Research ArticleExperimental Studies

Screening of Antimicrobial Agents for In Vitro Radiation Protection and Mitigation Capacity, Including those Used in Supportive Care Regimens for Bone Marrow Transplant Recipients

MICHAEL W. EPPERLY, DARCY FRANICOLA, DONNA SHIELDS, JEAN-CLAUDE RWIGEMA, BRANDON STONE, XICHEN ZHANG, WILLIAM MCBRIDE, GEORGE GEORGES, PETER WIPF and JOEL S. GREENBERGER
In Vivo January 2010, 24 (1) 9-19;

Abstract

Antibiotic and antifungal agents used in supportive care regimens for bone marrow transplantation recipients contribute to a significant dose-modifying effect of otherwise lethal total body irradiation. To determine whether drugs used in supportive care and other commonly used antibiotics such as tetracycline function as radiation protectors or damage mitigators in vitro, 13 drugs were tested for radiation protection and radiation damage mitigation of 32D cl 3 hematopoietic progenitor cells in clonagenic survival curves in vitro. Antibiotic/Antifungal agents including cilastatin, amikacin, ceftazidine, vancomycin, tetracycline, doxycycline, ciprofloxacin, metronidazole, methacycline, minocycline, meclocycline, oxytetracycline and rolitetracycline were added in 1, 10, or 100 micromolar concentrations to murine interleukin-3-dependent hematopoietic progenitor cell line 32D cl 3 cells either before or after irradiation of 0 to 8 Gy. Control irradiated 32D cl 3 cells showed radiosensitivity comparable to freshly explanted mouse marrow hematopoietic progenitor cells (D0 1.1±0.1 Gy, Ñ 1.5±0.4). Positive control GS-nitroxide JP4-039 (known radiation mitigator) treated 32D cl 3 cells were radioresistant (D0 1.2±0.1, Ñ 5.8±2.4 (p=0.009)). Of the 13 drugs tested, tetracycline was found to be a significant radiation mitigator (D0 0.9±0.1, Ñ 13.9±0.4 (p=0.0027)). Thus, the radiation dose-modifying effect of some antibiotics, but not those currently used in the supportive care (antibiotic/antifungal regimens) for marrow transplant patients, may act as radiation damage mitigators for hematopoietic cells as well as decreasing the growth and inflammatory response to microbial pathogens.

In experimental animals as well as clinical protocols of bone marrow transplantation, preparation of the host for infusion of donor hematopoietic stem cells often utilizes total-body irradiation or cytotoxic chemotherapy (1-5). In canine models (2-4, 6-12), the LD 50/30 (dose which produces bone marrow death in 50% of irradiated dogs at 30 days after irradiation) has revealed a significant dose modifying effect (DME) of the antibiotic and antifungal supportive care regimen. The DME has been shown in some canine model systems to increase from 4 to 7 Gy (1-3, 13-17). Supportive care regimens have been further modified in recent years, with the availability of new, more potent antibiotic and antifungal agents (1-3, 12). A similar irradiation DME of supportive care regimens has been demonstrated in canine (1-4), and non-human primate models that include marrow transplantation (18).

Antibiotics and antifungal agents used in current clinical bone marrow transplant supportive care regimens have been combined to prevent opportunistic infections facilitated by the leukopenia of the bone marrow-toxic agents, which include total-body irradiation (18-31). A question which has arisen during discussion of the potential mechanism of supportive care-mediated irradiation DME is that one or more of the antimicrobial agents could be acting as radiation damage mitigators, outside of their antimicrobial actions. Radiation mitigators are defined as those agents which can improve survival when added after exposure to irradiation, but before the appearance of clinical pathological or pathophysiological symptoms or effects (32). Known radiation mitigators used in clinical radiotherapy include WR2721 (amifostine) (33), nitroxides (Tempol) (34), and in experimental model systems, a series of new small molecule radiation damage mitigators (33).

There is recent evidence from chemical library screening experiments that analogs of some known antibiotics may have DNA-intercalating capacity and may function to stimulate DNA repair. These data have suggested that some antimicrobial agents, including those used in supportive care regimens, may have radiation damage mitigative properties. We tested the effect of each of 13 antimicrobial agents, including those used in current bone marrow transplantation clinical protocols, in a radiation sensitivity assay utilizing the interleukin-3(IL-3)-dependent murine hematopoietic progenitor cell line 32D cl 3 (34-35) as a marker cell line for human bone marrow stem cells.

