
fission-neutron: irradiation. However, some protective
drugs such as Amifostine and estradiol, which are effective
in the treatment of -radiation injury, showed less or no
effect on neutron-radiation damage.9,10) The therapeutic
efficacy of several hematopoietic growth factors (HGF) had also
been examined in animal models exposed to mixed
fissionneutron: irradiation.1113) But the percentage of neutrons in
the mixed radiation was relative low and the specific effects
of high-LET neutron irradiation in animals were not
apparent in those studies.
Granulocyte colony stimulating factor (G-CSF) is an HGF
that acts selectively on the neutrophil lineage and has been
used extensively in clinical settings for accelerating
hematopoietic recovery following chemotherapy or bone marrow
transplantation, and decrease the period of neutropenia in the
limited number of radiation accident victims studied.14)
Extensive studies have provided evidence that G-CSF is able
to stimulate neutrophil recovery and to promote survival
after lethal irradiation in murine,15,16) canine,1719) and
primate20) models. Canine models have already been
employed to study the effects of HGFs on haemopoiesis
under normal conditions and in a state of perturbation due
to exposures to ionizing radiation. It has been found that
rhG-CSF stimulates hematopoiesis in normal dogs and can
reverse the otherwise lethal myelosuppressive effect of
radiation exposure when administered shortly after irradiation.17)
Similar results were reported by MacVittie et al.18)
Furthermore, in the canine, G-CSF administered early and
continuously throughout the period of neutrophil recovery can
rescue animals in the supralethal dose range of TBI.19) In
these cases, G-CSF has displayed evident efficacy in
reducing neutropenia and enhancing survival of the canine model
exposed to lethal doses of 60Co gamma radiation.
In this study, we used the canine as a neutron-irradiated
model given a dose with a high ratio of neutrons and
evaluated the effects of rhG-CSF on the hematologic recovery and
survival of irradiated dogs. The effects of the drug were
further evaluated by studying the general conditi (...truncated)