Radioprotectors and Mitigators of Radiation-Induced Normal

Radioprotectors and Mitigators of Radiation-Induced Normal

Tissue Injury

D EBORAH C ITRIN ,a A NA P.C OTRIM ,c F UMINORI H YODO ,b B RUC

E J.B AUM ,c M URALI C.K RISHNA ,b

J AMES B.M ITCHELL b a

Radiation Oncology and b Radiation Biology Branches,Center for Cancer Research,National Cancer Institute and c Molecular Physiology and Therapeutics Branch,National Institute of Dental and

Craniofacial Research,National Institutes of Health,Bethesda,Maryland,USA

Key Words.Radioprotector ?Mitigators ?Amifostine ?Tempol

Disclosures:Deborah Citrin:None;Ana P.Cotrim:None;Fuminori Hyodo:None;Bruce J.Baum:None;Murali C.Krishna:None;James B.Mitchell:None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced,objective,and free from commercial bias.No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers.

A BSTRACT

Radiation is used in the treatment of a broad range of ma-lignancies.Exposure of normal tissue to radiation may re-sult in both acute and chronic toxicities that can result in an inability to deliver the intended therapy,a range of symptoms,and a decrease in quality of life.Radioprotec-tors are compounds that are designed to reduce the dam-age in normal tissues caused by radiation.These compounds are often antioxidants and must be present be-fore or at the time of radiation for effectiveness.Other agents,termed mitigators,may be used to minimize toxic-ity even after radiation has been delivered.Herein,we review agents in clinical use or in development as radio-protectors and mitigators of radiation-induced normal tis-sue injury.Few agents are approved for clinical use,but many new compounds show promising results in preclin-ical testing.The Oncologist 2010;15:360–371

I NTRODUCTION

Radiotherapy is commonly used as a component of therapy for a wide range of malignant conditions.It is estimated that half of all cancer patients will receive radiotherapy during the course of their treatment for cancer [1].Radiotherapy is frequently used to achieve local or regional control of ma-lignancies either alone or in combination with other modal-ities such as chemotherapy or surgery.

Irradiation of noncancerous “normal”tissues during the course of therapeutic radiation can result in a range of side effects including self-limited acute toxicities,mild chronic symptoms,or severe organ dysfunction.The likelihood of developing these complications relates to the volume of an organ irradiated,the radiation dose delivered,fractionation of the delivered dose,the delivery of radiation modifiers,and individual radiosensitivity.Efforts to reduce the toxic-ities associated with therapeutic radiation have centered on both technological improvements in radiation delivery and chemical modifiers of radiation injury.

The use of technology to reduce normal tissue toxicity

Correspondence:Deborah Citrin,M.D.,Radiation Oncology Branch,National Cancer Institute,CRC/B2-3500,Bethesda,Maryland 20892,USA.Telephone:301-496-5457;Fax:301-480-5439;e-mail:citrind@https://www.sodocs.net/doc/836059675.html, Received December 30,2008;accepted for publication April 5,2009;available online without subscription through the open access option.?AlphaMed Press 1083-7159/2010/$30.00/0doi:10.1634/theoncologist.2009-S104

T he

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includes techniques such as conformal radiotherapy,inten-sity-modulated radiotherapy,image-guided radiotherapy, and proton radiotherapy.Each of these aims to reduce the volume of normal tissue exposed to high doses of radiation compared with conventional therapies,thus reducing the risk for normal tissue toxicity.Studies of these modalities have shown that better normal tissue dose distributions and side effect profiles can be obtained using these technolo-gies.Although improvements have been realized in this re-gard,normal tissue toxicity remains a limiting factor in the treatment of many diseases with radiation therapy.Based on the intimate relationship between tumors and their nor-mal host tissues and surrounding critical structures and the need to irradiate clinically uninvolved normal tissue mar-gins that are potentially contaminated with microscopic dis-ease,it is anticipated that normal tissue toxicity will remain a concern for therapeutic radiation.

An alternative mechanism to reduce normal tissue tox-icity is the use of radiation modifiers/protectors,agents that when present prior to or shortly after radiation expo-sure alter the response of normal tissues to irradiation. This approach has also been viewed as an attractive coun-termeasure for possible nuclear/radiological terrorism.To be useful in the radiotherapy clinic,radioprotectors should ideally have several characteristics that relate to the ability of the agent to improve the therapeutic ratio.First,the agent should be selective in protecting normal tissues from radio-therapy without protecting tumor tissue,otherwise no ben-efit in the therapeutic index will be realized.Second,the agent should be delivered with relative ease and with min-imal toxicity.Finally,the agent should protect normal tis-sues that are considered sensitive such that acute or late toxicities in these tissues are either dose-limiting or respon-sible for a significant reduction in quality of life(i.e.,mu-cositis,pneumonitis,myelopathy,xerostomia,proctitis, and leukencephalopathy).Although a number of com-pounds have been described that meet most or all of these criteria in preclinical studies or in early clinical trials,only amifostine is currently in clinical use.Herein,we provide a classification of agents that are being evaluated to prevent or treat normal tissue injury,describe the events that occur after radiation that are responsible for the injury to normal tissue,and discuss some agents in development as radiation protectors and radiation mitigators.

C LASSIFICATION OF A GENTS

In general,chemical/biological agents used to alter normal tissue toxicity from radiation can be broadly divided into three categories based on the timing of delivery in relation to radiation:chemical radioprotectors,mitigators,and treat-ment[2].Agents delivered prior to or at the time of irradi-ation with the intent of preventing or reducing damage to normal tissues are termed radioprotectors.Agents delivered at the time of irradiation or after irradiation is complete,but prior to the manifestation of normal tissue toxicity,are de-scribed as mitigators of normal tissue injury.Finally,agents delivered to ameliorate established normal tissue toxicity are considered treatments.There is a growing body of liter-ature describing radioprotection or mitigation with a variety of agents after total body exposures or localized exposures.

A complete and exhaustive review of these agents is outside the scope of this review.Herein,we briefly highlight sev-eral classes of agents that have been described as radiation protectors and mitigators,and attempt to focus on agents with demonstrated or anticipated clinical usefulness for therapeutic radiation exposures.Treatment of established radiation normal tissue injury is outside the scope of this work.

An understanding of the events occurring during and shortly after irradiation of tissues and cells is important to understanding the mechanism of action of radioprotectors and mitigators.Figure1shows the sequence of events in cells and tissues following radiation exposure.Radiation can damage cells/tissues by both direct and indirect actions [3].The term“direct effects”describes radiation directly causing irreparable damage to critical targets within the cell,such as DNA.The term“indirect effects”describes the situation in which radiation interacts with other molecules of the cell that are not critical targets but are close enough to pass on this damage,typically in the form of free radicals. Because mammals are composed of roughly80%water,in-direct effects involve the production of radiolysis products of water,in particular,the hydroxyl free radical,which is a potent oxidant capable of breaking chemical bonds,initiat-ing lipid peroxidation,in the nano-to microsecond time-frame[4].