Materials and Methods

Cells and cell culture. The murine hematopoietic progenitor cell line 32D cl 3 (34, 35), dependent for growth in vitro upon IL-3 was grown in McCoys modified medium contained at 37°C in a high humidity incubator according to published methods (34-35). This cell line has been shown to be a sensitive indicator of the radiation protective and radiation mitigative properties of new candidate drugs (33).

Antimicrobial agents and analogs. Each of 13 drugs (Table I) was tested in triplicate experiments. Stock solutions of all drugs obtained from Sigma Chemical Co., St. Louis, MO, USA, were made by dissolving the drugs in sterile water at a concentration of 10 mM. Drugs were assayed for their ability to modify the radiosensitivity of 32D cl 3 murine hematopoietic progenitor cell line. The antibiotics were used at a concentration of 1, 10, or 100 μM by adding them to 32D cl 3 cells 1 hour before irradiation or immediately after irradiation. Cells were irradiated to doses ranging from 0 to 8 Gy, plated in methycellulose, and incubated at 37°C for 7 days, at which time colonies of greater than 50 cells were counted (34-35). The data show the mean±SEM of three separate experiments for D0 (final slope of irradiation survival curve expressed in Gy) and Ñ (shoulder on the survival curve) of each drug. The antibiotics were evaluated for their effect on D0 and Ñ. Some drugs when administered at 100 μM after irradiation showed no colonies, suggesting toxicity. The positive control radiation mitigator JP4-039 was added at 10 μM to cultures before or after irradiation, as published elsewhere (36, 37).

Irradiation survival curves. Cells were irradiated using a Cesium 137 Gamma cell irradiator, dose rate 100 cGy/min over a total dose range of 0 to 8 Gy. For evaluation of radiation protective capacity, cells were incubated for 24 hours at each concentration of antimicrobial before irradiation. For irradiation mitigation experiments, irradiated cells were centrifuged to a cell pellet and resuspended in medium containing 1, 10, or 100 micromolar concentrations of each antimicrobial, then plated in 0.8% methylcellulose containing medium for clonogenic survival curve assay. Cells were plated at 500, 1000, or 2000 cells per plate in triplicate at each dose according to published methods (34, 35). All experiments were carried out in triplicate.

View this table:
Table I.

Radiation protection and/or damage mitigation by supportive care antimicrobials. 32D cl 3 cells were incubated in the presence of 1, 10 or 100 μM of the antibiotics for 1 hour before irradiation or added to the cells after irradiation of 0 to 8 Gy. The cells were plated in methycellulose, incubated at 37°C for seven days at which time colonies of greater than 50 cells counted. Data was analyzed using linear quadratic and single-hit, multi-target models. -- Indicates that no colonies were detected at that concentration. All antibiotics were obtained from Sigma Chemical Company, St. Louis, MO.

Figure 1.
Figure 1.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 2.
Figure 2.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 3.
Figure 3.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 4.
Figure 4.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 5.
Figure 5.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 6.
Figure 6.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 7.
Figure 7.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 8.
Figure 8.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 9.
Figure 9.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

At 7 days after plating, colonies of 50 or more cells per colony were scored using an inverted microscope according to published methods (34, 35). Data are presented using each of two computer program plotting linear, quadratic, and the alpha/beta model as appropriate (35).

Results

Radiobiologic effects on 32D cl 3 cell clonagenic survival. We first tested the effect of each of 13 antibiotic and antifungal agents including those used in supportive care regimens in clinical and experimental (canine) bone marrow transplantation models. The results in Tables I and Figures 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 demonstrate some toxicity of drugs at high concentrations (for example, doxycycline at 100 μM after irradiation). The antibiotic/antinocardial agents, minocycline and rolitetracycline was toxic at all doses when added after irradiation (Table I). Irradiation survival curves with 32D cl 3 demonstrated a significant increase in the shoulder reflected as (Ñ) by the addition of the positive control GS-nitroxide, JP4-039 (37) before or after irradiation (Table I). Tetracycline was also a radiation mitigator by this assay at 100 μM (Table I) (Figure 8).

Radiation protection and damage mitigating properties of tetracycline analogs. Each of 6 tetracycline analogs evaluated by chemical library screening were tested for radiation protection or damage mitigating properties against 32D cl 3 cells at each of the three concentrations described in the Materials and Methods. These agents were not significant radiation damage mitigators or protectors in the 32D cl 3 assay (Table I) (Figures 9, 10, 11, 12 and 13).

