Radioprotectors and Chemoprotectors in the Management of Lung 123 2.2.6 Radioprotectors and Chemoprotectors in the Management of Lung Cancer

Ritsuko Komaki, Joe Chang, Zhongxing Liao, James D. Cox, K. A. Mason, and Luka Milas

CONTENTS Gov 2002). However, adding cytotoxic drugs to ra- diotherapy considerably improves treatment outcome, 2.2.6.1 Introduction 123 so that the combination of chemotherapy with radio- 2.2.6.2 Thiols as Radioprotective Agents 124 2.2.6.2.1 Amifostine: Preclinical Findings 124 therapy has currently become a common practice in 2.2.6.2.2 Amifostine: Clinical Studies 126 the treatment of advanced lung cancer. The addition 2.2.6.3 Prostanoids, COX-2, and COX-2 Inhibitors 128 of chemotherapy to radiotherapy has two principal 2.2.6.4 Growth Factors and Cytokines 129 objectives, to increase the chance of local tumor con- 2.2.6.5 Pentoxifylline 130 trol and to eliminate metastatic disease outside of the 2.2.6.6 Angiotensin Converting Enzyme (ACE) Inhibitors 130 radiation fi eld. The former can be achieved by reduc- 2.2.6.7 Radioprotective Gene Therapy: Superoxide ing burden in tumors undergoing radiotherapy Dismutase (SOD) 131 or by interfering with tumor cell radioresistance fac- 2.2.6.8 Concluding Remarks 131 tors, thereby rendering tumor cells more susceptible References 132 to destruction by radiation. Factors which contribute to tumor radioresistance include the failure of tumor cells to undergo after radiation, the cells’ 2.2.6.1 ability to effi ciently repair DNA damage, continued cell Introduction proliferation during the course of radiotherapy, cell radioresistance secondary to hypoxia that commonly Lung cancer is the leading cause of cancer death in most develops in solid tumors, and the presence in tumor developed countries. Almost one million new cases of cells of various abnormal molecular structures or dys- lung cancer occur worldwide each year (Jemal et al. regulated processes linked to cellular radioresistance 2004), and the prognosis remains poor with an overall (Milas et al. 2003a). survival at 5 years of only 15% (Jemal et al. 2004). Addition of induction (neoadjuvant) chemotherapy Between 70% and 85% of all cases are histologically to radiotherapy results in an increase in median sur- classifi ed as non-small cell lung carcinoma (NSCLC), vival time by approximately 4 months, and the overall comprised of squamous cell, adenocarcinoma, large survival rates at 2 years range from 10% to 15% (NCI cell, or undifferentiated histology, while the remaining 2002; Milas et al. 2003a,b; Dillman et al. 1990; belong to small cell histology (Jemal et al. 2004). At LeChevalier et al. 1991). These therapeutic gains the time of diagnosis the majority of patients present have been improved by using concurrent chemoradio- with locally advanced disease and many of them have therapy, i.e., by administering cytotoxic drugs during overt metastatic dissemination. has the course of radiation treatment (NCI 2002; Milas traditionally been the treatment of choice for locally et al. 2003a; Komaki et al. 2002a,b; Schaake-Koning advanced disease but has provided limited benefi ts et al. 1992; Curran et al. 2003). This combined treat- both in terms of local tumor control and patient sur- ment approach results in median survival times of vival, with 2- to 5-year survival commonly not ex- 13–14 months, and in survival rates at 5 years as high as ceeding 10% (National Cancer Institute Cancer 15%–20%. These improvements have been achieved by using standard chemotherapeutic agents, primarily cis- R. Komaki, MD, Professor of Radiation , Gloria platin-based drug combinations. Since direct compari- Lupton Tennison Endowed Professor for Lung Cancer Research son trials between induction and concurrent chemo- J. Chang, MD, PhD; Z. Liao, MD; J. D. Cox; MD, K. A. Mason, Milas radiotherapy have clearly demonstrated therapeutic MSc; L. , MD, PhD Schaake Koning Department of Radiation Oncology, The University of Texas, superiority of the latter approach ( - et M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, al. 1992; Curran et al. 2003), concurrent chemoradio- Houston, TX 77030, USA therapy can be regarded as the current standard of care 124 R. Komaki et al. for local-regionally advanced lung cancer. Still, the poor with a sulfhydryl, –SH, group at one terminus and a overall survival of lung cancer patients necessitates the strong basic function, an amino group, at the other introduction of treatment strategies that would further terminus. Some of the important radioprotective thi- improve local tumor control, patient survival rate, and ols are listed in Table 2.2.6.1. The general structure of quality of . these aminothiols is H2 N(CH2) x NH(CH2) y SH, and Many factors, known and unknown, limit thera- among them, phosphorothioates (such as WR 2721, peutic success of radiotherapy or chemoradiotherapy WR-3689, WR-151327) are the most effective and for lung cancer, with one major factor being the level least toxic (Murray and McBride 1996). Various of tolerance of normal tissues to the damage by these mechanisms have been proposed for the thiol-medi- agents. Toxicities associated with chemotherapy and ated of normal tissues. Thiols radiotherapy may limit the dose and duration of the (RSH) and their anions (RS-) rapidly bind to free treatment, adversely affect both short and long-term radicals such as OH and prevent them from reacting patient quality of life, be life-threatening, and increase with cellular DNA. This type of protection from DNA costs of patient care. Normal tissue toxicities are more damage by scavenging free radicals is oxygen depen- common and more serious after chemoradiotherapy dent (Travis 1984). Another mode of protection oc- than radiotherapy alone, and may be particularly ex- curs via H-atom donation (the fi xation-repair model). cessive in concurrent chemoradiotherapy. Because of Thiols compete with oxygen for radiation-induced the increased toxicity, the dose of chemotherapeutic DNA radicals. DNA radicals are “fi xed” (not repaired) agents in the setting of concurrent chemoradiotherapy by reacting with oxygen and potentially harmful hy- is signifi cantly reduced, which may lower drugs’ ability droxyperoxides may be generated. However, DNA to exert their effects on both local-regional tumor and radicals can be chemically repaired when they react disseminated disease. with thiols by donation of hydrogen (Durand 1983). Because normal tissue toxicity is a major barrier to Furthermore, intracellular oxygen can be depleted radiotherapy and chemoradiotherapy of lung cancer, ev- as a result of thiol oxidation (Durand and Olive ery effort must be taken to avert or minimize the injury 1989) that would decrease the rate of oxygen-me- to critical normal tissues or other side effects of these diated DNA damage fi xation. Finally, thiols induce treatments. Improvements are being sought primarily DNA packaging that may decrease accessibility of through better delivery of radiation therapy or the use of DNA sites to radiolytic attack. This mechanism may chemical or biological radio- or chemoprotective agents. be oxygen independent and may explain the protec- Technical improvements in radiotherapy include three- tion from densely such as neutrons dimensional treatment planning, conformational radio- (Savoye et al. 1997). therapy, or the use of protons. These normal tissue spar- ing strategies may allow administration of higher doses of radiation, chemotherapeutic drugs, or both, directed 2.2.6.2.1 towards achieving superior treatment outcome. Amifostine: Preclinical Findings This chapter overviews a selection of relevant pre- clinical fi ndings and limited clinical data on the use Amifostine (Ethyol) is a thiol-containing compound of radio- and chemo-protective agents to prevent or that has long been recognized for its strong radioprotec- reduce injury to normal tissues that limit radiother- tive properties and has already been used in clinical tri- apy of lung cancer. We particularly focused our dis- als (Brizel 2003). Amifostine does not readily cross the cussion on protection with amifostine, and presented cell membrane because of its hydrophilicity. The drug is the results of our recent clinical trial. Additional in- rapidly dephosphorylated to its active metabolite WR- formation can be found in other reviews on this topic 1065 and cleared from plasma with a half-life of 1–3 min (Murray and McBride 1996; Nieder et al. 2003). following iv administration (Shaw et al. 1999a). In con- trast to its brief systemic half-life, there is prolonged retention of the drug in normal tissues (Yuhas 1980). In the fi rst 30 min following administration, drug uptake 2.2.6.2 into normal tissues such as salivary gland, liver, kidney, Thiols as Radioprotective Agents heart, and has been demonstrated to be up to 100-fold greater than in tumor tissues (Yuhas Both preclinical and clinical investigations on chemi- 1980). Bio-distribution studies show that the highest cal protectors in radiotherapy have been dominated tissue levels of amifostine and its metabolites are found by thiols. The most effective compounds have those in salivary glands (Rasey et al. 1986). Radioprotectors and Chemoprotectors in the Management of Lung Cancer 125