After DNA damage has occurred,a number of processes occur in the damaged cell,tissue,or organism(Fig.1),in-cluding activation of DNA repair,activation of signal transduction,expression of radiation response genes,stim-ulation of proliferation,and initiation and perpetuation of inflammation.These pathways can be important for cell or tissue recovery after radiation exposure but may also play a role in the development of toxicity.Mitigators of radiation injury may target these pathways to prevent or reduce the expression of toxicity.

Radioprotectors:Reducing Agents/Free

Radical Scavengers

As described above,free radicals are responsible for per-petuating a large amount of the damage cause by ionizing radiation.Therefore,for an agent to protect cells from pri-

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mary free radical damage,the agent needs to be present at the time of radiation and in sufficient concentration to com-pete with radicals produced through radical-scavenging mechanisms.Many radical scavengers and antioxidants ex-ist that can limit the oxidative stress induced by free radi-cals.Superoxide dismutase (SOD),catalase,glutathione peroxidase,and glutathione reductase are a few examples of naturally occurring antioxidants that defend against free radical–mediated damage,where the substrates are specific to each enzyme.General antioxidant defense is also pro-vided by low molecular weight antioxidants,which are hy-drogen atom–donating reducing agents such as ascorbic acid,tocopherols,polyphenols,and thiols such as glutathi-one.In this situation,the oxidants are neutralized by hydro-gen atom donation,resulting in a less reactive or nonreactive product from the original oxidant and a radical product from the antioxidant,which no longer can exert detrimental effects.

Whereas radioprotectors need to have radical-scaveng-ing properties and can also exert general antioxidant activ-ity,all antioxidants cannot afford radioprotection [5].This dichotomy may be a result of the relative reactivity of radi-ation-induced reactive species compared with those gener-ated under conditions of general oxidative stress (i.e.,H 2O 2exposure).Scavenging hydroxyl radicals,such as those formed with radiation-induced damage,may be accom-plished by almost any unsaturated organic molecule or mol-ecule capable of H atom donation.Although hydroxyl radicals can be scavenged with equal efficiency by both ra-

dioprotectors and antioxidants,cellular and in vivo radio-protection is observed only with radioprotectors.This suggests that a secondary species is generated by hydroxyl radicals and is responsible for critical target (i.e.,DNA)damage.This less reactive secondary species may not be scavenged by conventional antioxidants either because they do not accumulate in proximity to the secondary radical or they may not have kinetic reactivity to scavenge them ef-fectively.Thus,thiols such as amifostine and the newly de-veloped nitroxides have sufficient reactivity to efficiently scavenge secondary radicals.Conversely,well-known an-tioxidants such as vitamin C and vitamin E do not act as classic radioprotectors.

Amifostine:A Radioprotector in Use Clinically

Sulfhydryl compounds such as cysteine and cysteamine have long been known to act as radioprotectors via free rad-ical scavenging and H atom donation [6,7].Since the initial description of sulfhydryl/thiol compounds as radioprotec-tors,more effective and less toxic agents have been de-scribed.Perhaps the best known agent in this class is amifostine.Other agents such as N-acetyl-L-cysteine and diethydithiocarbamate have also been described as radio-protectors,although with lower efficacy at equitoxic doses in mice,compared with amifostine [8].

Amifostine is a phosphorothioate that is not taken into cells until it is dephosphorylated by alkaline phosphatase [9].Once dephosphorylated,the agent freely diffuses into cells and can act as a free radical scavenger.Amifostine has

10-6

10-1010-17to 10-13

Time scale (sec)Events Modulation of damage

Energy absorption Excitation, ionization

OH radicals near target (DNA)

Secondary radicals

Any molecule

Radioprotectors Chemical radiation protectors

Thiols, nitroxides Type of intervention

Figure 1.Sequence of events following radiation exposure.The chart is divided into three parts by dashed lines suggesting events and reactions that might be modified by radiation protectors (top),radiation mitigators,and treatment (bottom).

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been shown to concentrate more rapidly in normal tissues than in tumor tissues in studies of tumor-bearing animals [10],which is thought to result from several factors,includ-ing the effects of tumor blood flow,the acidosis of tumors, and the lower expression of alkaline phosphatase.Addi-tional potential mechanisms of protection have been de-scribed,including induction of hypoxia through increased oxygen use[11,12]and condensation of DNA[13].

The radioprotective effects and selective concentration of amifostine into normal tissues led to extensive preclini-cal testing of the drug as a radioprotector and eventually to clinical testing.Amifostine has been evaluated as a radio-protector and chemoprotector in a large number of clinical trials,including a number of phase III trials.Randomized trials of amifostine as a radioprotector have been completed

for patients with squamous cell carcinoma of the head and neck,non-small cell lung cancer,and pelvic malignancies. These trials have included the use of amifostine in the set-ting of radiation and chemoradiation,both in the definitive and adjuvant settings.In these studies,amifostine was eval-uated as a mechanism to prevent or reduce acute and late xerostomia,mucositis,dysphagia,dermatitis,pneumonitis, proctitis,and cystitis.A number of series have also evalu-ated tumor control as an endpoint.Although many trials have been completed,many of the early reported series were small,used dosing schedules that varied markedly from one study to the next,and evaluated a heterogeneous group of patients.

More recently,amifostine was evaluated in additional randomized trials and was found to reduce toxicity when added to radiotherapy[14],leading the American Society of Clinical Oncology(ASCO)to state that amifostine may be considered for the prevention of xerostomia during frac-tionated radiotherapy[15,16].These guidelines state that current data do not support the use of amifostine in the set-ting of chemoradiotherapy,which has become standard therapy in a number of settings,especially in radiotherapy for advanced head and neck malignancies.Additionally,the 2008ASCO guidelines state that the data are insufficient to recommend the use of amifostine to prevent mucositis as-sociated with radiotherapy for head and neck malignancies or esophagitis associated with chemoradiotherapy for non-small cell lung cancer.Concerns about tumor protection and toxicity of the agent have led to controversy regarding the appropriate setting for its use[17].

Nitroxides:Promising Agents in Clinical Development Amifostine is the only radioprotector currently in clinical use.A number of other compounds are in various stages along the pathway of clinical development as radiation pro-tectors.Nitroxides are among the most promising agents for future use as radiation protectors.Although a number of these agents are useful in the laboratory as radiation protec-tors,not all have the requisite characteristics that allow them to be used clinically.We highlight the development of nitroxides as radioprotectors and describe the current status of their clinical development.

Our laboratory has shown that stable nitroxide free rad-icals and their one-electron reduction products,hydroxyl-amines,are recycling antioxidants that protect cells when exposed to oxidative stress,including superoxide and hy-drogen peroxide(Fig.2)[18].Likewise,preclinical studies have shown that the oxidized form of a nitroxide is a radio-protector in both in vitro(cell survival)[19]and in vivo(le-thal total body radiation)[20]models.Although the hydroxylamine exhibits antioxidant activity,it is incapable of protecting against radiation damage[19].The lead com-pound from this class for radioprotection is tempol(4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl).

