Induction of Cell-Proliferation Hormesis and Cell-Survival Adaptive Response in Mouse Hematopoietic Cells by Whole-Body Low-Dose Radiation

Guan-Jun Wang* and Lu Cai{dagger},{ddagger},1

* Institute of Hematopoietic Disorders, {dagger} Department of Toxicology, School of Preventive Medicine, Norman Bethune University of Medical Sciences, Changchun 130021, People's Republic of China; and {ddagger} Department of Pathology, University of Western Ontario, London, Ontario N6A 5C1, Canada

Received May 7, 1999; accepted October 4, 1999


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hormesis and a cytogenetic adaptive response induced by low-dose radiation (LDR) have been extensively documented. However, few studies have investigated the induction of an adaptive response by LDR for cell survival in vitro. In the present study, we investigated whether LDR could induce hormesis in hematopoietic cells and the adaptive response of these cells to subsequent high-dose radiation-induced cytotoxic effects. Mice were exposed in whole-body to 0 (as control), 0.05, 0.25, 0.50, 0.75, and 1.00 Gy of X-rays. They were killed 12, 24, 48, and 72 h later to observe the stimulating effect of LDR on total bone marrow cells per femur and bone marrow progenitor, colony-forming unit-granulocyte-macrophage (CFU-GM). Exposure to 0.5 Gy of X-rays resulted in significantly stimulating effects on both parameters with a maximum effect at 48 h, showing a cell-proliferation hormesis. In the next experiment, mice were irradiated by 0.5 Gy X-rays as an adaptive exposure (D1), and 6, 12, 24, 48, and 72 h later, they were exposed to 6 Gy X-rays as a challenging exposure (D2). Forty-eight h after D2, cytotoxic effects were analyzed using peripheral blood cells (red blood cells, white blood cells, and platelets) and bone marrow cells (total bone marrow cells of the femur, and bone marrow progenitors such as CFU-GM and erythroid burst-forming unit, BFU-E). An adaptive response to D2-induced cytotoxic effect, named as the cell-survival adaptive response, was found in both peripheral blood cells and bone marrow cells when D1 and D2 exposures were given at intervals of 24–48 h. These results suggested that LDR could induce both cell-proliferation hormesis and cell-survival adaptive response to subsequent high-dose radiation in bone marrow cells. It may be of potential importance, if this phenomenon is confirmed clinically, since it may be applied to reduce the adverse effect of radiotherapy.

Key Words: low-dose radiation; hematopoietic cells; hormesis; adaptive response; cell-survival response.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The biological effects of low-dose radiation (LDR) have attracted attention for nearly two decades. Luckey (1980) demonstrated that LDR could stimulate the metabolic activities of cells, such as DNA and protein synthesis, a phenomenon termed hormesis. Olivier et al. (1984) showed that lymphocytes exposed to LDR developed high resistance to subsequent radiation-induced chromosome aberrations, and this was termed adaptive response. To date, a body of evidence has documented that exposure of cells in vitro or in vivo to LDR enhanced metabolic activities of cells, including DNA, RNA, and protein synthesis, DNA repair, and antioxidant activities. These stimulatory effects consequently protected cells in vitro or in vivo from gene mutation, DNA damage, and chromosome aberrations caused by a subsequent exposure to radiation or other DNA-damaging chemicals (Cai 1999Go; Cai and Liu 1990Go; Cai and Wang 1995Go; Flores et al., 1996Go; Liu, 1992Go; Liu et al., 1987Go, 1990Go, 1992Go, 1996Go; Wojcike and Streffer 1994; Wolff 1992Go). It was found that the adaptive response could be induced not only by pretreatment with LDR, but also by pretreatment with low levels of other agents including anticancer drugs (bleomycin, mitomycin C or actinomycin D), free-radical generating agents such as hydrogen peroxide (H2O2) and metals, and physical stress such as mild hyperthermia (Cai 1999Go; Cai and Cherian 1996Go; Cai and Jiang 1995Go; Mozdarani and Saberi 1994Go; Wojcike and Streffer 1994; Wolff 1992Go; Wolff et al., 1988Go). However, in these studies, the major endpoints used were gene mutation, DNA damage, and chromosome aberrations, collectively referred to as the genotoxic adaptive response.