Figure 10.
Figure 10.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 11.
Figure 11.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 12.
Figure 12.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Figure 13.
Figure 13.

Each drug was added before or after irradiation to 32D cl 3 cells as described in the Materials and Methods. Cells were plated and scored as described in the Materials and Methods. Results are the mean±SEM of each agent at each concentration.

Discussion

The development of protocols for clinical bone marrow transplantation in patients with leukemia, lymphoma, multiple myeloma, and other non-hematopoietic system malignancies has taken into account the significant problem of opportunistic infection during the interval between transplant of donor hematopoietic stem cells and recovery of peripheral white blood cell counts (7-8, 34). This interval of leucopenia which can last 14-30 days, subjects the transplant recipient to a significant risk of opportunistic infections (19, 20). The use of laminar-flow rooms and meticulous sterile technique in the Marrow Transplant Unit has greatly minimized the incidence and severity of these opportunistic infections (38). Antibiotic and antifungal regimens used in the prophylactic care of transplant recipients prior to marrow ablative therapy (total-body irradiation or alkalinating agent therapy) as well as after donor marrow infusion have been continuously modified with the availability of newer, less toxic broad-spectrum antimicrobial agents (8-9, 12).

Bone marrow transplantation recipients are prepared using techniques of single fraction or fractionated total-body irradiation at a dose of radiation that produces the hematopoietic syndrome. The hematopoietic syndrome is by definition one that can be corrected by replacement of hematopoietic stem cells (32). Gastrointestinal, pulmonary, or other non-hematopoietic organs reversibly damaged by radiation are not rescued by bone marrow transplantation (33). Total body irradiation doses, fractionation schemes, and efforts to protect other non-hematopoietic tissues such as the lung, using a pulmonary transmission blocks have established guidelines for appropriate radiation doses and preparative regimens (26).

It is also assumed that these drugs work secondarily to decrease any inflammatory cytokine response to infection. Supportive care regimens may also have utility in the management of those victims of irradiation accidents who may not be candidates for marrow transplantation (32).

In the present studies, we sought to determine whether the common antibiotic tetracycline as well as one or more of the agents used in the modern supportive care regimen also act as radiation damage mitigators. To determine whether small molecules including antibiotic or antifungal agents are acting as radiation damage mitigators at this basic cellular level, an in vitro clonagenic survival assay system was used (39). Rapid assays for immediate irradiation induced apoptosis, or cell death after the first cell division are of value as well (36). The clonogenic survival curve measures cell death within the first 7 cell doublings after irradiation, and allows detection of lethal events which may be delayed past the first cell division (36). The results showed that tetracycline, like the positive control drug JP4-039 (37), was a radiation mitigator in vitro. Another study using siRNA screening of mRNA targets identified doxycycline as a potential radioprotector, but the drug was not effective in that study, as in the present study in clonagenic survival curve assays using 32D cl 3 cells, nor was it effective in vivo (39).

The present study supports efforts to design future generations of antibiotics and antifungal agents with a goal of also using them as radiation damage mitigators. Antibacterial/antifungal agents could be modified to have normal tissue radiation mitigation capacity to aid recovery of the total-body irradiated transplant recipient or radiation terrorist victim. Concerns for clinical application would include confirmation that the agents not alter the tumor cell killing effects of total-body irradiation. Screening new antimicrobials as well as those used in clinical supportive care regimens for radiation damage mitigation capacity should be of value in the development of treatments for victims of radiation accidents and radiation terrorism.

Footnotes

  • ↵* Supported by: NIH/NIAD U19AI068021, U19AI067769, U19AI067770, U19A1067769.

    • Received October 20, 2009.
    • Revision received December 16, 2009.
    • Accepted December 18, 2009.