As with any radioprotector,there is concern that sys-temic administration might protect tumor as well as normal tissue.Therefore,initial preclinical studies focused on top-ical application of tempol with the anticipation that sys-temic levels of the drug would be low and hence not sufficient to protect tumor tissue.Preclinical studies in guinea pigs revealed that topical application was effective at preventing radiation-induced alopecia[21,22].A phase I clinical trial in patients receiving whole-brain radiotherapy suggested that tempol may be effective at preventing radi-ation-induced alopecia with only mild(grade I and II)tox-icity[23].Both the preclinical and clinical studies showed that systemic levels of tempol were negligible following topical application.

Subsequent preclinical studies determined if tempol was capable of radioprotection when administered system-ically.Figure3A shows that tempol protects against radia-tion-induced damage to salivary glands and does not alter Oxidized form

(Nitroxide radical)

Reduced form

(Hydroxylamine)

Reduction

Reoxidation

Oxygen

Reactive oxygen species

Transition metals

N

OH

Reductants

Reactive oxygen species

?Free radical

?Antioxidant (SOD mimic)

?Radioprotector

?MRI contrast agent

?Non-free radical

?Antioxidant

?Nonradioprotector

?MRI Noncontrast

N

?

Figure2.Schematic diagram of nitroxide radical conversion to hydroxylamine and chemical properties associated with both forms.

Abbreviations:MRI,magnetic resonance imaging;SOD, superoxide dismutase.

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tumor growth after irradiation (Fig.3B),suggesting that de-livery of the agent prior to irradiation would not alter tumor control [24].A possible explanation for the apparent differ-ential protection of normal as opposed to tumor tissue is shown in Figure 4.In the oxidized form,tempol is paramag-netic and provides T 1contrast on magnetic resonance im-aging (MRI)[25].Because of this unique property,the active,radioprotective form of tempol can therefore be fol-lowed temporally using MRI.Tumors were grown on the neck region of a mouse that would allow a single MRI slice to include the tumor,salivary gland area,and normal leg

muscle (Fig.4A,4B).As shown in Figure 4C,tempol in-jection resulted in image enhancement,which decreased as a function of time after injection.The decrease in tempol MRI enhancement represents cellular reduction of tempol to the hydroxylamine tempol-H [26],which is nonradiopro-tective.By following the various regions of interest out-lined in Figure 4B,a quantitative temporal assessment of tempol concentration in its radioprotective form in tissue can be determined as shown in Figure 4D.This plot shows that the rate of reduction of tempol is similar for normal muscle and salivary gland tissue;however,it is signifi-cantly faster in tumor tissue.Collectively,the data shown in Figures 3and 4are consistent with the hypothesis that dif-ferential radioprotection resides in a faster reduction to the nonradioprotective hydroxylamine in tumor than in normal tissue [24].

These preclinical findings provide feasibility to eval-uate tempol as a radioprotector in clinical trials for can-cer patients treated with radiation.Coupling MRI with such a trial would permit a novel dimension that could provide extremely important information with respect to the timing of tempol administration and radiation treat-ment.For example,before radiation treatment,a pilot tempol/MRI scan could be conducted to determine the tempol reduction rates in tumor and normal tissues en-compassed in the proposed treatment field.Based on the reduction rates,the optimal timing of tempol administra-tion with respect to radiation treatment to provide selec-tive radioprotection to normal tissues could be determined.What is unique about this approach is that the therapeutic agent in this case (tempol)can be visualized by MRI.There are few therapeutic agents used in cancer management (ex-cluding radiolabeled agents)that can be followed by non-invasive imaging.Before such an approach can be considered for clinical trials,more research is required to determine if tempol reduction rates in tissues change during fractionated radiation https://www.sodocs.net/doc/836059675.html,stly,monitoring the profiles of reduction/oxidation of nitroxide–hydroxyl-amine couples may actually serve as a viable approach to assess the global redox status in tissue using MRI and have potential applications in various disease states resulting from oxidative stress and inflammation.

Other Antioxidants

With the understanding that free radicals perpetuate a sig-nificant amount of the damage caused by ionizing radiation,multiple vitamin antioxidants have been tested as a method to reduce the toxicity of radiotherapy.Antioxidant com-pounds such as glutathione,lipoic acid,and the antioxidant vitamins A,C,and E have been evaluated in this context.A great deal of preclinical and clinical information has been

20

15

10

5

025050075010001250150017502000

Time (days)

T u m o r V o l u m e (m m 3)

Control

TP (i.p.)Control

5 x

6 Gy

TP (i.p.)5 x 6 Gy Placebo Gel 5 x 6 Gy TP Gel 5 x 6 Gy

S a l i v a P r o d u c t i o n (% o f C o n t r o l )

A

B

Figure 3.Mice were exposed to local fractionated radiation treatment to the salivary glands (A)or tumor-bearing leg (B)with and without systemic tempol (TP)administration (275mg/kg given 10minutes prior to each radiation fraction).Note that the same TP dose and timing were used in each study.(A):Saliva production 2months postradiation for mice exposed to 5daily fractions of 6Gy.In addition to sys-temic delivery of TP,mice were also treated topically for 20minutes prior to radiation

with a TP gel formulation.(B):Radiation tumor (SCCVII)regrowth study for local frac-tionated radiation treatment with and without systemic TP administration.Tumors received 5daily fractions (Monday to Friday)of 3Gy.

Adapted from Cotrim AP,Hyodo F,Matsumoto K et al.Differential radiation protection of salivary glands versus tu-mor by Tempol with accompanying tissue assessment of Tem-pol by magnetic resonance imaging.Clin Cancer Res 2007;13:4928–4933,with permission.

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accumulated that describes the effects of combining radio-therapy with antioxidants.In general,the efficacy of these naturally occurring agents as radioprotectors is less than that for the synthetic agents previously described.It is im-portant to briefly review the available literature on the ra-dioprotective abilities of other available antioxidants and to understand the important implications of using these agents during the course of radiotherapy.

One of the major concerns with the use of supplemental nutritive antioxidants or other antioxidants during the course of radiotherapy is the possibility of tumor protection through nonselective free radical scavenging.As described above for agents such as amifostine,selective uptake or ac-tivity in tumor tissue is essential to realize a gain in the ther-apeutic ratio.

A number of trials have been performed with antioxi-dants delivered during the course of radiotherapy,with the goal of reducing normal tissue toxicity,in many instances with promising results.For example,antioxidants have been delivered concurrently during the course of

radiother-

Tempol Injection

A

Transverse Slice (2 mm)

SCC tumor Salivary gland

region Normal arm

Receiver coil

C

00.51 1.522.533.540

2

46810

Time (min)

l n (I n t

e n s i t y c h a n g e % )

Normal Leg Salivary Tumor

D

Normal Leg Salivary Gland Area

or Figure 4.T 1-weighted MRI images using tempol.(A):Schematic diagram of the placement of a tumor-bearing mouse in a res-onator and the MRI slice selected that includes normal muscle tissue,the salivary gland region,and the tumor in the contralateral leg.(B):T 2-weighted MR image of the selected slice before injecting tempol to ensure that the target tissues were in the field of view.(C):T 1-weighted images of the selected slice before injection of tempol and as a function of time after i.v.tempol injection.(D):Tempol reduction rates for the selected regions of interest shown in (B).