Table 2.2.6.1. Radioprotective thiols and phosphorothioates. [Reprinted from Kirk-Othmer (1996), with permission]

CAS Register Compound Number Structure

Thiols Dithiothreitol (DTT) [27565-41-9] HSCH2CH(OH)CH(OH)CH2SH 2-Mercaptoethanol (WR-15504) [60-24-2] HOCH2CH2SH Cysteamine (MEA, WR-347) [156-57-0] H2NCH2CH2SH 2-((Aminopropyl)amino)ethanethiol [31098-42-7] H2N(CH3)2NHCH2CH2SH (WR-1065) WR-255591 [117062-90-5] CH3NH(CH2)3NHCH2CH2SH WR-151326 [120119-18-8] CH3NH(CH2)3NH(CH2)3SH Phosphorothioates WR-638 [3724-89-8] H2NCH2CH2SPO3H2 WR-2721 [20537-88-6] H2N(CH2)3NHCH2CH2SPO3H2 WR-3689 [20751-90-0] CH3NH(CH2)3NHCH2CH2SPO3H2 WR-151327 [82147-31-7] CH3NH(CH2)3NH(CH2)3SPO3H2

WR, Walter Reed Army Institute of Research.

During the 1970s and 1980s extensive animal stud- bone marrow (Murray and McBride 1996; Milas ies explored the ability of amifostine to protect a vari- et al. 1988). The degree of radioprotection was de- ety of normal tissues against acute and late radiation pendent on the drug dose and time of administration injury and whether the drug improves therapeutic in relation to radiation exposure. In general, higher ratio of radiotherapy. A radioprotective effect was ob- doses of amifostine produced better protection up to served for acute injury of the bone marrow, esopha- a maximum dose of about 400 mg/kg (Murray and gus, jejunum, colon, hair follicles, testis, and immune McBride 1996; Milas et al. 1982, 1988) Maximum system (Murray and McBride 1996; Milas et al. radioprotection was achieved when amifostine was 1988). Amifostine was also a potent radioprotec- given 10–30 min before radiotherapy (Murray and tor of late responding tissues such as lung and sub- McBride 1996; Milas et al. 1982, 1988). In addi- cutaneous tissues (Milas et al. 1988; Travis et al. tion to normal tissue radioprotection, a number of 1985; Vujaskovic et al. 2002a,b; Lockhart 1990; studies have examined whether amifostine protects Hunter and Milas 1983). Protection of the lung tumors as well. Although some studies documented was achieved against both single and fractionated a small degree of tumor radioprotection, primarily of radiation, and was assessed by biochemical testing microscopic tumor foci, most studies showed no tu- such as reduction in hydroxyproline content of lung mor protection (Murray and McBride 1996; Milas tissue and functional assays such as breathing fre- et al. 1982, 1988; Wasserman et al. 1981). Therefore, quency (Travis et al. 1985; Vujaskovic et al. 2002a). preclinical studies support the notion of selective or Amifostine treatment was associated with reduction preferential normal tissue protection resulting in in- in accumulation of macrophages in irradiated lung creased therapeutic gain of radiotherapy. and profi brogenic cytokine activity (Vujaskovic et The mechanism of amifostine’s selective or pref- al. 2002b). Interestingly, while systemic application erential protection of normal tissues is related to of amifostine was radioprotective for the lung tissue several factors. Amifostine undergoes preferential (Travis et al. 1985; Vujaskovic et al. 2002a,b), in- rapid uptake into normal tissues but negligible or haled amifostine was ineffective (Lockhart 1990). slower uptake into tumor tissues. While normal tis- In contrast to the near universal protection of acutely sues actively concentrate amifostine against the con- responding tissues and lung, amifostine was not ef- centration gradient, solid tumors generally absorb fective in protecting brain from radiation injury, amifostine passively (Yuhas 1980). This selectivity which was attributed to the inability of the hydro- results, in part, from differences in pH and alkaline phyllic drug to cross the blood–brain barrier (Utley phosphatase at the level of the capillary endothelium, et al. 1984). Wide variation in the degree of radiopro- both being higher in normal tissues compared to tu- tection existed among various tissues, with protec- mors (Yuhas 1980; Rasey et al. 1985, 1986). The tion factors for murine normal tissues ranging from acidic tumor microenvironment inhibits alkaline 1.2 for hair follicles to greater than 2 for jejunum and phosphatase necessary for uptake and conversion 126 R. Komaki et al. of amifostine to the active protective thiol, WR-1065 apy in patients with locally advanced lung cancer. The (Calabro-Jones et al. 1985), a condition absent in results showed that amifostine signifi cantly reduced normal tissues. Once inside the cell, WR-1065 acts as radiation-induced pneumonitis (>= grade 3 from a scavenger of oxygen free radicals (Ohnishi et al. 56.3% to 19.4%, p<0.002), and esophagitis (>= grade 3 1992), which is reduced under hypoxic conditions from 84.4% to 38.9%, p<0.001) without compromising commonly present in solid tumors. In addition, ami- antitumor effi cacy (Antonadou et al. 2003). Movsas fostine may be less available to tumors because of et al. (2003) recently reported preliminary results of a their defective vascular network. phase III RTOG 98-01 trial in which 243 patients with Overall, a large body of preclinical data shows that stage II-IIIA/B NSCLC were treated with induction amifostine preferentially protects the majority of chemotherapy (paclitaxel and carboplatin) followed normal tissues, including the lung, from the effects by concurrent chemotherapy and hyperfractionated of DNA damaging agents, such as radiation. In ad- radiotherapy (69.6 Gy with 1.2 Gy/fraction, BID). dition to interaction with radiation, amifostine has Patients were randomized to receive amifostine i.v. been shown to exert independent antimetastatic 500 mg four times/week between the BID radiother- and antiangiogenic activity (Grdina et al. 2002; apy or no amifostine treatment. Although amifostine Giannopoulou and Papadimitriou 2003). Thus, did not signifi cantly reduce grade 3 or higher esopha- these preclinical data provide a strong rationale for gitis, both weight loss from baseline and swallowing the clinical development of combined modality can- dysfunction were lower in the amifostine group. cer treatment with amifostine and radiotherapy. At MDACC we investigated the ability of amifostine to reduce the severity and/or incidence of acute toxici- ties of concurrent chemotherapy and radiation ther- 2.2.6.2.2 apy for NSCLC (Komaki et al. 2002a, 2004). A total of Amifostine: Clinical Studies 64 patients with inoperable stage II or III NSCLC were treated with concurrent chemoradiotherapy. Both Clinical trials with amifostine began in the 1980s and groups received thoracic radiation therapy (TRT) with showed that the drug is generally well tolerated. Its ad- 1.2 Gy/fraction, 2 fractions per day, 5 days per week for ministration is associated with a number of transient a total dose 69.6 Gy. All patients received oral etoposide side effects including nausea, vomiting, sneezing, mild (VP-16), 50 mg Bid, 30 min before TRT beginning day 1 somnolence, hypotension, a metallic taste during infu- for 10 days, repeated on day 29, and cisplatin 50 mg/m2 sion, and occasional allergic reactions (Kligerman et iv on days 1, 8, 29, and 36. Patients in the study group al. 1988; Schuchter and Glick 1993). Hypotension received amifostine, 500 mg iv, twice weekly before appeared to be the most clinically signifi cant side ef- chemoradiation (arm 1); patients in the control group fect that could curtail treatment. A number of trials received chemoradiation without amifostine (arm 2). showed that amifostine reduces the severity of toxicity Patient and tumor characteristics were distributed of radiotherapy or chemotherapy (Kligerman et al. equally in both groups. Of the 64 patients enrolled, 62 1988; Brizel et al. 2000; Kemp et al. 1996). Brizel were evaluable (31 in arm 1, 31 in arm 2) with a mini- et al. (2000) reported a randomized trial showing that mum follow-up of 24 months. Important fi ndings from amifostine reduces both severity and duration of xero- this study on the incidence and severity of a number stomia in head and neck cancer patients treated with of chemoradiotherapy-induced toxicities are shown radiotherapy. This study led to FDA approval of ami- in Figs. 2.2.6.1 and 2.2.6.2. As shown in Fig. 2.2.6.1, fostine for this clinical indication. amifostine treatment increased the incidence of mild A number of clinical trials have been performed esophageal toxicity from 23% to 48%, but conversely it using amifostine in combination with chemoradio- markedly reduced the incidence of severe esophageal therapy for lung cancer (Koukourakis et al. 2000; toxicity from 35% to 16% (p=0.021). The reasons for Antonadou et al. 2001, 2003; Movsas et al. 2003; this divergent effect of amifostine on mild and severe Senzer 2002; Leong et al. 2003), including one at toxicity are not yet understood. Amifostine signifi - the University of Texas M. D. Anderson Cancer Center cantly reduced the incidence of constipation, pneumo- (MDACC) (Komaki et al. 2002a,b, 2004). Antonadou nitis, and neutropenic fever (Fig. 2.2.6.2). Of important et al. (2001, 2003) conducted a randomized phase III note, severe, grade 3, pneumonitis occurred in 16% of trial of concurrent chemotherapy (either paclitaxel or patients treated with chemoradiotherapy alone but carboplatin) and radiation treatment plus/minus daily in no patients that received amifostine in addition to amifostine given iv at 300 mg/m2 15–20 min before chemoradiotherapy. The most signifi cant side effect of each fraction of radiotherapy and before chemother- amifostine was hypotension occurring in 65% of pa- Radioprotectors and Chemoprotectors in the Management of Lung Cancer 127

