* Institute of Hematopoietic Disorders,
Department of Toxicology, School of Preventive Medicine, Norman Bethune University of Medical Sciences, Changchun 130021, People's Republic of China; and
Department of Pathology, University of Western Ontario, London, Ontario N6A 5C1, Canada
Received May 7, 1999; accepted October 4, 1999
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ABSTRACT |
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Key Words: low-dose radiation; hematopoietic cells; hormesis; adaptive response; cell-survival response.
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INTRODUCTION |
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Only a few studies have addressed the issue of LDR-induced hormesis for cell proliferation and adaptive response to subsequent radiation-induced cytotoxicity (Moquet et al., 1989; Park et al., 1999
; Raaphorst and Boyden 1999
; Sanderson and Morley 1986
; Sasaki 1995
; Shadley and Dai 1993
). First, the adaptive response for cell survival, called cell-survival adaptive response, coincided with the induction of a genotoxic adaptive response (Sanderson and Morley 1986
). In contrast, Moquet et al. (1989) demonstrated that LDR induced a genotoxic adaptive response without the induction of cell-survival adaptive response. Shadley and Dai (1993) showed that LDR could induce the cell-survival adaptive response, but the increase in cell survival could not be explained by the increase in non-aberrant cells. Therefore, the characteristics and mechanisms of a genotoxic adaptive response may differ from those of a cell-survival adaptive response. In studies on genotoxic adaptive response, in general, a single dose of radiation at 0.2 Gy or less is effective in inducing the reduction of DNA or chromosome damage caused by subsequent radiation (Cai and Cherian 1996
; Cai and Jiang 1995
; Mozdarani and Saberi 1994
; Wolff et al., 1988
). However, cells were more sensitive to the cytotoxic effect in the low-dose range of 0.10.3 Gy than in the dose range of 0.51.0 Gy (Joiner et al., 1996
). No direct relationship has been delineated between the mechanisms responsible for cellular hypersensitivity to LDR and those for LDR-induced genotoxic adaptive response (Joiner et al., 1996
; Marples and Joiner 1995
; Raaphorst and Boyden 1999
; Wouter and Skarsgard 1997).
A severe depression of hematopoietic function often takes place in patients undergoing radiotherapy and/or chemotherapy due to the high sensitivity of the hematopoietic system to radiation. Therefore, developing a strategy to protect and stimulate the hematopoietic stem cell pool is very important and desirable to counteract the adverse effects, and thus allow a more intensive and more effective therapy. Using various recombinant colony-stimulating factors (CSFs) or cytokines, a beneficial result had been achieved in both restoring hematopoietic function of irradiated animals and protecting bone marrow of patients who were accidentally exposed to radiation (Macvittie et al., 1990; Neta and Oppenheim 1988
). In addition, stimulation of the hematopoietic functions and protection of bone marrow from radiation were found in the animals pre-treated with other agents as compared to the animals without pretreatment. For example, certain toxic chemicals, such as protein-associated polysaccharides AM5 (Real et al., 1992
), the anticancer drug vincristine [VCR, (Johnke and Abernathy 1990
)], mild hyperthermia (Moroz et al., 1991
) and metals (Soderberg et al., 1988
), offered a marked protection from, or adaptive response to, radiation-induced hematopoietic depression. Pretreatment with low concentrations of AM5, VCR or mild hyperthermia stimulated and/or accelerated the recovery of the hematopoietic progenitor cells in the irradiated mice. As mentioned above, a genotoxic adaptive response could be induced not only by LDR, but also by a low concentration of other stresses. Therefore, we hypothesize that LDR may stimulate proliferation of hematopoietic cells as a cell-proliferation hormesis, and may also induce a cell-survival adaptive response to subsequent radiation. In mouse splenocytes, LDR was able to induce an enhancement of mitogen-stimulated cell proliferation (Hyun et al., 1997
), and cell-survival adaptive response to the second damaging radiation (Saenko et al., 1991
; Yoshida et al., 1993
). In bone marrow, it is still unclear if LDR could induce the hormetic or adaptive response. Therefore, in the present study, we investigated whether LDR could induce: (1) a cell-proliferation hormesis in bone marrow cells and (2) a cell-survival adaptive response of these cells to subsequent high-dose radiation.
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MATERIALS AND METHODS |
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A Phillips therapeutic X-ray machine operated at 200 kVp and 10 mA in the presence of 1 mm Al and 0.5 mm Cu filter plates was used for X-irradiation. The dose rates were 0.05 Gy/min for LDR or D1 and 0.287 Gy/min for D2, respectively.