Abbreviations:MRI,magnetic resonance imaging;SCC,squamous cell carcinoma.

Adapted from Cotrim AP,Hyodo F,Matsumoto K et al.Differential radiation protection of salivary glands versus tumor by Tempol with accompanying tissue assessment of Tempol by magnetic resonance imaging.Clin Cancer Res 2007;13:4928–4933,with permission.

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apy to reduce xerostomia [27],mucositis [28,29],pulmo-nary fibrosis [30],cystitis [31],and alopecia [32].With this approach of delivering the antioxidants concurrently,tumor protection has been raised as a major concern [33].

Unfortunately,the use of antioxidant vitamins,such as alpha tocopherol and beta carotene,during the course of ra-diotherapy was associated with evidence of poorer tumor control in randomized trials [28,34].The lower toxicity as-sociated with the use of these agents is appealing,but not at the cost of poorer tumor control.These findings reinforce the importance of preclinical testing of radioprotectors to verify a lack of tumor protection.Regardless of the extent of preclinical evidence supporting a lack of tumor protec-tion,clinical trials testing new radioprotectors should care-fully document tumor control.Topical application has been used to minimize the possibility of systemic absorption and interference with tumor response to radiation [32];how-ever,caution is advised because even topical applications for the prevention of mucositis in head and neck cancers have been associated with evidence of poorer tumor control [29].

When discussing antioxidants as radioprotectors,it is worth mentioning the use of SOD as a method to prevent radiotherapy-induced toxicity.Ionizing radiation results in the formation of superoxide radicals that are highly reactive and potentially damaging to cells.SOD is an enzyme that is naturally present in human cells.It catalyzes the conversion of superoxide to oxygen and hydrogen peroxide and func-tions as an antioxidant during normal conditions and after radiation.

Intracellular localization of SOD is critical to its effec-tiveness as an antioxidant;however,SOD is a large protein and does not freely enter into cells.To circumvent this lim-itation,much of the work evaluating SOD as a radioprotec-tor has used gene therapy to increase the levels of SOD in tissues to be irradiated to prevent or decrease radiation-induced mucositis [35],esophagitis [36],pneumonitis [37–39],and fibrosis [40,41]in animal models.Importantly,studies of tumor response after these delivery methods [39]and studies of tumor cell lines expressing various quantities of manganese SOD have been completed and suggest that this therapy does not decrease tumor response to radiation [42].Additional work needs to be completed to determine if these findings can be successfully translated into clinical trials.

Nonantioxidant Radioprotectors

Efforts to reduce early or late toxicities of radiotherapy have led to the development of a number of agents that can be delivered before or at the time of radiotherapy to enhance the survival of critical cell compartments.These agents do

not fit the description of a chemical radioprotector but do prevent radiation-induced cell death and can thus be de-scribed as radioprotectors.

One example of such an agent is the hormone melato-nin.Melatonin is thought to act as an antioxidant itself [43–45],but also acts to increase the expression of antioxidant enzymes such as SOD and glutathione peroxidase [46,47].Radioprotection with melatonin and melatonin analogs has been documented in a number of animal models [48–53].Importantly,melatonin has also been shown to have direct antitumor effects [54]and has been described as a radiation sensitizer for tumors in animal models [55].

The use of melatonin as a radiation sensitizer for tumor cells and as a radioprotector for normal cells was tested clinically in a phase II Radiation Therapy Oncology Group trial [56].In that study,patients were randomized to either morning or nighttime high-dose melatonin during radio-therapy.Melatonin was continued after radiotherapy until progression or until 6months.Although melatonin deliv-ered concurrently with radiation was well tolerated,there was no evidence that the treatment resulted in a longer sur-vival time or better neurologic function than in historical controls.

Targeting signal transduction pathways has also been explored as a mechanism to protect organisms and tis-sues from ionizing radiation.One example of this ap-proach is the use of the polypeptide CBLB502[57],which binds to and activates Toll-like receptor 5(TLR5),which is expressed in enterocytes [58]and intestinal en-dothelial cells [59].Activation of TLR5results in acti-vation of nuclear factor ?B,which is thought to play an important role in the response of the intestine to irradia-tion [60].Delivery of CBLB502prior to and shortly after radiation protected mice and rhesus monkeys from lethal total body irradiation,with evidence of less damage to the intestine and bone marrow [57].Importantly,no ev-idence of tumor protection from irradiation was evident.It is possible that this type of protector could be useful not only for accidental exposures but also for therapeutic radiation,when large areas of intestine or marrow could be considered dose limiting.

Radiation Mitigators

Radiation-induced late normal tissue toxicity is increas-ingly being appreciated as a phenomenon of ongoing changes in tissue after radiation but prior to the manifesta-tion of toxicity.These events include ongoing mitotic cell death and perpetually active cytokine cascades that can lead to vascular damage,tissue hypoxia,and excessive extracel-lular matrix deposition [61].Radiation mitigators aim to interrupt these cascades or intervene to prevent the perpet-

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uation of damage and thus reduce the expression of toxicity. Alternatively,radiation mitigators can be agents delivered during or shortly after exposure to repopulate a critical cell compartment such as the mucosa or bone marrow.In this in-stance,the mitigator is used to prevent acute toxicity.For ra-diologic terrorism and space research,much of the focus of mitigators has been in the field of developing chemopreventa-tives to reduce carcinogenesis of total body exposures.Table1 summarizes several promising radiation mitigators[16,62–82].A few examples are discussed in detail below.

Many cytokines and growth factors are radiation mitigators when used near the time of radiation.These agents stimulate the differentiation of stem cells in bone marrow or the intestine,thus preventing bone marrow failure or gastrointestinal syndrome after total body ex-posure.A number of cytokines and growth factors have been explored as radioprotectors/mitigators.For exam-ple,G-CSF can effectively reduce the lethality of total body radiation exposure by assisting in marrow recovery [83,84].Recently,interest in keratinocyte growth factor (KGF)as a possible mitigator has spurred both preclini-cal studies and clinical trials.

KGF is a growth factor that stimulates a number of cel-lular processes such as differentiation,proliferation,DNA repair,and detoxification of reactive oxygen species[78]. These properties make KGF an attractive method to stimu-late the recovery of mucosa after ionizing radiation.Ac-cordingly,delivery of KGF in animal models prevents radiation-induced xerostomia[79]and mucositis[85].

Palifermin is a recombinant human KGF that is ap-proved for use in decreasing the incidence and duration of severe oral mucositis in patients with hematologic malig-nancies who receive high doses of chemotherapy and radi-ation therapy followed by stem cell rescue.The success of palifermin in patients with mucositis after cytotoxic therapy [86]led to attempts to evaluate its use in patients with head and neck cancers receiving chemoradiotherapy,in whom mucositis can be severe and prolonged.