Fig. 2.2.6.1. Effect of amifostine on esophageal toxicity induced Fig. 2.2.6.2. Effect of amifostine on constipation, pneumonitis, by chemoradiotherapy in patients with NSCLC. [Modifi ed and neutropenic fever caused by chemoradiotherapy in pa- from Komaki et al. (2004) with permission] tients with NSCLC. [Modifi ed from Komaki et al. (2004) with permission] tients, consistent with fi ndings from other similar clin- ical studies. Figure 2.2.6.3 shows that amifostine had no signifi cant effect on tumor response to chemora- diotherapy, as determined by percent of local regional control, percent of distant metastases free survival and overall patient survival. We concluded that amifos- tine reduced the severity and incidence of the acute esophageal, pulmonary, and hematologic toxicity re- a sulting from concurrent cisplatin-based chemoradio- therapy, but had no apparent effect on tumor response to therapy. Another study from MDACC showed that amifostine can partially reverse the reduction of lung diffusion capacity caused by chemotherapy and/or ra- diotherapy (Gopal et al. 2002), further documenting amifostine-induced radioprotection of normal tissues during thoracic radiotherapy. The results of random- b ized clinical trials with iv amifostine in lung cancer are summarized in Table 2.2.6.2. Although the iv route of amifostine administration has been most commonly used in clinical trials, the practical advantages of sc administration have led to a clinical trial directly comparing routs of adminis- c tration. A study comparing the relative bioavailability Fig. 2.2.6.3. Kaplan-Meier survival curves showing the effect of of amifostine administered sc and iv was conducted amifostine on (a) overall survival rate, (b) locoregional (LR) in normal male volunteers. Amifostine was given ei- tumor control, and (c) distant-metastasis (DM)-free survival ther iv at a dose of 200 mg/m2 or sc at a fi xed dose after chemoradiotherapy in patients with NSCLC. [Modifi ed Komaki of 500 mg. The sc dose resulted in an area under the from et al. (2004) with permission] concentration–time curve for the bound form of WR- 1065 of 68% compared to that after iv administration. received 500 mg of amifostine as a single sc injec- There was greater inter-patient variability in drug tion 20 min prior to each radiotherapy fraction. The concentration following sc administration (Shaw et regimen was well tolerated, effectively reduced early al. 1999b; Bonner and Shaw 2002). toxicity of radiotherapy, and prevented treatment-in- Koukourakis et al. (2000) conducted a random- duced delays. Patients reported a reduction in hypo- ized Phase II study in 140 patients receiving radio- tension and nausea as compared with the iv adminis- therapy to assess the feasibility, tolerance, and cyto- tration. A phase III multi-center randomized trial to protective effi cacy of sc amifostine. Patients (n=70) compare iv vs sc amifostine vs no amifostine in pa- 128 R. Komaki et al.

Table 2.2.6.2. Randomized trials with amifostine in lung cancer. [From Komaki et al. (2004) with permission]

Reference Radiation dose Chemotherapy Amifostine dose Comments

Movsas 69.6 Gy @ 1.2 Gy Induction P+Cx2; 500 mg IV 4x/week No difference by NCI-CTC esophagitis et al. 2003 b.i.d. day 43 concurrent weekly C between b.i.d. Swallowing diaries n=242 RT fractions (p=0.03) & weight loss (p=0.05) favor amifostine (Median survival, 15.6 and 15.8 months) Leong 60–66 Gy @ 2.0 Gy Induction P+Cx2; 740 mg/m2 with each Esophagitis grade 2–3: et al. 2003 q.d. day 43 concurrent weekly P chemo (d 1, 22, 43, 50, 43% in amifostine, 70% n=60 57, 64, 71, 78) in control (not signifi cant) (median survival, 12.5 and 14.5 months) Senzer 64.8 Gy @ 1.8 Gy Concurrent P+C q wk 500 mg IV before No difference in toxicity, et al. 2002 q.d. day 1 x 7; gemcitabine & weekly chemo; 200 mg no survival data n=63 cisplatin x 3 after IV daily before RT (ongoing trial) chemoradiation Antonadou 55-60 Gy @ 2.0 Gy None 340 mg/m2 daily ↓ pneumonitis; et al. 2001 q.d. before RT ↓ esophagitis n=146 (no survival data) Antonadou 55-60 Gy @ 2.0 Gy Concurrent weekly 300 mg/m2 daily ↓ esophagitis (p<0.001) et al. 2003 q.d. P or C before Chemo/RT ↓ pneumonitis (p=0.009) n=73 and RT (no survival data) Komaki 69.6 Gy @1.2 Gy Concurrent cisplatin 500 mg IV 1st, 2nd ↓ degree of esophagitis, et al. 2004 b.i.d. day 1 IV d 1, 8, 29, 36 day each wk before ↓ pneumonitis n=62 Etoposide p.o. d 1-5 chemo & ↓ neutropenic fever 1st RT fraction 8–12, 29–33, 36–40 (median survival, 19 and 20 months)