Cytotoxic analysis.
Peripheral blood cells were collected from the orbital vein of mice at 48 h after D2. The numbers of RBC, WBC, and PLt were counted using a blood-cell-counting machine.
Bone marrow cells were collected in 2.5 ml of Iscove's modified Dulbecco's medium (IMDM) from femurs of mice at different times after LDR or at 48 h after D2. Bone marrow cells from both femurs were pooled for each mouse. Only nucleated cells were counted using hemocytometer. Total bone marrow cells per femur were calculated.
CFU-GM and BFU-E were cultured by methylcellulose methods according to previously reported procedures (Johnke and Abernathy 1990; Real et al., 1992
) with slight modifications. Bone marrow cells (1.0 x 105/ml for CFU-GM and 1.0 x 106/ml for BFU-E) were cultured in IMDM medium. For CFU-GM, the culture medium contained the following items in final concentration: 0.9% methylcellulose, 28% horse serum, and 10 µg/ml granulocyte-macrophage colony-stimulating factor (GM-CSF, Schering Plough Co.). For BFU-E, the culture medium contained 0.9% methylcellulose, 16% horse serum, 5% supernatant obtained from the cultures of PHA-stimulated human lymphocytes, 12% human serum (mixture from 5 or more volunteers), 1 U/ml erythropoietin (KIRIN, Japan), and 0.1 mM 2-mercaptoethanal. For both cell cultures, 100 µg/ml penicillin and 100 units/ml streptomycin were added, and the total volume per 2-femur sample was 3.5 ml. One-ml triplications of each sample were plated in 35 x 10-mm wells of tissue culture plates, and incubated under 5% CO2 in air at 37°C and 100% humidity. After incubation of these cells for 7 days, colonies of greater than 50 cells, observed with inverted microscope, were counted as CFU-GM. After incubation of these cells for 14 days, both cell groups, including 100 or more red-colored cells and 3 or more subcolonies with red-colored cells, were counted as colonies derived from BFU-E.
Statistic analysis.
The average numbers for total bone marrow cells per femur and bone marrow progenitors, CFU-GM and BFU-E, were obtained from 1012 mice. Data were analyzed according to one-way analysis of variation (ANOVA) and Bonferroni multiple comparison using GraphPAD Software. The level of significance was taken as p < 0.05. All results were presented as mean ± SE.
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RESULTS |
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DISCUSSION |
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Most previous studies on radiation hormesis were carried out using thymus (or thymocytes) and spleen (or splenocytes). Liu and his colleagues found that optimal dose and time for inducing a hormetic effect in thymocytes or splenocytes were 0.750.1 Gy and about 712 h, respectively (Ju et al., 1993; Liu 1992
; Liu et al., 1987
, 1990
, 1996
). However, most of these experiments were carried out in vitro using functional endpoints, which included the spontaneous incorporation of 3H-TdR into thymocytes, the reaction of splenocytes to Con A and LPS, UV-induced unscheduled DNA synthesis (UDS) in human lymphocytes or mouse splenocytes, and the ability to secrete certain cytokines. In the study of Yoshida et al. (1993), a cell-proliferation hormesis was found in the splenocytes of LDR-irradiated mice. The optimal dose and time for this response were 0.050.1 Gy and 7 h after LDR irradiation, respectively. If the dose was increased to 0.5 Gy, a marked cytotoxic effect was found in thymocytes and splenocytes. In contrast, we found the stimulating effect of 0.5 Gy X-rays in bone marrow cells at 48 h to be optimal. These discrepancies may result from several possibilities.
First, different tissues may require different optimal doses and times for induction of cell-proliferation hormesis and a cell-survival adaptive response. Raaphorst and Boyden (1999) reported that cell lines derived from different tissues, such as human normal fibroblasts, melanoma, and breast carcinoma, showed variations of the optimal LDR, from 0.2 to 1.0, and even 2 Gy, in inducing the cell-survival adaptive response in vitro. Compared to splenocytes and thymocytes, bone marrow cells were found to be highly resistant to radiation-induced cytotoxicity, since a dose of 0.5 Gy X-rays was not toxic for bone marrow cells (Grande and Bueren 1995), but very toxic for splenocytes and thymocytes (Yoshida 1993
). In addition, circulating CFU-GM and colony-forming unit-megakaryocytes (CFU-meg) in peripheral blood were even more sensitive to radiation-induced depression (D0 = 0.53 Gy for CFU-GM and 0.40 Gy for CFU-Meg) than bone marrow cells (D0 = 1.36 Gy for CFU-GM and 1.48 Gy for CFU-Meg) (Scheding et al., 1996
). All these results suggest that the optimal doses and exposure times of LDR for inducing cell-proliferation hormesis and cell-survival adaptive response may vary in different tissues, and even in the same cell type under different conditions.