Evaluation of palifermin in a phase II clinical trial as a method to reduce mucositis in patients receiving radi-

Table1.Representative radiation mitigators

Class Representative

agent(s)Proposed mechanism Use Clinical status[62]

Growth factor Palifermin Stimulates differentiation,proliferation,

DNA repair,and detoxification of

reactive oxygen species[78]Mitigation of mucositis

[16],mitigation of

xerostomia[79]

In use to prevent or reduce

mucositis after transplantation;

ongoing testing with radiation,

chemotherapy,or both to

prevent mucositis

Protease inhibitor Bowman-Birk

proteinase inhibitor DNA repair:increases fidelity of and

stimulates DNA repair[63–65]

Chemopreventative

[66],antifibrotic[67]

Ongoing testing as a

chemopreventative

Dithiolthione Oltipraz Increased nonprotein sulfhydryl in

cells:enhances radiation-inducible

glutathione S-transferase and

microsomal epoxide hydrolase

expression Chemopreventative,

protector against total

body exposures[68]

Ongoing testing as a

chemopreventative

ACE inhibitor Captopril,enalapril,

ramipril Inhibition of angiotensin II production,

suppression of proliferation,inhibition

of nitric oxide synthase,prevention of

radiation-induced TGF-?,suppression

of chronic oxidative stress,suppression

of aldosterone[69]

Prevention of

radiation-induced

nephropathy[70],optic

neuropathy[71],and

pneumonitis[72]

Ongoing and recently completed

clinical trials for prevention of

radiation-induced nephropathy

and pneumonitis;clinical data

available suggesting

stabilization of renal function in

established radiation-induced

nephropathy[69]

Isoflavone Genistein Hematopoietic stem cell quiescence

[69],tyrosine kinase inhibitor[73],

antioxidant Chemopreventative,

protector against total

body exposures[74]

Ongoing testing as a

chemopreventative,direct

anticancer agent,radiation

sensitizer in tumor tissue

Hmg-CoA reductase inhibitors(statins)Simvastatin,pravastatin,

lovastatin

Inhibition of the

Rho/CCN2/extracellular matrix cascade

[75]

Mitigation of radiation

enteropathy[76],

pulmonary fibrosis[77]

Ongoing trials testing as a

mitigator of rectal injury with

radiation,testing as a

chemopreventative

COX2inhibitors/NSAIDs Celecoxib,aspirin,

ibuprofen,Inhibits COX2activity in the setting of

increased COX2expression and

prostaglandin synthesis after radiation

[80]

Radiation sensitizer

[81],

chemopreventative

[82],mitigator of

mucositis

Ongoing trials as a

chemopreventative,ongoing and

completed trials as a radiation

sensitizer for tumors,ongoing

trials for prevention of mucositis

TGF-?signaling inhibitors Halofuginone,1D11,

SM16Inhibits TGF-?signaling that results in

activation of profibrotic pathways

Antifibrotic Ongoing clinical trials in disease

characterized by fibrosis

Abbreviations:ACE,angiotensin-converting enzyme;COX2,cyclooxygenase2;Hmg-CoA,3-hydroxy-3-methyl-glutaryl-coenzyme A;NSAIDs,nonsteroidal anti-inflammatory drugs;TGF,transforming growth factor.367

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ation and chemotherapy for head and neck cancer did not find significantly less mucositis,dysphagia,or xerosto-mia with the agent than with placebo when evaluating the total study population;however,patients who received hyperfractionated radiotherapy had a lower incidence of mucositis and a shorter duration of mucositis [87].A number of methodological problems led investigators to conclude that future studies should employ standardized tools for the assessment of mucositis,increase the dura-tion of assessments to ensure that this period encom-passes the resolution of mucositis in most patients,and use higher doses of palifermin.Because normal mucosa and squamous tumors may express the receptor for KGF,the investigators simultaneously reported the long-term follow-up of survival and progression-free survival out-comes in this study,showing that the delivery of palifer-min did not influence disease control.

Mitigators of late radiation damage frequently target ra-diation fibrosis,a common and potentially debilitating complication of therapeutic radiotherapy.A variety of agents that protect against fibrosis have been evaluated as mitigators of radiation fibrosis.Transforming growth factor (TGF)-?plays a critical role in the development of radia-tion-induced fibrosis.It is therefore not surprising that many of the agents that have been used to prevent the de-velopment of radiation fibrosis directly or indirectly inhibit the TGF-?signaling pathway.

TGF-?receptor inhibition has shown the ability to pre-vent lung fibrosis after radiation exposure in animal models [88,89].An alternative mechanism is the use of halofugi-none,a small molecule that inhibits TGF-?signaling,which has been shown in animal models to inhibit radia-tion-induced fibrosis [90].Many of these agents are inter-esting for possible translation into the clinical setting;however,given the important role of TGF-?in tumor dor-mancy,progression,and metastasis [91],a thorough evalu-ation of tumor protection with these strategies is obviously important to ensure safe clinical translation.

C ONCLUSIONS AN

D F UTUR

E D IRECTIONS

Radiation therapy is frequently used in the definitive man-agement and palliative care of patients with cancer.Treat-ment of tumor tissue inevitably results in the irradiation of surrounding normal tissues.Acute and late radiation-in-duced normal tissue toxicity can have a significant impact on compliance with therapy and quality of life.Technolog-ical advances may result in lower normal tissue exposure,but it is expected that technologic approaches will not com-pletely prevent toxicity in irradiated fields.

The use of compounds to protect normal tissues or min-imize toxicity after damage has occurred may provide the

ability to reduce toxicity for patients treated with radiother-apy and may provide methods to treat individuals exposed to radiation through terrorism.Evidence of efficacy,lack of tumor protection,and acceptable toxicity are all important considerations for developing these agents.Amifostine re-mains the only agent currently in clinical use as a radiopro-tector.A number of other candidate compounds,such as tempol,will be tested in future years as a way to reduce ra-diation-induced normal tissue toxicity and complications.Although prevention of radiation toxicity may provide the best opportunity to minimize impact on quality of life,few radioprotectors are in clinical use and the treatment of radiation injury remains an important mechanism to deal with radiation-induced toxicity.Antifibrotic treatments,such as pentoxyfilline and vitamin E,have shown promise in clin-ical trials.Newer technologies,such as gene therapy,may of-fer the ability to reverse radiation-induced toxicities such as xerostomia [92].Technologic improvements and the develop-ment of radioprotectors,mitigators,and treatments for toxicity are all important areas of research as methods for improving quality of life in patients who have received radiotherapy.

F INAL C OMMENT

The distinguished clinician/scientist who is honored and recognized by this special issue,Dr.Eli Glatstein,is a true champion of translational research.In fact,he was practic-ing translational research long before the term became pop-ular.While Eli never considered himself a bench scientist,he was constantly probing the radiation biology literature for novel approaches to treating cancer.His conviction to translate laboratory findings to clinical trials was influ-enced by two major figures in radiation oncology and biol-ogy,Henry Kaplan and Jack Fowler,under whom Eli trained.Eli often quoted Kaplan,“If you want to treat Hodgkin’s disease you have to think like a Reed Sternberg cell,”emphasizing the need and necessity of understanding the biology to effectively treat the cancer.From Jack Fowler,he acquired two fundamental traits,enthusiasm for research (and life)and the talent for diplomatically and ef-fectively questioning established dogma.Eli does not shy away from addressing tough issues.In thought-provoking editorials over the years on a variety of topics,Eli has es-tablished himself as the conscience of the radiation oncol-ogy community.