P, paclitaxel; C, carboplatin; RT, radiation therapy; NCI-CTC, NCI common toxicity criteria. tients with locally advanced NSCLC receiving concur- factors, and hypoxia. Prostanoids play a role in the rent chemoradiotherapy is ongoing. A phase II study pathogenesis of various pathological states includ- of the effi cacy of s.c. administration of amifostine in ing infl ammation, where PGE2, a potent vasodilator surgically resected NSCLC patients treated with post- and an immunosuppressive substance, is the major operative radiotherapy is ongoing at MDACC. prostaglandin involved. PGE2, produced in abundance by pro-infl ammatory mononuclear cells such as mac- rophages, mediates the typical symptoms of infl am- mation due to its vasodilatory action. This augments 2.2.6.3 edema formation caused by substances that increase Prostanoids, COX-2, and COX-2 Inhibitors vascular permeability such as histamine. PGE2 is also involved in the development of erythema and heat In response to physiological signals, stress or injury at the site of infl ammation. Since radiation-induced including radiation injury, cells produce prostanoids lung injury is characterized by infl ammatory tissue [prostaglandins (PGs) and thromboxanes (TBX)], a reactions, PGE2 and other PGs, as well as pro-infl am- family of diverse, highly biologically active lipids de- matory cytokines, are produced in injured tissue in rived from enzymatic metabolism of arachidonic acid abundance. Because different prostanoids have com- by COX-1 or COX-2 enzymes. COX-1 is ubiquitous and plementary or antagonistic activities, the fi nal biologi- responsible for prostanoid production in normal tis- cal effect on tissues depends on the balance of similar sues where prostanoids exert numerous homeostatic and opposing actions of the prostanoids involved. physiological functions. In contrast, COX-2 is an in- Production of PGE2 and other pro-infl ammatory ducible enzyme involved in prostaglandin production prostanoids can be suppressed by non-steroidal anti- in pathologic states, particularly in infl ammatory pro- infl ammatory drugs (NSAIDs), which inhibit both iso- cesses and cancer. COX-2 is induced by various factors forms of COX enzyme, or by selective COX-2 inhibitors. including infl ammatory cytokines (such as TNF-α, IL- Since selective COX-2 inhibitors do not inhibit pros- 1β, and platelet activity factors), oncogenes, growth tanoid production in normal tissues, they are less toxic Radioprotectors and Chemoprotectors in the Management of Lung Cancer 129 than commonly used NSAIDs. Interestingly, both pros- the lung. Radiation alters the magnitude and dy- tanoids and their inhibitors have been reported to exert namic activity of factors already present in affected radioprotective actions on normal tissues. Exogenous tissues. Response to radiation occurs within minutes administration of PGE2, other PGs, or PG analogs prior or hours after irradiation and can persist for days and to irradiation of mice was shown to protect a variety of months, infl uencing the pathogenesis of both early tissues including hematopoietic tissue, jejunal mucosa, and late radiation damage. The principal action of dermis, and testis (reviewed in Hanson 1998; Milas growth factors and cytokines is on cell and tissue pro- and Hanson 1995). PGs vary widely in their radiopro- liferation, as well as cell loss. Hence, growth factors tective ability; however, the PG analog misoprostol was affect all of the major determinants of cell and tissue amongst the most effective. Paradoxically, inhibiting radioresponse: total number of clonogenic cells, cell PGs by NSAIDs has also been shown to protect many cycle redistribution, cell repopulation, cellular repair tissues, including the lung, against radiation injury mechanisms, and tissue microenvironment such as (Milas and Hanson 1995; Michalowski 1994). For tumor hypoxia and acidity. Many growth factors may example, Milas et al. (1992) reported that the NSAID be affected upon tissue irradiation, those that have indomethacin can protect lung from radiation cytotoxic actions and those that have cytoprotective damage, but the protection was limited to the early ability, so that the extent of tissue damage depends pneumonitis phase of injury. Preliminary investigations on the interaction of cytokines with similar or op- in our laboratory using the selective COX-2 inhibitor posing activities. Involvement of growth factors and SC-236 did not demonstrate signifi cant protection from cytokines in pathogenesis of lung radiation damage radiation-induced pneumonitis when the drug was is discussed in more detail in Chap. 11.6. administered a few days before and after lung irradia- Since some growth factors and cytokines may act tion. Subsequent experiments, using a different COX-2 protectively, attempts have been made to protect tis- inhibitor, celecoxib, provided suggestive evidence that sues that are at risk from lung cancer radiotherapy. giving the inhibitor during the development phase of Basic fi broblast growth factor (b-FGF) was found to acute pneumonitis may reduce either the latency or se- protect endothelial cells both in vitro (Haimovitz- verity of lung injury. It should be emphasized that even Friedman et al. 1991) and in vivo (Haimovitz- in the absence of lung radioprotection by COX-2 inhibi- Friedman et al. 1991; Fuks et al. 1994) from radia- tors, therapeutic gain is still improved by their adminis- tion. To confer radiation resistance in vitro, b-FGF had tration because of their potent enhancement of tumor to be present at the time of radiation exposure and/or radioresponse. The ability of COX-2 inhibitors to selec- within several hours after irradiation. This protective tively enhance tumor radioresponse has been reviewed effect was abolished by treatment with anti-b-FGF an- in detail elsewhere (Milas 2001; Milas et al. 2003b; tibodies. The radioprotective effect of b-FGF was at- Choy and Milas 2003). tributed to its ability to increase cellular repair. A sub- Corticosteroids are highly potent anti-infl amma- sequent study by the same group (Fuks et al. 1994) tory drugs used for symptomatic treatment of radia- showed that mice could be protected from lethal doses tion-induced pneumonitis. They inhibit production of whole lung irradiation if given iv b-FGF immedi- of all prostanoids because, in addition to their abil- ately before or within 2 h after irradiation. The effect ity to inhibit COX enzymes, they prevent release of was attributed to the protection of endothelial cells arachidonic acid from membrane phospholipids by against radiation-induced apoptosis. Histology of ir- stimulating the generation and secretion of lipocor- radiated lung tissue, but not of lungs exposed to both tins. Wa r d et al. (1992a) showed that steroid admin- b-FGF and radiation, showed apoptotic changes in the istration to at the time of radiation delivery pro- endothelial cell lining of the pulmonary microvascu- tected rats from lung interstitial edema, delayed or lature within 6–8 h after radiation exposure. Also, his- suppressed radiation-induced alveolitis, but did not tological features of radiation-induced pneumonitis affect development of pulmonary fi brosis. were absent in mice treated with b-FGF. These results were not confi rmed in a subsequent study by Tee and Travis (1995) that assessed the radioprotective ac- tion of b-FGF in two strains of mice having different 2.2.6.4 susceptibilities to radiation-induced lung injury. The Growth Factors and Cytokines reasons for the discrepancy are unclear, but some dif- ferences in experimental conditions such as radiation Growth factors and cytokines play a critical role in dose, fi eld size of radiation, and mouse strain could pathogenesis of radiation injury, including that to have accounted for this disparity. 130 R. Komaki et al.

