- Open Access
Antitumor enhancement of celecoxib, a selective Cyclooxygenase-2 inhibitor, in a Lewis lung carcinoma expressing Cyclooxygenase-2
© Park et al; licensee BioMed Central Ltd. 2008
- Received: 03 July 2008
- Accepted: 11 November 2008
- Published: 11 November 2008
The goal of this study was to determine the effects of a selective Cyclooxygenase (COX)-2 inhibitor on the inhibition of tumor growth and pulmonary metastasis in a Lewis Lung Carcinoma (LLC) animal model.
For immunoblot analysis of COX-2 and PGE2, cells were treated with irradiation in the presence or absence of celecoxib. The right thighs of male, 6-week old C57/BL mice were subcutaneously injected with 1 × 106 LLC cells. The animals were randomized into one of six groups: (1) no treatment, (2) 25 mg/kg celecoxib daily, (3) 75 mg/kg celecoxib daily, (4) 10 Gy irradiation, (5) 10 Gy irradiation plus 25 mg/kg celecoxib daily, and (6) 10 Gy irradiation plus 75 mg/kg celecoxib daily. Mice were irradiated only once, and celecoxib was administered orally. Mice were irradiated with 4-MV photons once the tumor volume of the control group reached 500 mm3. All mice were sacrificed when the mean tumor volume of control animals grew to 4000 mm3. The left lobes of the lungs were extracted for the measurement of metastatic nodules.
Irradiation resulted in a dose-dependent increase in PGE2 production. PGE2 synthesis decreased markedly after treatment with celecoxib alone or in combination with irradiation. Compared to mice treated with low dose celecoxib, mean tumor volume decreased significantly in mice treated with a high dose of celecoxib with or without irradiation. Mice treated with a high dose celecoxib alone, with irradiation alone, or with irradiation plus celecoxib had markedly fewer metastatic lung nodules than controls. The mean metastatic area was the smallest for mice treated with irradiation plus a high dose celecoxib.
Oral administration of high dose celecoxib significantly inhibited tumor growth, as compared to a low dose treatment. Radiotherapy in combination with high dose celecoxib delayed tumor growth and reduced the number of pulmonary metastases to a greater extent than celecoxib or radiotherapy alone.
- Tumor Volume
- Lung Metastasis
- PGE2 Level
- PGE2 Synthesis
Radiotherapy is a common treatment for localized cancers. The radiation dose is important for tumor control. However, the therapeutic efficacy of radiotherapy is often limited by normal tissue damage within or nearby the field of radiation. In clinical practice, the radiation dose is optimized according to the probability of tumor control compared to the risks of complications due to the effects on normal tissue [1, 2]. Combining chemotherapeutic agents concurrently with radiotherapy has improved tumor control and survival. However, this combined approach also increases systemic and local toxicities during radiotherapy. Because of the increased toxicity, the overall treatment duration of radiotherapy, in addition to chemotherapy, is usually prolonged when compared to the treatment time of radiotherapy alone [3, 4]. This increased duration may decrease its efficacy for tumor control within the radiation field.
To further improve tumor response and reduce normal tissue toxicity from radiotherapy or chemoradiotherapy, many novel approaches have investigated several agents in preclinical and clinical settings. These approaches include those that selectively interfere with certain molecular processes and signaling pathways that regulate proliferation, survival, and function of normal cells. Because these agents are preferentially associated with specific sites of the cancer cells, their targeting is predicted to improve the tumor response to radiotherapy or chemoradiotherapy without additional toxicity to normal tissue. Among these agents, inhibition of cyclooxygenase (COX)-2 has been investigated as a potentially useful agent for the treatment of cancer.
COX-2 is normally present in cells and tissues of the brain and kidneys, but is induced in pathological states such as inflammation and tumors. COX-2 promotes carcinogenesis, tumor proliferation, angiogenesis, prevention of apoptosis, and immunosuppression . COX-2 overexpression has been associated with tumor behavior and prognosis in several cancers . Selective inhibition of COX-2 activity in several animal models has been associated with the decrease of new blood vessel production in tumors, a decrease in new vessel formation and an increase in tumor cell apoptosis. The selective inhibition of COX-2 activity has been associated with enhanced radiation sensitivity of tumors without enhancing the effects of radiation on normal tissue [7–9].
