Affiliations of authors: H. Choy, Vanderbilt-Ingram Cancer Center, Nashville, TN; L. Milas, University of Texas M.D. Anderson Cancer Center, Houston, TX.
Correspondence to: Hak Choy, MD, Department of Radiation Oncology, Vanderbilt University Medical Center, 1301 22nd Ave. South, Nashville, TN 372325671 (e-mail: hak.choy{at}utsouthwestern.edu).
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ABSTRACT |
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INTRODUCTION |
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Radiotherapy in combination with surgery and chemotherapy has improved treatment for patients with localized and locally advanced cancers. For example, radiotherapy may facilitate tumor removal by permitting more complete or less radical surgery and may help ensure the elimination of cancer cells following surgery. In addition, radiotherapy can be combined with certain chemotherapeutic agents to increase the radiation sensitivity of cancers and to eliminate occult tumor cells located beyond the effective radiation field. Combined-modality therapy has produced moderate improvements in the therapeutic outcome for several cancers, including those of the breast and colon, nonsmall-cell lung and esophageal cancers, and head-and-neck squamous cell carcinoma.
Results of preclinical investigations demonstrating that molecular therapies enhance the effect of radiation have generated a surge in the number of clinical trials designed to evaluate combined-modality therapy. Since the early 1980s it has been known that inhibiting the production of prostaglandins, hormone-like substances that control blood pressure, muscle contractions, and inflammation, potentiates radiation responses in irradiated tissues. However, it has only been within the past decade that the existence of an inducible form of the key enzyme in prostaglandin synthesis, cyclooxygenase 2 (COX-2), has been appreciated. Studies conducted in experimental models have shown that selectively blocking COX-2 activity is associated with the antitumor effects of radiation without enhancing the effects of radiation in normal tissues. These experimental findings are now being tested in clinical trials as a particularly promising approach to combined-modality therapy.
Here we review the English-language literature with respect to studies of the influence of prostaglandins on tissue radiation response, and we propose a potential mechanism by which enhancement of radioresponse in tumors occurs through inhibition of prostaglandin production. Our objective is to present the experimental foundation supporting current clinical trials that combine standard radiotherapy or radiochemotherapy regimens with COX-2 inhibition for the purpose of stimulating interest and participation in these trials. We searched the entire MEDLINE database for articles on prostaglandin responses to radiation published since 1992 and references contained therein. We also searched the MEDLINE database for references to cyclooxygenase and to cyclooxygenase and radiation in the published proceedings of the annual meetings of the major cancer research organizations for 1998 through 2003.
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CELLULAR EFFECTS OF RADIATION |
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PROSTAGLANDINS AND RADIATION |
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Eicosanoids are biologically active lipid molecules (i.e., prostaglandins, thromboxanes, and leukotrienes) that mediate the diverse responses of the affected cell and neighboring cells to radiation (9,12,13). Eicosanoids affect the immune, vascular, and coagulation systems and regulate cell growth and differentiation. Most cells produce a variety of eicosanoids that may have complementary or antagonistic activities. For example, prostaglandin E2 (PGE2) is a potent vasodilator and is immunosuppressive; prostaglandin F2 (PGF2
) is a potent vasoconstrictor, PGI2 is a vasodilator and inhibitor of platelet aggregation, and thromboxane A2 (TXA2) is a platelet aggregator and vasoconstrictor (13).
In many tissues, radiation exposure is associated with an increase in eicosanoid production. Within hours after irradiation, increased levels of prostaglandins and thromboxanesprostaglandin E1 (PGE1), PGE2, PGF2, PGI2, TXA2, and TXB2are detectable in most tissues, and the increased eicosanoid levels may persist for several days or weeks (1424). Although in vitro findings have been inconsistent, data indicate that the eicosanoids produced in response to radiation, particularly prostaglandins, are radioprotective for normal cells, but only when administered before irradiation. For example, in studies with cultured cells, an analogue of PGE2 given 2 hours before 10 Gy of radiation (137Cs) was associated with an increase in the proportion of surviving normal fibroblasts (25). In animal models, treatment with various eicosanoids 12 hours before radiation consistently conferred protection to the normal gastrointestinal tract (2629), bone marrow (30), and hair follicles (31).