References

  1. ↵
    1. Graves SS,
    2. Hogan W,
    3. Kuhr CS,
    4. Diaconescu R,
    5. Harkey MA,
    6. Georges GE,
    7. Sale GE,
    8. Zellmer E,
    9. Baran S,
    10. Storb R
    : Stable trichimerism after marrow grafting from 2 DLA-identical canine donors and nonmyeloablative conditioning. Blood 110: 418-423, 2007.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Yunusov MY,
    2. Kerbauy F,
    3. Abrams K,
    4. Zellmer E,
    5. Spector M,
    6. Kuhr CS,
    7. Hwang B,
    8. Storer B,
    9. Georges GE,
    10. Nash RA
    : Intussusception in canine recipients of hematopoietic cell grafts and surgical correction. Comp Med 57: 287-291, 2007.
    OpenUrlPubMed
  3. ↵
    1. Takatu A,
    2. Nash RA,
    3. Zaucha JM,
    4. Little MT,
    5. Georges GE,
    6. Sale GE,
    7. Zellmer E,
    8. Kuhr CS,
    9. Lothrop CD Jr,
    10. Storb R
    : Adoptive immunotherapy to increase the level of donor hematopoietic chimerism after nonmyeloablative marrow transplantation for severe canine hereditary hemolytic anemia. Biol Blood Marrow Transplant 9: 674-682, 2003.
    OpenUrlPubMed
  4. ↵
    1. Mielcarek M,
    2. Georges GE,
    3. Storb R
    : Denileukin diftitox as prophylaxis against graft-versus-host disease in the canine hematopoietic cell transplantation model. Biol Blood Marrow Transplant 12: 899-904, 2006.
    OpenUrlPubMed
  5. ↵
    1. Deeg HJ,
    2. Gooley TA,
    3. Flowers ME,
    4. Sale GE,
    5. Slattery JT,
    6. Anasetti C,
    7. Chauncey TR,
    8. Doney K,
    9. Georges GE,
    10. Appelbaum FR
    : Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 102: 3912-3918, 2003.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Storb R,
    2. Yu C,
    3. Wagner JL,
    4. Deeg HJ,
    5. Nash RA,
    6. Kiem HP,
    7. Leisenring W,
    8. Shulman H
    : Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 89: 3048-3054, 1997.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Appelbaum FR,
    2. Meyers JD,
    3. Deeg HJ,
    4. Graham T,
    5. Schuening F,
    6. Storb R
    : Toxicity trial of prophylactic 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl] guanine (gancyclovir) after marrow transplantation in dogs. Antimicrob Agents Chemother 32: 271-273, 1988.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Haralambie E,
    2. Schmidt-Weinmar A
    : Infections after experimental cadaver bone marrow transplantation in beagle dogs. Transplantations with and without selective gastrointestinal decontamination. Infection 16: 36-41, 1988.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Storb R,
    2. Deeg HJ,
    3. Appelbaum FR,
    4. Schuening FW,
    5. Raff RF,
    6. Graham TC
    : The biology of graft rejection in a canine model of marrow transplantation. Transplant Proc 19(6 Suppl 7): 18-22, 1987.
    OpenUrlPubMed
    1. Deeg HJ,
    2. Atkinson K,
    3. Weiden PW,
    4. Storb R
    : Mechanisms of tolerance in canine radiation chimeras. Transplant Proc 19(6 Suppl 7): 75-81, 1987.
    OpenUrlPubMed
    1. Prummer O,
    2. Calvo W,
    3. Fliedner TM
    : Variation of treatment conditions alters the outcome of fetal liver transplantation in dogs. Thymus 10: 19-31, 1987.
    OpenUrlPubMed
  12. ↵
    1. Vriesendorp HM,
    2. Heidt PJ,
    3. Zurcher C
    : Gastrointestinal decontamination of dogs treated with total body irradiation and bone marrow transplantation. Exp Hematol 9: 904-916, 1981.
    OpenUrlPubMed
  13. ↵
    1. Weisdorf D,
    2. Chao N,
    3. Waselenko JK,
    4. Dainiak N,
    5. Armitage JO,
    6. McNiece I,
    7. Confer D
    : Acute radiation injury: contingency planning for triage, supportive care, and transplantation. Biol Blood Marrow Transplant 12: 672-682, 2006.
    OpenUrlCrossRefPubMed
    1. Horwitz ME,
    2. Morris A,
    3. Gasparetto C,