Second, the toxic effect of radiation on bone marrow cells is different in vitro from in vivo. LDR (0.1 Gy) was able to induce an elevation of lipid peroxide (LPO) in murine bone marrow cell microsomes only after in vitro irradiation (Schwenke et al., 1994). In the case of whole-body irradiation, the same dose of exposure did not increase the LPO level of bone marrow cells, which might be due to the existence of cellular radical scavengers and other metabolic reactions (Schwenke et al., 1994
). The difference between in vitro and in vivo treatment for the optimal induction of the genotoxic adaptive response has been demonstrated in previous studies. In vivo studies with chromosome aberrations in mouse germ cells (Cai et al., 1993
), UV-induced UDS in splenocytes of adapted mice (Wojcike and Tuschl, 1990), and spleen colony formation (Saenko et al., 1991
) indicated a longer duration period (40 days, 12 days, and 30 days, respectively) than in vitro studies with chromosome aberrations in human lymphocytes, CHO cells, and human melanoma cells [3 cell cycles (Cai and Liu 1990
; Shadley et al., 1987
), 1 cell cycle (Ikushima 1987
), and less than 20 h (Kim et al., 1996
), respectively].
Third, the discrepancy in the optimal doses and times in inducing the two kinds of adaptive responses may result from differences in the mechanisms underlying the responses (Wouters and Skarsgard 1997). In a variety of cells in vitro, the optimal doses of LDR in inducing the cell-survival adaptive response are approximately 0.5 and 1 Gy (Raaphorst and Boyden 1999
). These doses are different from those that induce a genotoxic adaptive response. In the present study, for the induction of the cell-survival adaptive response in bone marrow cells, we cannot rule out the involvement of mechanisms underlying the induction of the genotoxic adaptive response by LDR such as the enhancement of DNA repair and antioxidant capacity. However, the relatively long post-irradiation time for the induction of cell-proliferation hormesis (maximum at 48 h, Fig. 1
) and cell-survival adaptive response (maximum at 24 h, Figs. 2 and 3
) as compared to that for the induction of genotoxic adaptive response does not support the idea that a single mechanism underlies these two kinds of adaptive responses.
For the specific case of the induction of cell-proliferation hormesis and cell-survival adaptive response in bone marrow, we propose that an indirect mechanism, the alteration of bone marrow microenvironmental conditions, may act as the main factor to determine the induction of cell-survival adaptive response. Cell death depends on either severe DNA damage, or cell membrane damage, or both. Schwenke et al. (1994) demonstrated higher radioresistance to radiation-induced LPO of bone marrow cells in vivo than in vitro due to efficient antioxidants or free radical scavengers in vivo that modify the radiation-induced damage. Therefore, LDR might induce effects such as release of cytokines, which in turn enhance the resistance of bone marrow cells to the radiation-induced cytotoxic effect. LDR stimulates the CSF secretion in lung and thymus, and the expression of CSF receptors in bone marrow cells (Zhang 1993). The possibility that the extracellular factors activate the proliferative response and make cells adaptive to subsequent radiation may also explain why the post-irradiation time for the induction of cell-proliferation hormesis and cell-survival adaptive response in bone marrow cells by LDR was longer than that for the induction of genotoxic adaptive response (maximum around 6 h).
Finally, the present study may have a potential importance for clinical application of LDR. Radiotherapy has been widely used for the treatment of certain kinds of tumors, and severe lethal infection or bleeding due to hematopoietic dysfunction are often obstacles to continuation of radiotherapy. We found that pre-exposure of mice to LDR could markedly prevent the hematopoietic depression caused by subsequent radiation, as a result of a cell-survival adaptive response. Two recent in vitro studies have indicated that the cell-survival adaptive response could be induced by LDR in normal cell lines, but not in neoplastic cell lines (Park et al., 1999), or a lesser adaptive response in neoplastic than in normal cell lines (Raaphorst and Boyden 1999
). This information suggests a mechanism to reduce the adverse effect of radiation on the hematopoietic system and enhance the efficient treatment of cancer. Further efforts will focus on finding differences between hematopoietic cells and tumor cells in the optimal LDR doses and/or schedules for the induction of a cell-survival adaptive response. Clinical therapeutic doses and schedules may then be adopted to favor the induction of an adaptive response of bone marrow cells and increase in the hypersensitivity of tumor cells to radiation therapy.
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NOTES |
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