In experimental and clinical studies with prostaglandin synthesis inhibitors such as indomethacin, the therapeutic index of radiotherapy was improved in that the antitumor effects or radiation were enhanced without substantially enhancing its effects on normal tissues. For example, in a mouse model of fibrosarcoma, daily treatment with indomethacin before radiotherapy was associated with improvements in responses to both single- (32) and fractionated-dose (33) radiotherapy. Indomethacin treatment was associated with prolonged delays in tumor growth, an increased rate of cure, and increased time to recurrence with little or no change in the radioresponse of normal tissues. The radiation-enhancing effect of indomethacin appears to require a functioning immune system, because mice with an immune system compromised either genetically or by whole-body irradiation showed less radiation enhancement with indomethacin treatment than tumor-bearing mice with intact immune systems. These findings are consistent with and supported by other studies reporting that indomethacin treatment is associated with both the reversal of the immunosuppressive effects of radiation (3437) and the radioprotection of hematopoietic cells (32,38,39).
Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) also have direct antitumor effects that have been demonstrated preclinically in numerous systems (41) and clinically in one randomized controlled trial (40). In the clinical study, 135 patients with a variety of metastatic solid tumors were randomly assigned to receive treatment with indomethacin, prednisolone, or placebo. Patients treated with indomethacin survived statistically significantly longer (P<.05) than placebo-treated patients, and pooled observations from patients on anti-inflammatory treatment (indomethacin group plus prednisone group) revealed a significantly prolonged survival compared with placebo-treated patients (P<.03) (Fig. 1) (40). Furuta and colleagues (41) reported that in murine tumor models the tumor growth-inhibiting effects of indomethacin were seen only against prostaglandin-producing tumors, indicating that inhibition of prostaglandin synthesis was likely related to the antitumor activity. In addition, they reported that the direct antitumor activity of indomethacin was not affected by the immunogenicity of the tumor or by host immunocompetence but was associated with the inhibition of the neovascularization that is required for tumor growth (39). Thus, potential mechanisms for the radiation-enhancing effects of NSAIDs include the reversal of prostaglandin-induced immunosuppression and the direct inhibitory effects of NSAIDs on tumor neovascularization independent of any radiation-induced response.
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COX-2 EXPRESSION AND TUMORIGENESIS |
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Cyclooxygenase, also called prostaglandin H (PGH) synthase and prostaglandin endoperoxide synthase, is the rate-limiting enzyme in the conversion of membrane-derived arachidonic acid to prostaglandin H2 (PGH2). PGH2 is the common precursor that isomerases convert into the various prostaglandins and TXA2 (Fig. 2) (49). Cyclooxygenase exists in two forms, COX-1 and COX-2 (5053). NSAIDs inhibit the activities of both COX-1 and COX-2, whereas selective COX-2 inhibitors only inhibit COX-2 activity. COX-1 inhibition is believed to cause the adverse effects of NSAIDs on the upper gastrointestinal tract (5457). Details of the biochemistry and molecular biology of the COX-1 and COX-2 isoforms have been previously reviewed (5861).
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ROLE OF COX-2 IN CANCER PROGRESSION |
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COX-2 AND TUMOR ANGIOGENESIS |
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COX-2derived prostaglandins stimulate production of angiogenic growth factors (122124), and several studies (73,125,126) have reported associations between COX-2 expression in human cancers and levels of VEGF production and tumor microvessel density. Selective inhibition of COX-2 activity in several animal models is associated with decreases in VEGF production in tumors (100,119,126), decreases in new vessel formation (127130), and increases in tumor cell apoptosis (96,100,127). Direct evidence that COX-2 stimulates angiogenesis was obtained in the rat corneal model: A basic fibroblast growth factor (bFGF)containing pellet implanted in the rat cornea induces a strong neovascularization response accompanied by corneal thickening and an expanded stroma filled with COX-2expressing fibroblasts, endothelial cells, and macrophages (131). Although the bFGF-induced neovasculature contained many COX-2expressing endothelial cells, no such cells were seen in the established limbic vessels in the corneal tissue sections. PGE2 and TXB2 expression was increased in the angiogenic cornea, compared with the normal cornea. Compared with untreated angiogenic corneal tissue, oral celecoxib (30 mg/kg per day) inhibited the angiogenic response of angiogenic corneal tissue by 78.6%, reduced PGE2 production by 78%, reduced TXB2 production by 68%, and induced endothelial cell apoptosis in the corneal microvessels (131).