Keratinocyte growth factor (KGF) is another cell (Kwon et al. 2000). This study showed that pentoxifyl- growth factor that has been investigated for its abil- line was modestly effective, increasing median time to ity to protect against radiation-induced lung damage. relapse by 2 months and median survival time from 7 Although a member of the FGF family (FGF-7), KGF’s to 18 months. Though pentoxifylline has been shown cell growth stimulatory activity is confi ned to epithe- to modestly improve tumor radioresponse, it has most lial cells (Rubin et al. 1989; Miki et al. 1992). KGF was often been used to reduce normal tissue radiation in- shown to be a good stimulator of proliferation of type jury. Preclinical studies in experimental animals have, II pneumocytes in vitro and in vivo (Panos et al. 1993; in general, shown pentoxifylline to be radioprotective Ulich et al. 1994), a type of cells considered to play an but the degree of protection was highly variable. As important role in repair of injured lung tissue. Yi et al. an illustration, Lefaix et al. (1999) reported striking (1996) showed that intratracheal administration of KGF regression of subcutaneous fi brosis induced by radia- to rats 2 or 3 days before exposure of rats to 18 Gy bilat- tion to the skin surface of pigs using a combination of eral thoracic irradiation reduced severity of radiation- pentoxifylline and alpha-tocopherol (vitamin E). On induced pneumonitis and fi brosis observed histologi- the other hand, pentoxifylline has also been shown to cally. However, there was no signifi cant improvement have little or no effect on acute skin or lung injuries in survival. In contrast, KGF was highly effective (Dion et al. 1989; Koh et al. 1995; Rube et al. 2002; both in preventing development of bleomycin-induced Wa r d et al. 1992b). With respect to lung injury, pent- fi brosis and in improving the survival of treated ani- oxifylline inhibited the radiation-induced increase in mals. Signifi cant protection was also rendered against TNF_ mRNA during the acute phase of radiation in- the damage infl icted by the combined bleomycin plus jury, pneumonitis, but the impact of this biochemical radiation treatment. A more recent study (Terry et al. change on lung injury was unclear (Rube et al. 2002). In 2004) showed that a single intratracheal administration another study (Wa r d et al. 1992b), pentoxifylline was of rHuKGF to normal mice increased proliferation of found to further increase radiation-induced produc- alveolar epithelial cells 3–7 days later. This treatment tion of prostanoids (PGI2 and TXA2), while decreasing afforded signifi cant protection against lethality from endothelial dysfunction accompanied by increases in radiation-induced pneumonitis when the mice were ir- lung wet weight, , and hydroxyproline content in radiated at day 7 after administration of rHuKGF. the irradiated lung. A recent randomized clinical trial, Regarding radioprotective abilities of cytokines, it however, using prophylactic pentoxifylline showed a is worth mentioning that sc administration of recom- signifi cant reduction in both early and late radiation- binant IL-11 (rIL-11) rendered signifi cant protection induced lung toxicities in patients with breast and lung to mice from fatal thoracic irradiation (Redlich et cancer (Ozturk et al. 2004). al. 1996). The observed radioprotection was attrib- uted to the rIL-11-induced inhibition of radiation- induced expression of TNF mRNA as well as TNF production by macrophages. 2.2.6.6 Angiotensin Converting Enzyme (ACE) Inhibitors

