RhG-CSF Improves Radiation-induced Myelosuppression and Survival in the Canine Exposed to Fission Neutron Irradiation

Journal of Radiation Research, Jul 2011

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-γ 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 rhG-CSF-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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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. - 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)


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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. RhG-CSF Improves Radiation-induced Myelosuppression and Survival in the Canine Exposed to Fission Neutron Irradiation, Journal of Radiation Research, 2011, pp. 472-480, 52/4, DOI: 10.1269/jrr.10103