Not only is Eli an accomplished experimental radiation oncologist,but he is also a well-rounded oncologist in gen-eral.Eli has participated in and contributed to countless rounds in surgery and medical oncology,positively influ-encing a younger generation of oncologists and crystalliz-ing ideas for future translational studies involving multidisciplinary approaches to cancer treatment.Through-

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out his career,Eli has consistently embraced the concept that an in-depth understanding of the biology of cancer is the correct path toward improving cancer treatment.His support and dedication to this concept is appreciated by all of those who have been fortunate to work with him.

A CKNOWLEDGMENTS

This work was supported by the Intramural Research Pro-gram of the Center for Cancer Research,National Cancer Institute,National Institutes of Health,and the Division of Intramural Research,National Institute of Dental and Craniofacial Research.

A UTHOR C ONTRIBUTIONS

Conception/Design:Deborah Citrin,Ana P.Cotrim,Fuminori Hyodo,Bruce J. Baum,Murali C.Krishna,James B.Mitchell

Manuscript writing:Deborah Citrin,Ana P.Cotrim,Fuminori Hyodo,Bruce J.Baum,Murali C.Krishna,James B.Mitchell

Final approval of manuscript:Deborah Citrin,Ana P.Cotrim,Fuminori Hyodo,Bruce J.Baum,Murali C.Krishna,James B.Mitchell

R EFERENCES

1Ringborg U,Bergqvist D,Brorsson B et al.The Swedish Council on Tech-nology Assessment in Health Care(SBU)systematic overview of radio-therapy for cancer including a prospective survey of radiotherapy practice in Sweden2001—summary and conclusions.Acta Oncol2003;42:357–365.

2Stone HB,Moulder JE,Coleman CN et al.Models for evaluating agents intended for the prophylaxis,mitigation and treatment of radiation injuries.

Report of an NCI Workshop,December3–4,2003.Radiat Res2004;162: 711–728.

3Hall EJ,Giaccia AJ.Radiobiology for the Radiologist,Sixth Edition.Phil-adelphia:Lippincott Williams&Wilkins,2006:5–15.

4von Sonntag C.The Chemical Basis of Radiation Biology.London:Taylor &Francis,1987:31–56.

5Xavier S,Yamada K,Samuni AM et al.Differential protection by nitrox-ides and hydroxylamines to radiation-induced and metal ion-catalyzed ox-idative damage.Biochim Biophys Acta2002;1573:109–120.

6Patt HM,Tyree EB,Straube RL et al.Cysteine protection against X irradi-ation.Science1949;110:213–214.

7Bacq ZM.The amines and particularly cysteamine as protectors against roentgen rays.Acta Radiol1954;41:47–55.

8Landauer MR,Davis HD,Dominitz JA et https://www.sodocs.net/doc/836059675.html,parative behavioral tox-icity of four sulfhydryl radioprotective compounds in mice:WR-2721,cys-teamine,diethyldithiocarbamate,and N-acetylcysteine.Pharmacol Ther 1988;39:97–100.

9Calabro-Jones PM,Fahey RC,Smoluk GD et al.Alkaline phosphatase pro-motes radioprotection and accumulation of WR-1065in V79–171cells in-cubated in medium containing WR-2721.Int J Radiat Biol Relat Stud Phys Chem Med1985;47:23–27.

10Yuhas JM.Active versus passive absorption kinetics as the basis for selec-tive protection of normal tissues by S-2-(3-aminopropylamino)-ethylphos-phorothioic acid.Cancer Res1980;40:1519–1524.

11Purdie JW,Inhaber ER,Schneider H et al.Interaction of cultured mamma-lian cells with WR-2721and its thiol,WR-1065:Implications for mecha-nisms of radioprotection.Int J Radiat Biol Relat Stud Phys Chem Med 1983;43:517–527.

12Glover D,Negendank W,Delivoria-Papadopoulos M et al.Alterations in oxygen transport following WR-2721.Int J Radiat Oncol Biol Phys1984;

10:1565–1568.

13Savoye C,Swenberg C,Hugot S et al.Thiol WR-1065and disulphide WR-33278,two metabolites of the drug ethyol(WR-2721),protect DNA against fast neutron-induced strand breakage.Int J Radiat Biol1997;71:193–202.

14Kouvaris JR,Kouloulias VE,Vlahos LJ.Amifostine:The first selective-target and broad-spectrum radioprotector.The Oncologist2007;12:738–747.15Schuchter LM,Hensley ML,Meropol NJ et al.2002update of recommen-dations for the use of chemotherapy and radiotherapy protectants:Clinical practice guidelines of the American Society of Clinical Oncology.J Clin Oncol2002;20:2895–2903.

16Hensley ML,Hagerty KL,Kewalramani T et al.American Society of Clin-ical Oncology2008clinical practice guideline update:Use of chemother-apy and radiation therapy protectants.J Clin Oncol2009;27:127–145.

17Brizel DM,Overgaard J.Does amifostine have a role in chemoradiation treatment?Lancet Oncol2003;4:378–381.

18Soule BP,Hyodo F,Matsumoto K et al.Therapeutic and clinical applica-tions of nitroxide compounds.Antioxid Redox Signal2007;9:1731–1743.

19Mitchell JB,DeGraff W,Kaufman D et al.Inhibition of oxygen-dependent radiation-induced damage by the nitroxide superoxide dismutase mimic, tempol.Arch Biochem Biophys1991;289:62–70.

20Hahn SM,Tochner Z,Krishna CM et al.Tempol,a stable free radical,is a novel murine radiation protector.Cancer Res1992;52:1750–1753.

21Cuscela D,Coffin D,Lupton GP et al.Protection from radiation-induced alopecia with topical application of nitroxides:Fractionated studies.Cancer J Sci Am1996;2:273–278.

22Goffman T,Cuscela D,Glass J et al.Topical application of nitroxide pro-tects radiation-induced alopecia in guinea pigs.Int J Radiat Oncol Biol Phys1992;22:803–806.

23Metz JM,Smith D,Mick R et al.A phase I study of topical Tempol for the prevention of alopecia induced by whole brain radiotherapy.Clin Cancer Res2004;10:6411–6417.

24Cotrim AP,Hyodo F,Matsumoto K et al.Differential radiation protection of salivary glands versus tumor by Tempol with accompanying tissue as-sessment of Tempol by magnetic resonance imaging.Clin Cancer Res 2007;13:4928–4933.

25Matsumoto K,Hyodo F,Matsumoto A et al.High-resolution mapping of tumor redox status by magnetic resonance imaging using nitroxides as re-dox-sensitive contrast agents.Clin Cancer Res2006;12:2455–2462.

26Hyodo F,Matsumoto K,Matsumoto A et al.Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive con-trast agents.Cancer Res2006;66:9921–9928.

27Chitra S,Shyamala Devi CS.Effects of radiation and alpha-tocopherol on saliva flow rate,amylase activity,total protein and electrolyte levels in oral cavity cancer.Indian J Dent Res2008;19:213–218.