    4. Sullivan K,
    5. Long G,
    6. Chute J,
    7. Rizzieri D,
    8. McPherson J,
    9. Chao N
    : Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients. Biol Blood Marrow Transplant 14: 591-594, 2008.
    OpenUrlPubMed
    1. Koh LP,
    2. Chao NJ
    : Nonmyeloablative allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors: a review. Blood 40: 20-24, 2007.
    OpenUrl
    1. Chao NJ
    : Accidental or intentional exposure to ionizing radiation: Biodosimetry and treatment options. Exp Hematol 35: 24-27, 2007.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Puzova H,
    2. Szabova K,
    3. Cerman SJ,
    4. Puza A,
    5. Kunstadt E,
    6. Zaduban M
    : The problem of autoinfection after total-body lethal irradiation of dogs with 60Co. Folia Biol 8: 298-308, 1962.
    OpenUrl
  18. ↵
    1. Vriesendorp HM,
    2. Chu H,
    3. Ochran TG,
    4. Besa PC,
    5. Champlin RE
    : Radiobiology of total body radiation. Bone Marrow Transplant 14 Suppl: S4-S8, 1994.
    OpenUrlPubMed
  19. ↵
    1. Thomas ED
    : Observations on supralethal whole-body irradiation and marrow transplantation in man and dog. Ann NY Acad Sci 114: 393-402, 1964.
    OpenUrlPubMed
  20. ↵
    1. Thomas ED,
    2. Storb R,
    3. Buckner CD
    : Total-body irradiation in preparation for marrow engraftment. Transplant Proc 8: 591-593, 1976.
    OpenUrlPubMed
    1. Kuna P,
    2. Dostal M,
    3. Petyrek P
    : Effect of chemical radioprotectors and subsequent therapy on the survival of dogs subjected to lethal gamma irradiation. Voen Med Zh 2: 68-69, 1982.
    OpenUrlPubMed
    1. Ladiges WC,
    2. Storb R,
    3. Thomas ED
    : Canine models of bone marrow transplantation. Lab Anim Sci 40: 11-15, 1990.
    OpenUrlPubMed
    1. Deeg HJ,
    2. Seidel K,
    3. Hong DS,
    4. Yu C,
    5. Huss R,
    6. Schuening FG,
    7. Ewel CH,
    8. Storb R
    : In vivo radioprotective effect of AcSDKP on canine myelopoiesis. Ann Hematol 74: 117-122, 1997.
    OpenUrlCrossRefPubMed
    1. Sandmaier BM,
    2. McSweeney P,
    3. Yu C,
    4. Storb R
    : Nonmyeloablative transplants: preclinical and clinical results. Semin Oncol 27: 78-81, 2000.
    OpenUrlPubMed
    1. Panse JP,
    2. Storb R,
    3. Storer B,
    4. Santos EB,
    5. Wentzel C,
    6. Sandmaier BM
    : Prolonged allogeneic marrow engraftment following nonmyeloablative conditioning using 100 cGy total body irradiation and pentostatin before and pharmacological immunosuppression after transplantation. Transplantation 80: 1518-1521, 2005.
    OpenUrlPubMed
  26. ↵
    1. Storb R,
    2. Raff RF,
    3. Graham T,
    4. Appelbaum FR,
    5. Deeg HJ,
    6. Schuening FG,
    7. Sale G,
    8. Seidel K
    : Dose rate-dependent marrow toxicity of TBI in dogs and marrow sparing effect at high dose rate by dose fractionation. Biol Blood Marrow Transplant 5: 155-161, 1999.
    OpenUrlCrossRefPubMed
    1. Zaucha JM,
    2. Yu C,
    3. Mathioudakis G,
    4. Seidel K,
    5. Georges G,
    6. Sale G,
    7. Little MT,
    8. Torok-Storb B,
    9. Storb R
    : Hematopoietic responses to stress conditions in young dogs compared with elderly dogs. Blood 98: 322-327, 2001.
    OpenUrlAbstract/FREE Full Text
    1. Rozhdestvensky L,
    2. Sernichenko A
    : Experimental approach to improving early postirradiation restoration in the hematopoietic system of irradiated canines. J Radiat Res 45: 45-51, 2004.
    OpenUrlPubMed
    1. Kahl C,
    2. Mielcarek M,
    3. Iwata M,
    4. Harkey MA,
    5. Storer B,
    6. Torok-Storb B
    : Radiation dose determines the degree of myeloid engraftment after nonmyeloablative stem cell transplantation. Biol Blood Marrow Transplant 10: 826-833, 2004.
    OpenUrlPubMed
    1. MacVittie TJ,
    2. Farese AM,
    3. Jackson W 3rd