Much of the COX-2 stimulating tumor angiogenesis appears to be derived from host stromal tissue. The contribution of host-derived COX-2 to tumor growth was investigated in mice genetically deficient in COX-2 production (COX-2-/- mice) by Williams and colleagues (125). They reported that the growth of tumors derived from Lewis lung carcinoma cells was markedly attenuated in COX-2-/- mice compared with COX-2+/+ (i.e., wild-type) mice. Tumors in the COX-2-/- mice had a 30% reduction in vascular density compared with tumors in the wild-type mice, and VEGF production by stromal fibroblasts in the COX-2-deficient mice was reduced by 94% compared with that in the wild-type mice. Wild-type mice treated with the COX-2-selective inhibitor celecoxib also showed reduced tumor growth and 92% reduction in VEGF production by stromal fibroblasts, compared with tumors in untreated wild-type mice, confirming the role of COX-2 in promoting angiogenesis and tumor growth in this model. Additional evidence that stimulation of tumor vascularization is an important, and possibly the principal, contribution of COX-2 to tumor growth has also been seen in other studies (71,123,127,132).
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COX-2 EXPRESSION AND RADIOTHERAPY |
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An association between COX-2 expression and responses to radiation has also been seen in patients with cancer of the cervix or breast. In patients with invasive cervical cancer treated with radiotherapy, 5-year survival was 35% in those with high COX-2expressing cervical cancers, compared with 75% in those whose tumors produced no or low levels of COX-2 (Fig. 5) (137). In patients with locally advanced breast cancer treated with twice-weekly paclitaxel and radiation, a 30-fold lower expression of COX-2 was seen in the tumors of the 7 of 21 patients who achieved a complete pathologic response than in those patients that did not have a complete response (138). These studies suggest that COX-2 level in the tumor may predict response to radiotherapy and raise questions about how the COX-2 status of the tumor affects tumor radioresponse.
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MECHANISMS OF RADIATION POTENTIATION BY COX-2 INHIBITORS |
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Increased COX-2 Expression Following Irradiation
Exposure to ionizing or ultraviolet radiation increases the in vitro expression of COX-2 and the synthesis of prostaglandins in normal and tumor cells (1416,20,135,141,142). In tumor cells, these increases may be a protective response to counter the cytotoxic effects of radiation and can be blocked with nonselective as well as selective inhibitors of COX activity, thereby increasing the radiation sensitivity of the cells (137). The apoptosis-inhibiting activity of COX-2derived prostaglandins has been described in several studies carried out in different experimental systems (135,143). Prostaglandins may contribute to repair of sublethal DNA damage caused directly or indirectly by radiation, and inhibiting this activity may enhance radiosensitivity (135,143). Alternatively, or in addition, COX-2 inhibition of cell cycling, mediated indirectly through effects on regulatory cyclins and cyclin-dependent kinases, may arrest the cells in G2M, the most radiosensitive phase of the cell cycle. This cell cycle arrest has been seen in some model systems (32,143) but not in others (135) and, thus, may vary among different types of cells.