28Bairati I,Meyer F,Gélinas M et al.Randomized trial of antioxidant vita-mins to prevent acute adverse effects of radiation therapy in head and neck cancer patients.J Clin Oncol2005;23:5805–5813.

29Ferreira PR,Fleck JF,Diehl A et al.Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis:A double-blind random-ized trial.Head Neck2004;26:313–321.

30Misirlioglu CH,Demirkasimoglu T,Kucukplakci B et al.Pentoxifylline

369

Citrin,Cotrim,Hyodo et al.

https://www.sodocs.net/doc/836059675.html, at The Medical Library of the Chinese PLA on November 19, 2010 https://www.sodocs.net/doc/836059675.html, Downloaded from

and alpha-tocopherol in prevention of radiation-induced lung toxicity in pa-tients with lung cancer.Med Oncol 2007;24:308–311.

31Sanchiz F,Milla A,Artola N et al.Prevention of radioinduced cystitis by

orgotein:A randomized study.Anticancer Res 1996;16:2025–2028.32Halperin EC,Gaspar L,George S et al.A double-blind,randomized,pro-spective trial to evaluate topical vitamin C solution for the prevention of radiation https://www.sodocs.net/doc/836059675.html,S Cancer Consortium.Int J Radiat Oncol Biol Phys 1993;26:413–416.33Camphausen K,Citrin D,Krishna MC et al.Implications for tumor control

during protection of normal tissues with antioxidants.J Clin Oncol 2005;23:5455–5457.34Meyer F,Bairati I,Fortin A et al.Interaction between antioxidant vitamin

supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality:A randomized trial among head and neck cancer patients.Int J Cancer 2008;122:1679–1683.35Guo H,Seixas-Silva JA Jr,Epperly MW et al.Prevention of radiation-induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (SOD2)transgene.Radiat Res 2003;159:361–370.36Stickle RL,Epperly MW,Klein E et al.Prevention of irradiation-induced

esophagitis by plasmid/liposome delivery of the human manganese super-oxide dismutase transgene.Radiat Oncol Investig 1999;7:204–217.37Epperly MW,Bray JA,Krager S et al.Intratracheal injection of adenovirus

containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis.Int J Radiat Oncol Biol Phys 1999;43:169–181.38Epperly MW,Travis EL,Sikora C et al.Manganese [correction of Magne-sium]superoxide dismutase (MnSOD)plasmid/liposome pulmonary radio-protective gene therapy:Modulation of irradiation-induced mRNA for IL-I,TNF-alpha,and TGF-beta correlates with delay of organizing alveolitis/fibrosis.Biol Blood Marrow Transplant 1999;5:204–214.39Epperly MW,Defilippi S,Sikora C et al.Intratracheal injection of manga-nese superoxide dismutase (MnSOD)plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation.Gene Ther 2000;7:1011–1018.40Delanian S,Baillet F,Huart J et al.Successful treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide dismutase:Clinical trial.Radiother Oncol 1994;32:12–20.41Lefaix JL,Delanian S,Leplat JJ et al.Successful treatment of radiation-induced fibrosis using Cu/Zn-SOD and Mn-SOD:An experimental study.Int J Radiat Oncol Biol Phys 1996;35:305–312.42Urano M,Kuroda M,Reynolds R et al.Expression of manganese superox-ide dismutase reduces tumor control radiation dose:Gene-radiotherapy.Cancer Res 1995;55:2490–2493.43Reiter RJ,Tan DX,Burkhardt S.Reactive oxygen and nitrogen species and

cellular and organismal decline:Amelioration with melatonin.Mech Age-ing Dev 2002;123:1007–1019.44Reiter RJ,Tan DX,Manchester LC et al.Melatonin:Detoxification of ox-ygen and nitrogen-based toxic reactants.Adv Exp Med Biol 2003;527:539–548.45Lopez-Burillo S,Tan DX,Mayo JC et al.Melatonin,xanthurenic acid,res-veratrol,EGCG,vitamin C and alpha-lipoic acid differentially reduce oxi-dative DNA damage induced by Fenton reagents:A study of their individual and synergistic actions.J Pineal Res 2003;34:269–277.46Kaya H,Delibas N,Serteser M et al.The effect of melatonin on lipid per-oxidation during radiotherapy in female rats.Strahlenther Onkol 1999;175:285–288.

47Okatani Y,Wakatsuki A,Shinohara K et al.Melatonin stimulates glutathi-one peroxidase activity in human chorion.J Pineal Res 2001;30:199–205.48Blickenstaff RT,Brandstadter SM,Reddy S et al.Potential radioprotective

agents.1.Homologs of melatonin.J Pharm Sci 1994;83:216–218.49Vijayalaxmi,Meltz ML,Reiter RJ et al.Melatonin and protection from

whole-body irradiation:Survival studies in mice.Mutat Res 1999;425:21–27.50Topkan E,Tufan H,Yavuz AA et https://www.sodocs.net/doc/836059675.html,parison of the protective effects

of melatonin and amifostine on radiation-induced epiphyseal injury.Int J Radiat Biol 2008;84:796–802.51Manda K,Ueno M,Anzai K.Cranial irradiation-induced inhibition of neu-rogenesis in hippocampal dentate gyrus of adult mice:Attenuation by mel-atonin pretreatment.J Pineal Res 2009;46:71–78.52Hussein MR,Abu-Dief EE,Kamel E et al.Melatonin and roentgen irradi-ation-induced acute radiation enteritis in Albino rats:An animal model.Cell Biol Int 2008;32:1353–1361.53Manda K,Anzai K,Kumari S et al.Melatonin attenuates radiation-induced

learning deficit and brain oxidative stress in mice.Acta Neurobiol Exp (Wars)2007;67:63–70.54Akagi T,Ushinohama K,Ikesue S et al.Chronopharmacology of melatonin

in mice to maximize the antitumor effect and minimize the rhythm distur-bance effect.J Pharmacol Exp Ther 2004;308:378–384.55Blask DE,Barthold HJ,Dauchy RT et al.Melatonin radiosensitizes tumors

and radioprotects normal tissues:Time-of day dependency.Am Assoc Can-cer Res 2000;Abstract 338.56Berk L,Berkey B,Rich T et al.Randomized phase II trial of high-dose mel-atonin and radiation therapy for RPA class 2patients with brain metastases (RTOG 0119).Int J Radiat Oncol Biol Phys 2007;68:852–857.57Burdelya LG,Krivokrysenko VI,Tallant TC et al.An agonist of Toll-like

receptor 5has radioprotective activity in mouse and primate models.Sci-ence 2008;320:226–230.58Uematsu S,Jang MH,Chevrier N et al.Detection of pathogenic intestinal

bacteria by Toll-like receptor 5on intestinal CD11c ?lamina propria cells.Nat Immunol 2006;7:868–874.59Maaser C,Heidemann J,von Eiff C et al.Human intestinal microvascular

endothelial cells express Toll-like receptor 5:A binding partner for bacte-rial flagellin.J Immunol 2004;172:5056–5062.60Wang Y,Meng A,Lang H et al.Activation of nuclear factor kappaB in vivo

selectively protects the murine small intestine against ionizing radiation-induced damage.Cancer Res 2004;64:6240–6246.61Bentzen SM.Preventing or reducing late side effects of radiation therapy:

Radiobiology meets molecular pathology.Nat Rev Cancer 2006;6:702–https://www.sodocs.net/doc/836059675.html,.Vol 2008.Accessed January 12,2009.