Angiotensin converting enzyme (ACE) converts an- 2.2.6.5 giotensin I to angiotensin II, which is a potent va- Pentoxifylline soconstrictor and hypertensive factor. Captopril is an inhibitor of ACE that has been shown to protect Pentoxifylline (Trental), a methylxanthine derivative, is against radiation injury of a number of tissues includ- hemorheologic agent capable of reducing or ameliorat- ing the lung. In addition to inhibition of ACE, capto- ing late radiation sequelae. In , pentoxifylline is pril is a free radical scavenger (Chopra et al. 1989) used to treat persistent soft tissue ulcerations and ne- and exhibits superoxide dismutase (SOD)-like activity crosis. It has a variety of physiological activities includ- (Roberts and Robinson 1995). Captopril reduces ra- ing inhibition of platelet aggregation, regulation of tis- diation-induced pulmonary endothelial dysfunction sue damaging cytokines such as tumor necrosis factor (Wa r d et al. 1988), pulmonary fi brosis (Wa r d et al. alpha (TNF_), and enhances blood fl ow in injured mi- 1990a, 1992c), and delays radiation-induced pulmo- crovasculature. The drug may increase radioresponse nary arterial hypoperfusion in rats (Graham et al. of solid tumors by increasing tumor oxygenation (Lee 1988). Moreover, ACE inhibitor prophylaxis in rats et al. 2000), and as such was tested in a clinical phase receiving whole lung radiation was found to reduce III trial in NSCLC in combination with radiotherapy radiation-induced activation of ACE, plasminogen ac- Radioprotectors and Chemoprotectors in the Management of Lung Cancer 131 tivator, and production of prostaglandins, and throm- (Petkau 1987) and can even reduce preexisting ra- boxane (Wa r d et al. 1988). When added to the feed diation-induced fi brosis (Delanian et al. 1994). When after irradiation, captopril reduced early lung reaction given prior to radiation the activity of SOD has gen- in rats receiving fractionated hemithoracic irradiation erally been attributed to its radical scavenging effects, (Wa r d et al. 1993). In addition to pulmonary protec- whereas when given after radiation the effects are most tion, ACE inhibition also protects against radiation likely related to its anti-infl ammatory and or immuno- injury of other tissues including kidney (Moulder et stimulatory properties (Murray and McBride 1996). al. 1993), skin (Wa r d et al. 1990b), jejunum (Yo on et Another SOD, recombinant CuZnSOD was shown to al. 1994), and heart (Yarom et al. 1993). With respect protect the lung of hamsters from radiation-induced to the heart, Yarom et al. (1993) showed that capto- damage as evidenced by the absence of severe histo- pril ameliorated the decrease in capillary function, in- pathologic tissue changes 4–16 weeks after irradiation crease in mast cells, fi brosis, number of atrial granules, and the prevention of elevation of total protein content and changes in nerve terminals, but it failed to prevent in bronchoalveolar lavage (Breuer et al. 2000). the progressive functional deterioration of the heart More recently, a novel approach has been advanced following irradiation. Mechanisms of captopril-medi- for radioprotective gene therapy using the antioxidant ated radioprotection are not fully understood, but are manganese superoxide dismutase delivered to spe- at least partially related to its antihypertensive activity cifi c target organs such as lung and esophagus by gene and its thiol-like function. transfer vectors including plasmid/liposomes (PL) Based on promising preclinical observations on and adenovirus (Greenberger et al. 2003). Radiation radioprotection by ACE inhibitors, several clinical protection by MnSOD transgene overexpression at the studies were performed. Wa n g et al. (2000) reported cellular level has been demonstrated to be localized to a retrospective clinical study of ACE inhibitors given the mitochondrial membrane. Intraesophageal admin- for the management of hypertension in patients with istration of MnSOD-PL prior to irradiation induces lung cancer treated with defi nitive radiotherapy. The transgene expression for 48–72 h, and an associated de- study showed ACE inhibitors given at a dose within crease in radiation-induced expression of infl ammatory the range used to treat hypertension did not decrease cytokine mRNA and protein and esophagitis (Epperly the incidence or delay the onset of symptomatic ra- et al. 2001, 2003). Intratracheal injection of adenovirus diation pneumonitis. Currently, a phase II RTOG ran- containing MnSOD protected against radiation-induced domized clinical trial using captopril is ongoing. The organizing alveolitis in mice (Epperly et al. 1999). In ad- primary goal of this study is to test whether captopril dition, intratracheal MnSOD-PL gene therapy reduced given after completion of radiotherapy can reduce radiation induced infl ammatory cytokines without ren- the incidence or severity of pulmonary damage after dering protection to orthotopic Lewis lung cancer (Guo aggressive defi nitive chemoradiotherapy. et al. 2003). Preclinical animal studies suggested that radioprotective gene therapy reduces the radiation tox- icities and may facilitate dose escalation protocols to im- prove the therapeutic ratio of lung cancer radiotherapy. 2.2.6.7 However, the effi cacy and specifi city of this approach Radioprotective Gene Therapy: need further investigation. Application of MnSOD-PL Superoxide Dismutase (SOD) gene therapy in the setting of fractionated chemo-radio- therapy is being tested in clinical trials for prevention of The manganese superoxide dismutase (MnSOD) lo- esophagitis in patients with non-small cell lung cancer. cated within the mitochondria is one of nature’s most The gene therapy approach to specifi cally deliver agents effi cient catalysts. The enzyme protects redox ma- to targeted tissues is not limited to MnSOD but has high chinery within the mitochondria from the superoxide potential for delivery of a wide array of agents including radical produced during normal respiration. In many both cytotoxic and radioprotective agents. pathological conditions, such as infl ammation caused by radiation-induced free radical damage, superoxide is abundantly produced and may overwhelm the cell’s ability to effi ciently remove thus leading to tissue injury. 2.2.6.8 Via its antioxidant activity, MnSOD inactivates superox- Concluding Remarks ide and hence has potential to protect against free-radi- cal induced injury. Early studies showed that systemic Normal tissue damage remains a major limiting fac- administration of SOD can prevent radiation injury tor in cancer radiotherapy, and chemoradiotherapy 132 R. Komaki et al. where the improvement in tumor control and sur- mutase inhibits radiation-induced lung injury in hamsters. vival of patients is accompanied by increased rate and Lung 170:19-29 severity of treatment related toxicity. For many years Brizel DM (2003) Does amifostine have a role in chemoradiation treatment? Lancet Oncol 4:378-380 scientists have explored various approaches to mini- Brizel DM, Wasserman TH, Henke M et al (2000) Phase III ran- mize damage to tissues, including the use of chemical domized trial of amifostine as a radioprotector in head and and biological radioprotective agents. As elaborated neck cancer. J Clin Oncol 18:3339-3345 in this chapter, many of these agents exert signifi cant Calabro-Jones PM, Gahey RC, Smoluk GD et al (1985) Alkaline radioprotection and chemoprotection in experimen- phosphatase promotes radioprotection and accumulation of WR-1065 in V79-171 cells incubated in medium containing tal animal models and some of them have been tested WR-2721. Int J Radiat Biol 47:23-27 in clinical trials. Amifostine has undergone the most Chopra M, Scott N, McMurray J et al (1989) A free radical scav- extensive investigation, both preclinical and clinical. enger. Br J Clin Pharmacol 27:396-399 A number of clinical trials, including a recent one Choy H, Milas L (2003) Enhancing radiotherapy with cyclooxy- from MDACC described in Sect. 2.2.6.2.2, provided genase-2 enzyme inhibitors: a rational advance? J Natl Cancer Inst 95:1440-1452 encouraging results both with respect to reduction Curran WJ, Scott CB, Langer CJ et al (2003) Long-term benefi t is of the incidence and/or severity of esophagitis and observed in a phase III comparison of sequential vs concur- pneumonitis. Agents discussed have complex mecha- rent chemo-radiation for patients with unresected stage III nisms of action, and affect a variety of radiation-in- NSCLC: RTOG 9410. Proc Am Sco Clin Oncol 22:621 (abstract duced tissue reactions both directly and indirectly. 2499) Delanian S, Baillet F, Huart J et al (1994) Successful treatment of Radiation elicits the release of many substances, such radiation-induced fi brosis using liposomal Cu/Zn superoxide as growth factors, cytokines and prostanoids, which dismutase: clinical trial. Radiother Oncol 32:12-20 can have both radioprotective and radioenhancing Dillman RO, Seagren SL, Propert KJ et al (1990) A randomized properties. Since the fi nal outcome of treatment criti- trial of induction chemotherapy plus high-dose radiation cally depends on the balance between these compet- versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940-945 ing processes, the use of radioprotective agents may Dion MW, Hussey DH, Osborne JW (1989) The effect of pentoxi- act on only some of the many factors involved. This is fylline on early and late radiation injury following fraction- likely one of the reasons for the inconsistency in the ated irradiation of C3H mice. Int J Radiat Oncol Biol Phys literature on radioprotection. Rapid achievements in 17:101-107 recombinant technology and genetic engineering are Durand RE (1983) Radioprotection by WR-2721 in vitro and low oxygen tensions: Implications for its mechanisms of action. opening possibilities to upregulate or downregulate Br J Cancer 47:387-392 cellular expressions of diverse factors involved in Durand RE, Olive PL (1989) Radiosensitization and radioprotec- tissue responses to radiation and to select appro- tion by BSO and WR-2721: the role of oxygenation. Br J Cancer priate factors to achieve a predetermined response. 60:417-522 For example, redirecting the actions or optimizing Epperly MW, Bray JA, Krager S et al (1999) Intratracheal injec- trion of adenovirus containing the MnSOD transgene the concentrations of a given response factor may protects athymic nude mice from irradiation-induced orga- become useful in increasing the therapeutic ratio of nizing alveolitis. Int J Radiat Oncol Biol Phys 43:169-181 radiotherapy by enhancing tumor radioresponse, or Epperly MW, Gretton JA, DeFilippi SJ et al (2001) Modulation of by reducing damage of normal tissues with radio- radiation-induced cytokine elevation associated with esopha- protectors. gitis and esophageal stricture by manganese superoxide dis- mutase-plasmid/liposome (SOD2-PL) gene therapy. Radiat Res 155:2-14 Epperly MW, Guo HL, Jefferson M et al (2003) Cell phenotype References specifi c kinetics of expression of intratracheally injected man- ganese superoxide dismutase plasmid/liposomes (MnSOD- Antonadou D, Coliarakis N, Synodinou M et al (2001) Random- PL) during lung radioprotective gene therapy. Gene Ther ized phase III trial of radiation treatment plus/minus amifos- 2:163-171 tine in patients with advanced stage lung cancer. Int J Radiat Ferlay J, Bray F, Pisani P et al (2001) Cancer incidence, mortal- Oncol Biol Phy 51:915-922 ity and prevalence worldwide, Version 1.0 GLOBOCAN 2000. Antonadou D, Throuvalas N, Petridis A et al (2003) Effect of IARC cancer base no 5. IARC Press, Lyon amifostine on toxicities associated with radiochemotherapy Fuks Z, Persaud RS, Alfi eri A et al (1994) Basic Fibroblast growth in patients with locally advanced non-small cell lung cancer. factor protects endothelial cells against radiation-induced Int J Radiat Oncol Biol Phys 57:402-408 programmed cell death in vitro and in vivo. Cancer Res Bonner HS, Shaw LM (2002) New dosing regimens for amifostine: 54:2582-2590 a pilot study to compare the relative bioavailability of oral Giannopoulou E, Papadimitriou E (2003) Amifostine has antian- and subcutaneous administration with intravenous infusion. giogenic properties in vitro by changing the redox status of J Clin Pharmacol 42:166-174 human endothelial cells. Free Radic Res 37:1191-1199 Breuer R, Tochner Z, Conner MW et al (2000) Superoxide dis- Gopal R, Cox JD, Liao Z et al (2002) Effects of amifostine on lung Radioprotectors and Chemoprotectors in the Management of Lung Cancer 133