Induction of Apoptosis
Radiation potentiation by COX-2 may involve effects on p53. Cells with irreparably damaged DNA activate p53 and die through the controlled process of apoptosis regulated in part by p53 activity. Han and colleagues (144) investigated potential functional interactions between COX-2 and p53 in several human and murine cell lines. They found that p53-induced apoptosis was enhanced greatly in COX-2 knockout cells, compared with cells expressing wild-type levels of COX-2, suggesting that COX-2 has an inhibitory effect on p53-induced apoptosis. Furthermore, they found that apoptosis induced by DNA damage in p53+/+ normal cells was enhanced in cells treated with the selective COX-2 inhibitor NS-398 compared with untreated cells. These results suggest that COX-2 expression increases in response to genotoxic stresses that induce p53 expression, that COX-2 expression protects cells from apoptosis in response to stresses that induce p53 expression, and that this protection can be reversed by inhibiting COX-2 activity
Immunostimulation and Inhibition of Angiogenesis
In animal models, selective inhibition of COX-2 activity is associated with enhanced radiation sensitivity of tumor tissue but not of normal (i.e., non-tumor) tissues (134). The potentiation of radiation effects on tumor xenografts appears to require COX-2 expression by the tumor cells themselves (136), although in at least one report, the antitumor effect of selective COX-2 inhibition was independent of the ability of the tumor cells to express COX-2 (71). In the animal models used in this latter study (71), COX-2 was expressed primarily by the angiogenic blood vessels, the preexisting vasculature adjacent to the primary tumor, and the blood vessels invading metastatic lesions rather than by the tumors themselves. In another study (68), COX-2 expression in human pulmonary, colonic, and mammary tumors was examined with the use of antibodies specific for COX-2. In those human tumors, COX-2 was localized to the cytoplasm of the tumor cells and the non-neoplastic epithelial cells adjacent to the tumors, but was not expressed in epithelial cells distal to the tumors. These findings suggest that the tumors themselves, as well as the tumor environment (i.e., stromal components and infiltrating cells), contribute to COX-2 overexpression and thus may be affected by selective COX-2 inhibition.
Inhibition of the angiogenic response in irradiated tumors is one of the potential mechanisms that may play a major role in radiation potentiation through selective COX-2 inhibition (133,134). Radiation affects the tumor vasculature, particularly the proliferating angiogenic endothelial cells, as well as other stromal components and the tumor cells themselves. In addition, COX-2derived prostaglandins stimulate tumor angiogenesis, and selective COX-2 inhibitors block angiogenic activity (71).
Other mechanisms, such as immunosuppression, may also contribute to radiation potentiation through selective COX-2 inhibition. The immunosuppressive effects of prostaglandins are known (145148), and increased prostaglandin production by radiation-induced COX-2 may relieve suppressive effects of humoral and cellular immunologic mediators on tumor growth. Conversely, reducing the immunosuppressive effects of prostaglandins might inhibit tumor growth and increase the efficacy of radiotherapy. For example, Stolina and colleagues (149) reported that COX-2 inhibition in a murine model of Lewis lung carcinoma was associated with a marked lymphocytic infiltration of the tumor, which was associated with reduced tumor growth. In this experimental system, COX-2 inhibition was associated with a decrease in the production of the immunosuppressive cytokine interleukin (IL)-10 by antigen-presenting cells and restoration of production of the immunostimulatory cytokine IL-12. Results of studies with indomethacin in the murine fibrosarcoma model also suggested that host immunocompetence is a factor in radioenhancement with indomethacin (33). Although it appears likely that immunologic factors contribute to the antitumor activity of COX-2 inhibition and, possibly, to its radioenhancing effects, this remains an emerging concept. To date, no studies have directly evaluated the extent to which host immunocompetence contributes to radioenhancement.
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VEGF AS A MEDIATOR OF ENDOTHELIAL CELL RESPONSE TO RADIATION |
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CLINICAL TRIALS WITH CELECOXIB AND RADIOTHERAPY |
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NSCLC presents difficult challenges at every stage of treatment, from therapy for operable disease to management of metastatic cancer. Radiotherapy is assuming an increasing role in the management of NSCLC, and several studies combining celecoxib and radiation have been initiated. The Radiation Therapy Oncology Group (RTOG) (a multi-institutional cooperative organization with foundation headquarters in Philadelphia, PA) is conducting two studies: a phase II study of postoperative adjuvant therapy focusing on the combination of celecoxib (400 mg two times/day) and radiation (50.4 Gy) in patients with completely resected stage I/II NSCLC, and a phase I/II trial of the same treatment combination in patients with locally advanced NSCLC (stages IIB, IIIA, and IIIB) and an intermediate prognosis. In the phase I/II study, patients are treated with fractionated radiation (66 Gy) and receive twice-daily celecoxib for up to 2 years. In both studies, objectives include assessing the tolerability of celecoxib at 400 mg twice daily, evaluating the role of biomarkers as predictors of celecoxib activity, and examining whether celecoxib improves response and survival.