63Dittmann KH,Gueven N,Mayer C et al.The radioprotective effect of BBI

is associated with the activation of DNA repair-relevant genes.Int J Radiat Biol 1998;74:225–230.64Dittmann K,Virsik-K?pp P,Mayer C et al.Bowman-Birk protease inhib-itor activates DNA-dependent protein kinase and reduces formation of ra-diation-induced dicentric chromosomes.Int J Radiat Biol 2003;79:801–808.65Dittmann K,Mayer C,Kehlbach R et al.The radioprotector Bowman-Birk

proteinase inhibitor stimulates DNA repair via epidermal growth factor re-ceptor phosphorylation and nuclear transport.Radiother Oncol 2008;86:375–382.66Kennedy AR,Davis JG,Carlton W et al.Effects of dietary antioxidant sup-plementation on the development of malignant lymphoma and other neo-

370

Radiation-Induced Normal Tissue

Injury

at The Medical Library of the Chinese PLA on November 19, 2010

https://www.sodocs.net/doc/836059675.html, Downloaded from

plastic lesions in mice exposed to proton or iron-ion radiation.Radiat Res 2008;169:615–625.

67Dittmann K,Toulany M,Classen J et al.Selective radioprotection of nor-mal tissues by Bowman-Birk proteinase inhibitor(BBI)in mice.Strahlen-ther Onkol2005;181:191–196.

68Kim SG,Nam SY,Kim CW.In vivo radioprotective effects of oltipraz in gamma-irradiated mice.Biochem Pharmacol1998;55:1585–1590.

69Moulder JE,Cohen EP.Future strategies for mitigation and treatment of chronic radiation-induced normal tissue injury.Semin Radiat Oncol2007;

17:141–148.

70Moulder JE,Fish BL,Cohen EP et al.Angiotensin II receptor antagonists in the prevention of radiation nephropathy.Radiat Res1996;146:106–110.

71Kim JH,Brown SL,Kolozsvary A et al.Modification of radiation injury by ramipril,inhibitor of angiotensin-converting enzyme,on optic neuropathy in the rat.Radiat Res2004;161:137–142.

72Ward WF,Molteni A,Ts’ao CH et al.Radiation pneumotoxicity in rats: Modification by inhibitors of angiotensin converting enzyme.Int J Radiat Oncol Biol Phys1992;22:623–625.

73Yousefi S,Green DR,Blaser K et al.Protein-tyrosine phosphorylation reg-ulates apoptosis in human eosinophils and neutrophils.Proc Natl Acad Sci U S A1994;91:10868–10872.

74Landauer MR,Srinivasan V,Seed TM.Genistein treatment protects mice from ionizing radiation injury.J Appl Toxicol2003;23:379–385.

75Haydont V,Bourgier C,Pocard M et al.Pravastatin inhibits the Rho/CCN2/ extracellular matrix cascade in human fibrosis explants and improves radi-ation-induced intestinal fibrosis in rats.Clin Cancer Res2007;13:5331–5340.

76Wang J,Boerma M,Fu Q et al.Simvastatin ameliorates radiation enterop-athy development after localized,fractionated irradiation by a protein C-independent mechanism.Int J Radiat Oncol Biol Phys2007;68:1483–1490.

77Williams JP,Hernady E,Johnston CJ et al.Effect of administration of lo-vastatin on the development of late pulmonary effects after whole-lung ir-radiation in a murine model.Radiat Res2004;161:560–567.

78Finch PW,Rubin JS.Keratinocyte growth factor/fibroblast growth factor7,

a homeostatic factor with therapeutic potential for epithelial protection and

repair.Adv Cancer Res2004;91:69–136.

79Lombaert IM,Brunsting JF,Wierenga PK et al.Keratinocyte growth factor

prevents radiation damage to salivary glands by expansion of the stem/ progenitor pool.S TEM C ELLS2008;26:2595–2601.

80Yeoh A,Gibson R,Yeoh E et al.Radiation therapy-induced mucositis:Re-lationships between fractionated radiation,NF-kappaB,COX-1,and COX-2.Cancer Treat Rev2006;32:645–651.

81Sminia P,Kuipers G,Geldof A et al.COX-2inhibitors act as radiosensitizer in tumor treatment.Biomed Pharmacother2005;59(suppl2):S272–S275. 82Guadagni F,Ferroni P,Palmirotta R et al.Non-steroidal anti-inflammatory drugs in cancer prevention and therapy.Anticancer Res2007;27:3147–3162.

83Bertho JM,Frick J,Prat M et https://www.sodocs.net/doc/836059675.html,parison of autologous cell therapy and granulocyte-colony stimulating factor(G-CSF)injection vs.G-CSF injec-tion alone for the treatment of acute radiation syndrome in a non-human primate model.Int J Radiat Oncol Biol Phys2005;63:911–920.

84Uckun FM,Souza L,Waddick KG et al.In vivo radioprotective effects of recombinant human granulocyte colony-stimulating factor in lethally irra-diated mice.Blood1990;75:638–645.

85Farrell CL,Rex KL,Kaufman SA et al.Effects of keratinocyte growth fac-tor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice.Int J Radiat Biol1999;75:609–620.

86Spielberger R,Stiff P,Bensinger W et al.Palifermin for oral mucositis after intensive therapy for hematologic cancers.N Engl J Med2004;351:2590–2598.

87Brizel DM,Murphy BA,Rosenthal DI et al.Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma.

J Clin Oncol2008;26:2489–2496.

88Anscher MS,Thrasher B,Zgonjanin L et al.Small molecular inhibitor of transforming growth factor-beta protects against development of radiation-induced lung injury.Int J Radiat Oncol Biol Phys2008;71:829–837.

89Anscher MS,Thrasher B,Rabbani Z et al.Antitransforming growth factor-beta antibody1D11ameliorates normal tissue damage caused by high-dose radiation.Int J Radiat Oncol Biol Phys2006;65:876–881.

90Xavier S,Piek E,Fujii M et al.Amelioration of radiation-induced fibrosis: Inhibition of transforming growth factor-beta signaling by halofuginone.

J Biol Chem2004;279:15167–15176.

91MassaguéJ.TGF?in cancer.Cell2008;134:215–230.

92Baum BJ,Zheng C,Cotrim AP et al.Transfer of the AQP1cDNA for the correction of radiation-induced salivary hypofunction.Biochim Biophys Acta2006;1758:1071–1077.

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DOI: 10.1634/theoncologist.2009-S104

2010;15;360-371

Oncologist and James B. Mitchell Deborah Citrin, Ana P. Cotrim, Fuminori Hyodo, Bruce J. Baum, Murali C. Krishna

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