function in patients with non-small-cell lung cancer treated phase III randomized multicenter trial. Radiother Oncol by radiation therapy and chemotherapy. In: Perez CA, Brady 56:175-179 LW (eds) UPDATES: principles and practice of radiation LeChevalier T, Arriagada R, Quoix E, et al (1991) Radiotherapy oncology, vol 3(4), 3rd edn. Lippincott Williams and Wilkins, alone versus combined chemotherapy and radiotherapy in New York nonresectable non-small-cell lung cancer: First analysis of a Graham NN, Evans ML, Dahlen DD et al (1988) Drug suppression randomized trial in 353 patients. J Natl Cancer Inst 83:417-423 of late radiation injury in the rat lung. 36th annual meeting of Lee I, Biaglow JE, Lee J et al (2000) Physiological mechanisms the Radiation Research Society, Philadelphia, 16-21 April of radiation sensitization by pentoxifylline. Anticancer Res Grdina DJ, Kataoka Y, Murley JS et al (2002) Inhibition of spon- (6B):4605-4609 taneous metastases formation by amifostine. Int J Cancer Lefaix JL, Delanian S, Jean Jacques, et al (1999) Striking regression 97:135-141 of subcutaneous fi brosis induced by high doses of gamma rays Greenberger JS, Epperly MW, Gretton J et al (2003) Radioprotec- using a combination of pentoxifylline and α-tocopherol: an tive gene therapy. Curr Gene Ther 3:183-195 experimental study. Int J Radiat Oncol Biol Phys 43:839-847 Guo H, Epperly MW, Bernarding M et al (2003) Manganese super- Leong SS, Tan EH, Fong KW, et al (2003) Randomized double- oxide dismutase-plasmid/liposome (MnSOD-PL) intratra- blind trial of combined modality treatment with or without cheal gene therapy reduction of irradiation induced infl am- amifostine in unresectable stage III non-small cell lung cancer. matory cytokines does not protect orthotopic Lewis lung J Clin Oncol 21:1767-1774 carcinomas. In Vivo 17:13-21 Lockhart SP (1990) Inhaled thiol and phosphothiol radioprotec- Haimovitz-Friedman A, Vlodavsky I, Chaudhuri A et al (1991) tors fail to protect the mouse lung. Radiother. Oncol. 19:187- Autocrine effects of fi broblast growth factor in repair of radia- 191 tion damage in endothelial cells. Cancer Res 51:2552 Michalowski AS (1994) On radiation damage to normal tissues Hanson W (1998) Eicosanoid-induced radioprotection and che- and its treatment: II. Anti-infl ammatory drugs. Acta Oncol. moprotection: laboratory studies and clinical applications. 33:139-157 In: Bump E, Malaker K (eds) Radioprotectors: chemical, bio- Miki T, Bottaro DP, Fleming TP, et al (1992) Determination of logical and clinical perspectives. CRC Press, Boca Raton, pp ligand-binding specifi city by alternative splicing: two distinct 197-221 growth factor receptors encoded by a single gene. Proc Natl Hunter N, Milas L (1983) Protection byS-2-(3-Aminopropyl- Acad Sci USA 89:246-250 amino)-ethylphosphorothioic acid against radiation-induced Milas L (2001) Cyclooxygenase-2 (COX-2) enzyme inhibitors as leg contractures in mice. Cancer Res 43:1630-1632 potential enhancers of tumor radioresponse. Semin Radiat Jemal A, Tiwari RC, Murray T et al (2004) Cancer statistics, 2004. Oncol 11:290–299 CA Cancer J Clin 54:8-29 Milas L, Hanson WR (1995) Eicosanoids and radiation. Eur J Kemp G, Rose P, Lurain J et al (1996) Amifostine pretreatment Cancer 31A:1580-1585 for protection against cyclophosphamide-induced and cispla- Milas L, Hunter N, Reid BO, et al (1982) Protective effects of tin-induced toxicities: results of a randomized control trial in S-2-(3-Aminopropylamino)-ethylphosphorothioic acid patients with advanced ovarian cancer. J Clin Oncol 14:2101- against radiation damage of normal tissues and a fi brosar- 2112 coma in mice. Cancer Res 42:1888-1897 Kirk-Othmer (1996) Encyclopedia of chemical technology, vol 20, Milas L, Murray D, Brock, VA, et al (1988) Radioprotectors in 4th edn. Wiley, New York tumor radiotherapy: Factors and settings determining thera- Kligerman MM, Turrisi AT, Urtasan RC et al (1988) Final report peutic ratio. Pharmacol Ther 30:179-187 on Phase I trial of WR-2721 before protracted fractionated Milas L, Nishiguchi I, Hunter N, et al (1992) Radiation protec- radiation therapy. Int J Radiat Oncol Biol Phys 14:1119-1122 tion against early and late effects of ionizing irradiation by Koh W-J, Stelzer KJ, Peterson LM, et al (1995) Effect of pentoxifyl- the prostaglandin inhibitor indomethacin. Adv. Space Res. 12: line on radiation-induced lung and skin toxicity in rats. Int J 265-271 Radiat Oncol Biol Phys 31:71-77 Milas L, Mason KA, Liao Z, et al (2003a) Chemoradiotherapy: Komaki R, Lee JS, Kaplan B, et al (2002a) Randomized phase emerging treatment improvement strategies. Head and Neck III study of chemoradiation with or without amifostine for 25:152-167 patients with favorable performance status inoperable stage Milas L, Mason K, Liao Z, et al (2003b) Role of Cyclooxygenase-2 II-III non-small cell lung cancer: preliminary results. Semin (COX-2) and its inhibition in tumor biology and radiotherapy. Radiat Oncol 12:46-49 In: Nieder C, Milas L, Ang KK (eds) Biological modifi cation of Komaki R, Seiferheld W, Ettinger D, et al (2002b) Randomized radiation response: cytokines, growth factors and other bio- phase II chemotherapy and radiotherapy trial for patients logical targets. Springer-Verlag, Berlin Heidelberg New York, with locally advanced inoperable non-small-cell lung cancer: pp 241-258 Long-term follow-up of RTOG 92-04. Int J Radiat Oncol Moulder JE, BL, Cohen EP (1993) Treatment of radiation 53:548-557 nephropathy with ACE inhibitors. Int J Radat Oncol Biol Phys Komaki R, Lee JS, Milas L, et al (2004) Effects of amifostine on 27:93-99 acute toxicity from concurrent chemotherapy and radio- Movsas B, Scott C, Langer C, et al (2003) Phase III study of ami- therapy for inoperable non-small cell lung cancer: report of fostine in patients with locally advanced NSCLC receiving a randomized comparative trial. Int J Radiat Oncol Biol Phy chemotherapy and hyperfractionated radiation: RTOG 98-01. 58:1369-1377 Proc Am Soc Clin Oncol 22:636 Koukourakis MI, Kyrias G, Kakolyris S, et al (2000) Subcutaneous Murray D, McBride WH (1996) Radioprotective agents. In: Kirk- administration of amifostine during fractionated radiotherapy: Othmer Encyclopedia of Chemical Technology, 4th ed, vol. 20, A randomized Phase 11 Study. J Clin Oncol 18:2226–2233 pp 963-1006 Kwon HC, Kim SK, Chung WK et al (2000) Effect of pentoxifyl- National Cancer Institute. Cancer. Gov. Non-small cell lung cancer line on radiation response of non-small cell lung cancer: a (PGQ): treatment. Health professional version, June 2002 134 R. Komaki et al.