Patients with previously untreated stage III NSCLC are being enrolled in a phase II trial of celecoxib in combination with standard paclitaxel, carboplatin, and radiation therapy at the Vanderbilt Cancer Center (VCC, Nashville, TN). Preliminary results from this study suggest that changes in circulating levels of VEGF may be a marker of the response to celecoxib (162). Another phase II study at VCC combining celecoxib with radiation and taxane chemotherapy in patients with recurrent NSCLC (treated with at least one prior chemotherapy regimen) has produced two partial responses and three disease stabilizations among 13 evaluable patients, none of whom had responded to previous therapy. A third VCC study is assessing the benefit of radiation (62.5 Gy) combined with daily celecoxib among patients with inoperable stage I/II NSCLC. A phase I study at the University of Texas M.D. Anderson Cancer Center (MDACC, Houston, TX) is evaluating radiotherapy and celecoxib (100400 mg twice daily) in patients with medically inoperable NSCLC, including those with locally advanced disease and poor performance status, stage I/II disease and co-morbidities that preclude surgery, and stage IIIA/B disease previously treated with platinum-based induction therapy. Toxicity data for the 27 patients enrolled to date indicate that celecoxib is not associated with any increase in radiation-induced toxicity in normal tissues. The only toxicity other than the acute radiation-induced toxicity was grade 3 pneumonitis, which was seen in two patients 1 month after completion of radiation and celecoxib therapy (163).
Other Cancers
Clinical trials combining celecoxib, chemotherapy, and radiotherapy are also being conducted in other cancers in which radiation is a prominent component of standard therapy. A phase I study at MDACC is examining escalating doses of celecoxib (at 0, 400, or 800 mg/day) and radiation (50.4 Gy) combined with fluorouracil and cisplatin in patients with unresectable or recurrent esophageal cancer. The Hoosier Oncology Group (Walther Cancer Institute, Indianapolis, IN) is conducting a phase II study of celecoxib with chemoradiation therapy in patients with potentially resectable esophageal cancer. In a preliminary report of this study, it was concluded that the addition of celecoxib to chemotherapy and radiation is well tolerated. Thirty-one patients have enrolled, and 22 patients have undergone surgery; 24 patients remain alive and are receiving celecoxib maintenance therapy (164). The RTOG is evaluating the effects of celecoxib combined with external-beam radiotherapy and brachytherapy concurrent with 5-fluorouracil and cisplatin and radiation (45 Gy) on locoregional and distant control of disease, disease-free survival, and overall survival in patients with locally advanced cancer of the cervix. The New Approaches to Brain Tumor Therapy (NABTT) Central Nervous System (CNS) Consortium (Johns Hopkins University, Baltimore, MD) is conducting a trial of radiation and celecoxib in patients with glioblastoma multiforme. Recently, Pannullo and colleagues (165) reported encouraging preliminary results of a phase I trial with temozolomide and celecoxib in 18 patients with relapsed or refractory malignant glioma following resection and radiotherapy. The treatment in that trial was well tolerated, with partial response observed in four of 13 patients and disease stabilization in eight of 13 patients.
The results of these early-phase studies in NSCLC and esophageal, cervical, and brain cancer, which are expected over the next few years, will determine whether the current enthusiasm for combining COX-2 inhibitors and radiation is maintained and justifies the initiation of randomized controlled clinical trials.
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NOTES |
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Manuscript received February 26, 2003; revised July 21, 2003; accepted July 28, 2003.
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