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2.2.6 Radioprotectors and Chemoprotectors in the Management of Lung Cancer

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2.2.6 Radioprotectors and Chemoprotectors in the Management of Lung Cancer Radioprotectors and Chemoprotectors in the Management of Lung Cancer 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 cell 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 cell death 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. Radiation therapy 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 Oncology, 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 life. 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 radiation protection 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 ionizing radiation 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 bone marrow 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.
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