    : Defining the full therapeutic potential of recombinant growth factors in the post radiation-accident environment: the effect of supportive care plus administration of G-CSF. Health Phys 89: 546-555, 2005.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Deeg HJ,
    2. Meyers JD,
    3. Storb R,
    4. Graham TC,
    5. Weiden PL
    : Effect of trimethoprim-sulfamethoxazole on hematological recovery after total-body irradiation and autologous marrow infusion in dogs. Transplantation 28: 243-246, 1979.
    OpenUrlPubMed
  32. ↵
    1. Stone HB,
    2. Coleman CN,
    3. Moulder JE,
    4. Ang KK,
    5. Anscher MS,
    6. Barcellos-Hoff MH,
    7. Dynan WS,
    8. Fike JR,
    9. Grdina DJ,
    10. Greenberger JS,
    11. Hauer-Jensen M,
    12. Hill RP,
    13. Kolesnick RN,
    14. MacVittie TJ,
    15. Marks C,
    16. McBride WH,
    17. Metting N,
    18. Pellmar T,
    19. Purucker M,
    20. Robbins MEC,
    21. Schiestl RH,
    22. Seed TM,
    23. Tomaszewski J,
    24. Travis EL,
    25. Wallner PE,
    26. Wolpert M,
    27. Zaharevitz D
    : Models for evaluating agents intended for the prophylaxis, mitigation, and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003. Rad Res 162: 711-718, 2004.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Greenberger JS
    : Perspectives/opinion ‘Radioprotection’. In Vivo 23: 323-336, 2009.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Epperly MW,
    2. Osipov AN,
    3. Martin I,
    4. Kawai K,
    5. Borisenko GG,
    6. Jefferson M,
    7. Bernarding M,
    8. Greenberger JS,
    9. Kagan VE
    : Ascorbate as a redox-sensor and protector against irradiation-induced oxidative stress in 32D cl 3 hematopoietic cells and subclones overexpressing human manganese superoxide dismutase. Int J Radiat Oncol Biol & Phys 58: 851-861, 2004.
    OpenUrlPubMed
  35. ↵
    1. Epperly MW,
    2. Bernarding M,
    3. Gretton J,
    4. Jefferson M,
    5. Nie S,
    6. Greenberger JS
    : Overexpression of the transgene for manganese superoxide dismutase (MnSOD) in 32D cl 3 cells prevents apoptosis induction by TNF-α, IL-3 withdrawal and ionizing irradiation. Exp Hematol 31: 465-474, 2003.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Jiang J,
    2. Belikova NA,
    3. Xiao J,
    4. Zhao Q,
    5. Greenberger JS,
    6. Wipf P,
    7. Kagan VE
    : A mitochondria-targeted nitroxide/hemi-gramicidin S conjugate protects mouse embryonic cells against γ-irradiation. Int J Radiat Oncol Biol Phys 70: 816-825, 2008.
    OpenUrlPubMed
  37. ↵
    1. Rajagopalan MS,
    2. Gupta K,
    3. Epperly MW,
    4. Franicola D,
    5. Zhang X,
    6. Wang H,
    7. Zhao H,
    8. Tyurin VA,
    9. Pierce JG,
    10. Kagan VE,
    11. Kanai AJ,
    12. Greenberger JS
    : The mitochondrial targeted JP4-039 augments potentially lethal irradiation damage. In Vivo 23: 717-726, 2009.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Chao N
    : Hematopoietic stem cell transplantation. Curr Opin Hematol 11: 373-374, 2004.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Jiang J,
    2. McDonald P,
    3. Dixon TM,
    4. Franicola D,
    5. Zhang X,
    6. Nie S,
    7. Epperly LD,
    8. Kagan VE,
    9. Lazo JS,
    10. Greenberger JS
    : Druggable genome siRNA library screening identifies Glybencamide as a novel radioprotector. Radiat Res 172: 414-422, 2009.
    OpenUrlPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Screening of Antimicrobial Agents for In Vitro Radiation Protection and Mitigation Capacity, Including those Used in Supportive Care Regimens for Bone Marrow Transplant Recipients
MICHAEL W. EPPERLY, DARCY FRANICOLA, DONNA SHIELDS, JEAN-CLAUDE RWIGEMA, BRANDON STONE, XICHEN ZHANG, WILLIAM MCBRIDE, GEORGE GEORGES, PETER WIPF, JOEL S. GREENBERGER
In Vivo Jan 2010, 24 (1) 9-19;
Twitter logo Facebook logo Mendeley logo

Jump to section