Nieder C, Jermic B, Astner S, et al (2003) Radiotherapy-induced tection with keratinocyte growth factor. Int J Radiat Oncol lung toxicity: Risk factors and prevention strategies. Antican- Biol Phys 58:435-444 cer Res 23:4991-4998 Travis E (1984) The oxygen dependence of protection by amino- Ohnishi ST, Ohnishi T, Glick JH, et al (1992) In vitro study on the thiols: implications for normal tissues and solid tumors. Int J antioxidant activities of Amifostine (WR-2721). Proc Amer Radiat Oncol Biol Phys 10:1495-1501 Assoc Cancer Res 33:419 (2503A) Travis EL, Thames HD, Jr, Tucker SL, et al (1985) Late functional Ozturk B, Egehan I, Atavci S et al (2004) Pentoxifylline in preven- and biochemical changes in mouse lung after irradiation: Dif- tion of radiation-induced lung toxicity in patients with breast ferential effects of WR-2721. Rad Res 103:219-231 and lung cancer: a double-blind randomized trial. Int J Radiat Ulich TR, Yi ES, Longmuir K, et al (1994) Keratinocyte growth Oncol Biol Phys 58:213-219 factor is a growth factor for type II pneumocytes in vivo J Panos RJ, Rubin JS, Aaronson SA, et al (1993) Keratinocyte Clin Invest 93:1298-1306 growth factor and hepatocyte growth factor/scatter factor are Utley JF, Seaver N, Newton GL, et al (1984) Pharmacokinetics of heparin-binding growth factors for alveolar type II cells in WR-1065 in mouse tissue following treatment with WR-2721. fi broblast-conditioned medium. J Clin Invest 92:969-977 Int J Radiat Oncol Biol Phys 10:1525-1528 Petkau A (1987) Role of superoxide dismutase in modifi cation of Vujaskovic Z, Feng Q, Rabbani ZN, et al (2002a) Assessment of radiation injury. Brit J Cancer 55 (Suppl VIII):87-95 the protective effect of amifostine on radiation-induced pul- Rasey JS, Krohn KA, Menard TW, et al (1986) Comparative bio- monary toxicity. Exp Lung Res 28:577-590 distribution and radioprotection studies with three radiopro- Vujaskovic Z, Feng Q, Rabbani ZN, et al (2002b) Radioprotection tective drugs in mouse tumors. Intl J Radiat Oncol Biol Phys of lungs by amifostine is associated with reduction in profi - 12:1487-1490 brogenic cytokine activity. Radiat Res 157:656-660 Rasey JS, Grunbaum Z, Krohn KA, et al (1985) Biodistribution of Wang LW, Fu XL, Clough R, et al (2000) Can angiotensin-convert- the radioprotective drug 35S-labeled 3-amino-2-hydroxypro- ing enzyme inhibitors protect against symptomatic radiation pyl phosphorothioate (WR77913). Radiat Res 102:130-137 pneumonitis? Radiat Res 153:405-410 Redlich CA, Gao X, Rockwell S et al (1996) IL-11 enhances sur- Ward HE, Kemsley L, Davies L, et al (1992a) The effect of ste- vival and decreases TNF production after radiation-induced roids on radiation-induced lung disease in the rat. Radiat Res thoracic injury. J Immunol 157:1705-1710 136:22-28 Roberts NA and Robinson PA (1995) Copper chelates of anti- Ward WF, Kim YT, Molteni A, et al (1988) Radiation-induced rheumatic and anti-infl ammatory agents and their super- pulmonary endothelial dysfunction in rats: Modifi cation by oxide dismutase-like activity and stability. Br J Rheumatol an inhibitor of angiotensin converting enzyme. Int J Radiat 24:128-136 Oncol Biol Phys 15:135-140 Rube CE, Wilfert F, Uthe D et al (2002) Modulation of radiation- Ward WF, Molteni A, Ts’ao C, et al (1990a) Captopril reduces col- induced tumour necrosis factor alpha (TNF-alpha) expres- lagen and mast cell accumulation in irradiated rat lung. Int J sion in the lung tissue by pentoxifylline. Radiother Oncol Radiat Oncol Biol Phys 19:1405-1409 64:177-187 Ward WF, Molteni A, Ts’ao C, et al (1990b) The effect of captopril Rubin JS, Osada H, Finch PW, et al (1989) Purifi cation and char- on benign and malignant reactions in irradiated rat skin. Br acterization of a newly identifi ed growth factor specifi c for J Radiol 63:349-354 epithelial cells. Proc Natl Acad Sci USA Ward WF, Molteni A, Ts’ao C, et al (1992c) Radiation pneumotox- Savoye C, Swenberg C, Hugot S (1997) Thiol WR-1065 and disul- icity in rats: Modifi cation by inhibitors of angiotensin con- phide WR-33278, two metabolities of the drug ethyol (WR- verting enzyme. Int J Radiat Oncol Biol Phys 22:623-625 2721), protect DNA against fast neutron-induced strand Ward WF, Kim YT, Molteni A, et al. (1992b) Pentoxifylline does breakage. Int J Radiat Biol 71:193-202 not spare acute radiation reactions in rat lung and skin. Radiat Schaake-Koning C, van den Bogaert W, Dalesio O, et al (1992) Res 129:107-111 Effects of concomitant cisplatin and radiotherapy on inoper- Ward WF, Lin PP, Wong PS, et al (1993) Radiation pneumonitis able non-small-cell lung cancer. N Engl J Med 326:524-530 in rats and its modifi cation by the angiotensin-converting Schuchter LM and Glick J (1993) The current status of WR-2721 enzyme inhibitor captopril evaluated by high resolution com- (Amifostine): A chemotherapy and radiation therapy protec- puter tomography. Radiat Res 135:81-87 tor. J. Clin. Oncol 14: 3112-3120 Wasserman TH, Phillips TL, Ross G, et al (1981) Differential pro- Senzer N (2002) A phase III randomized evaluation of amifostine tection against cytotoxic chemotherapeutic effects on bone in stage IIIA/IIIB non-small cell lung cancer patients receiv- marrow CFUs by WR-2721. Cancer Clin Trials 4:3-6 ing concurrent carboplatin, paclitaxel, and radiation therapy Yarom R, Harper IS, Wynchangk, et al. (1993) Effect of captopril followed by gemcitabine and cisplatin intensifi cation: prelimi- on changes in rat’s hearts induced by long-term irradiation. nary fi ndings. Semin Oncol 29:38-41 Radat Res 133:187-197 Shaw LM, Bonner H, Lieberman R (1999a) Pharmacokinetic pro- Yi ES, Williams ST, Lee H, et al (1996) Keratinocyte growth factor fi le of amifostine. Sem Oncol 23:18-22 ameliorates radiation- and bleomycin-induced lung injury Shaw LM, Bonner HS, Schuchter L, et al (1999b) Pharmacokinet- and mortality. Am J Pathol 149:1963-1970 ics of Amifostine: Effects of doses and method of administra- Yoon S, Park J, Jang H, Bahk Y and Shinn K. (1994) Radiopro- tion. Semin Oncol 26(2 Suppl 7):34-36 tective effect of captopril on the mouse jejunal mucosa. Int J Tee PG and Travis EL (1995) Basic fi broblast growth factor does Radiat Oncol Biol Phys 30:873-878 not protect against classical radiation pneumonitis in two Yuhas JM (1980) Active versus passive absorption kinetics as strains of mice. Cancer Res 55:298-302 the basis for selective protection of normal tissues by S-2-(3- Terry NHA, Brinkely J, Doig AJ, et al (2004) Cellular kinetics of Aminopropylamino)-ethylphosphorothioic acid. Cancer Res murine lung: model system to determine basis for radiopro- 40:1519-1524