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., 1989Go; Park et al., 1999Go; Raaphorst and Boyden 1999Go; Sanderson and Morley 1986Go; Sasaki 1995Go; Shadley and Dai 1993Go). First, the adaptive response for cell survival, called cell-survival adaptive response, coincided with the induction of a genotoxic adaptive response (Sanderson and Morley 1986Go). 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 1996Go; Cai and Jiang 1995Go; Mozdarani and Saberi 1994Go; Wolff et al., 1988Go). However, cells were more sensitive to the cytotoxic effect in the low-dose range of 0.1–0.3 Gy than in the dose range of 0.5–1.0 Gy (Joiner et al., 1996Go). 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., 1996Go; Marples and Joiner 1995Go; Raaphorst and Boyden 1999Go; 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., 1990Go; Neta and Oppenheim 1988Go). 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., 1992Go), the anticancer drug vincristine [VCR, (Johnke and Abernathy 1990Go)], mild hyperthermia (Moroz et al., 1991Go) and metals (Soderberg et al., 1988Go), 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., 1997Go), and cell-survival adaptive response to the second damaging radiation (Saenko et al., 1991Go; Yoshida et al., 1993Go). 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.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mice and irradiation.
In all experiments, adult Kunming mice (male and female) were used and their body weights were about 25 ± 3 grams. Animals were treated and housed in accordance with guidelines approved by Norman Bethune University's Animal Care Committee. In the first experiment, mice were divided into 6 groups exposed to different doses of LDR (0, 0.05, 0.25, 0.50, 0.75, or 0.10 Gy of X-rays). After LDR, they were killed at 12, 24, 48, and 72 h to collect bone marrow cells. In the second experiment, both LDR and high-dose radiation were used. The LDR and high-dose radiation were called D1 and D2, respectively. Mice were grouped into 3 groups: control (without any treatment), D2 alone (irradiated by 6 Gy only), and D1 + D2 groups. For D1 + D2 groups, mice were exposed to the optimal LDR (0.5 Gy X-rays, as D1), and to 6 Gy X-rays (as D2) at 6, 12, 24, and 72 h later. Mice were killed at 48 h after D2 to collect the blood for counting red blood cells (RBC), white blood cells (WBC), and platelets (PLt). In addition, bone marrow for investigating total bone marrow cells per femur, bone marrow progenitors such as colony-forming unit-granulocyte-macrophage (CFU-GM), and erythroid burst-forming units (BFU-E) were collected. Six Gy X-rays were used as D2, since LD50/30 (a dose making 50% of animals die within 30 days) for mouse is 7–8 Gy (Hall 1988) and asublethal dose (6 Gy) was used extensively in previous studies to investigate radiation-induced damage and radioprotection (Hsu et al., 1990Go; Inoue et al., 1995Go).

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 1990Go; Real et al., 1992Go) 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 10–12 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.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hormetic Effect Induced by LDR on Cell-Proliferation of Bone Marrow Cells
In order to find out the optimal doses of LDR to induce a hormetic response on bone marrow cells, mice were irradiated with 0, 0.05, 0.25, 0.50, 0.75, and 1.0 Gy of X-rays. They were killed 12, 24, 48, and 72 h later for counting total bone marrow cells per femur and for analysis of CFU-GM. As shown in Figure 1Go, LDR did not markedly decrease the total bone marrow cells/femur at all post-irradiation times. For CFU-GM, in general, LDR also did not cause a statistically significant depression except for a few doses at certain post-irradiation times. For example, at 12 and 24 h post-irradiation, exposure to 0.05, 0.25, 0.75, and 1.0 Gy X-rays caused certain depression of CFU-GM (Fig. 1Go). In contrast, 0.5 Gy X-rays significantly increased total bone marrow cells and bone marrow CFU-GM, starting at 24 h, reaching a maximum level at 48 h, and remaining high until 72 h post-irradiation. This experiment indicated that LDR could induce a cell-proliferation hormesis in bone marrow cells. The optimal dose of LDR at the rate of 0.05 Gy/min in inducing this hormetic effect was about 0.5 Gy at 48 h after radiation.



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FIG. 1. LDR hormetic effect on bone marrow cells. Mice were exposed to different doses of LDR as indicated and then killed at 12, 24, 48, and 72 h later to collect bone marrow cells. Total bone marrow nucleated cells per femur and CFU-GM was determined. Results were obtained from 12 mice for each experimental point and presented as mean ± SE a (p < 0.05) and b (p < 0.01) indicate the decrease effect vs. control; c (p < 0.05) and d (p < 0.01) indicate the increase effect vs. control (dose = 0).

 
LDR-Induced Cell-Survival Adaptive Response of Bone Marrow Cells to High-Dose Irradiation
Further studies were conducted to determine whether the optimal hormetic dose observed above could induce a cell-survival adaptive response in bone marrow cells to subsequent high-dose radiation. Mice pre-irradiated by D1 (0.5 Gy) were exposed to D2 (6 Gy X-rays) at intervals of 6, 12, 24, 48, and 72 h. After D2, mice were killed at 48 h to observe the cytotoxic effects on peripheral blood cells, including RBC, WBC, and PLt, total bone marrow cells, and 2 bone marrow progenitors, including FU-GM and BFU-E (Fig. 2Go). Exposure to D2 alone markedly reduced the numbers of RBC (from 3.6 ± 0.25 x 1012 to 0.89 ± 0.18 x 1012 ), WBC (from 11.4 ± 1.05 x 109 to 0.6 ± 0.1 x 109), and PLt (from 3.39 ± 0.50 x 1011 to 1.79 ± 0.13 x 1011 ). However, if mice were irradiated with D1 at different times prior to D2, the D2-induced decrease in the cell number could be partially prevented. The decrease in PLt number was completely prevented by D1 independent of interval times between D1 and D2 (up to 72 h). RBC numbers were 50–60% of control in D1 + D2 groups at a 24-h interval or longer, whereas it was approximately 25% of control following D2 alone (Fig. 2Go). WBC numbers were also significantly higher in the D1 + D2 group (10–15% of control) at intervals of 12–72 h than that in the D2-alone group (only about 5% of control) (Fig. 2Go).



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FIG. 2. Adaptive response induced by D1 in peripheral blood cells. Mice were exposed to D1 (0.5 Gy) and then were irradiated with D2 (6 Gy) at different time intervals as indicated. After D2, mice were killed at 48 h to collect blood cells. RBC, WBC, and PLt were counted from 10 mice as described in Materials and Methods, and presented as mean ± SE; * and **: p < 0.05 and p < 0.01, respectively, vs. D2 alone (open circle).

 
Data for total bone marrow cells per femur and two bone marrow progenitors (CFU-GM and BFU-E) are presented in Figure 3Go. Again, D2 alone significantly decreased total bone marrow cells (from 216x105 to 4x105 per femur), CFU-GM (from 58.5±1.5 to 11.5±1.5 per 2x105 cells) and BFU-E (from 55.5±4.5 to 12.5±1.5 per 2x105 cells). The D2-induced decrease in the cell numbers could be prevented partially by pre-exposure of mice to D1 (0.5 Gy). The maximum preventive effect occurred at 24 h post-D1, with a less preventive effect at 48 and 72 h (Fig. 3Go).



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FIG. 3. Adaptive response induced by D1 in bone marrow cells. Mice were exposed to D1 (0.5 Gy) and then irradiated with D2 at different time intervals as indicated. After D2, mice were killed at 48 h to collect bone marrow cells. Total bone marrow nucleated cells per femur, CFU-GM, and BFU-E progenitors were determined. Data were obtained from 10 mice for each experimental point and presented as mean ± SE; * and **: p < 0.05 and p < 0.01, respectively, vs. D2 alone (open circle).

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous studies have demonstrated the induction of a hormetic effect in peripheral immune cells (such as lymphocytes, thymocytes, and splenocytes) and a genotoxic adaptive response by LDR (Cai 1999Go; Cai and Liu 1990Go; Cai and Wang 1995Go; Flores et al., 1996Go; Liu 1992Go; Liu et al., 1987Go, 1990Go, 1992Go, 1996Go; Wojcike and Streffer 1994; Wojcike and Tuschl 1990; Wolff 1992Go). In the present study, we provide evidence for the hormetic effect of LDR on the hematopoietic system. Both total bone marrow cells per femur and bone marrow progenitors (CFU-GM) in mice irradiated with 0.5 Gy X-rays at a low-dose rate (0.05 Gy/min) increased at 24–72 h of post-irradiation, indicative of cell-proliferation hormesis (Fig. 1Go). Exposure to LDR also resulted in an adaptive response of these cells to D2-induced cytotoxic effects, designated the cell-survival adaptive response. The cell-survival adaptive response showed a resistance to D2-induced depression of both peripheral blood cells (i.e., RBC, WBC, and PLt; Fig. 2Go) and bone marrow cells (total bone marrow cells per femur and bone marrow progenitors, CFU-GM or BFU-E; Fig. 3Go). These results support those obtained previously in other tissues for the hormesis and genotoxic adaptive response. However, there are some inconsistencies for the optimal dosage and duration needed to induce cell-survival adaptive response in bone marrow cells compared to those needed to induce a genotoxic adaptive response in other tissues.

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 0.75–0.1 Gy and about 7–12 h, respectively (Ju et al., 1993Go; Liu 1992Go; Liu et al., 1987Go, 1990Go, 1996Go). 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 0.05–0.1 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 1995Go), but very toxic for splenocytes and thymocytes (Yoshida 1993Go). 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., 1996Go). 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., 1994Go). 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., 1994Go). 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., 1993Go), UV-induced UDS in splenocytes of adapted mice (Wojcike and Tuschl, 1990), and spleen colony formation (Saenko et al., 1991Go) 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 1990Go; Shadley et al., 1987Go), 1 cell cycle (Ikushima 1987Go), and less than 20 h (Kim et al., 1996Go), 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 1997Go). 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 1999Go). 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. 1Go) and cell-survival adaptive response (maximum at 24 h, Figs. 2 and 3GoGo) 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 1993Go). 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., 1999Go), or a lesser adaptive response in neoplastic than in normal cell lines (Raaphorst and Boyden 1999Go). 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.


    NOTES
 
1 To whom correspondence should be addressed at present address: 511 S. Floyd Street, MDR Building, Gastro Lab (Rm. 531), Louisville, KY 40202. Fax: (502) 852-6904. E-mail: lcai1{at}hotmail.com. Back


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 DISCUSSION
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