In this study, we evaluated the effect of a selective COX-2 inhibitor as a radiation sensitizer in order to inhibit tumor growth and pulmonary metastasis in a Lewis Lung Carcinoma (LLC) animal model.
Animals and Tumor Cells
Male, 6-week old C57/BL mice (Ajou animal laboratory, Suwon, Korea) were used for these experiments. The mice were acclimated for 1 week, and caged in groups of five or less in an air conditioned room. Mice were fed a diet of animal chow and water ad libitum. LLC cells were purchased from the American Type Tissue Collection. LCC cells were maintained in DMEM supplemented with 10% fetal bovine serum and penicillin-streptomycin. Cells were grown in monolayers in 100 mm dishes, and were maintained in a humidified 5% CO2 incubator at 37°C.
Stock solutions of celecoxib were made by dissolving the compound in DMSO, then were stored at -20°C. Concentrated drug stocks were diluted in DMEM before administration to cells or mice.
Immunoblot Analysis of COX-2
Cells were pretreated with 10 or 30 μM celecoxib for 1 h at 37°C. After treatment, the cells were irradiated at a dose of 5 Gy or 10 Gy. At 24 or 48 h post treatment, the cells were washed twice with PBS and lysed in buffer (Upstate). Supernatant protein concentrations were determined by Bradford assay using bovine serum albumin (BSA, Sigma Chemical Co.) as a standard. Aliquots of total protein (40 μg) was denatured and fractionated by SDS-polyacrylamide gel electrophoresis (4–12% gels). The separated proteins were transferred to a 0.22 μm nitrocellulose membrane. The nonspecific binding sites were blocked for 1 h in 5% non-fat dry milk and in Tris-buffered saline (TBS). The membranes were incubated with monoclonal anti-COX-2 (610204, BD biosciences) and anti-α tubulin (Oncogene) for approximately 1 h at room temperature. The membranes were washed in buffer containing TBS plus 0.05% Tween-20 and incubated in the appropriate secondary antibody (P0447, Dakocytonation). Signals were detected using enhanced chemiluminescence (Pierce).
Determination of PGE2 Synthesis
1 × 106 cells were either untreated, or treated with 30 μM celecoxib for 1 hr and then with 0, 5, or 10 Gy irradiation. After each treatment, supernatant PGE2 levels were assayed in triplicate. Determination of PGE2 levels by enzyme immunoassay was accomplished using a PGE2 monoclonal enzyme immunoassay kit (Cayman Chemical). Quantification was performed according to the manufacturer's instructions.
In vivo Tumor Growth and Quantitation of Lung Metastases
A suspension of 1 × 106 LLC cells in 0.1 ml of growth medium was injected subcutaneously into the shaved right thighs of mice. The study groups (n = 12 per group) consisted of an untreated control (group 1), 25 mg/kg celecoxib daily (group 2), 75 mg/kg celecoxib daily (group 3), 10 Gy irradiation (group 3), 10 Gy irradiation plus 25 mg/kg celecoxib daily (group 5), and 75 mg/kg 10 Gy irradiation plus celecoxib daily (group 6).
Celecoxib was administered by lavage (0.1 mL) every afternoon from one day before the cell injection until the day of euthanasia or death. For tumor irradiation, mice were put under general anesthesia and restrained using adhesive tape and customized devices constructed from a 50 ml syringe. Once the tumors in the control group reached a mean volume of 500 mm3, the tumors in the right thighs were irradiated with 10 Gy using a 4 MV x-ray for one fraction. Following injection of the tumor cells, the primary tumors were measured three times a week at two perpendicular diameters using a Vernier caliper, and tumor volumes were evaluated based on the formula, volume = 0.5 × a × b2 where a = length and b = width.
All mice were euthanized when the mean tumor volume in the control group reached 4000 mm3. The left lobes of the lungs were extracted, fixed in 10% formalin, and processed for the quantitation of metastatic nodules. The number of metastatic nodules was measured in the maximum sagittal plane from 5 μm paraffin-embedded lung tissue sections. The dimension of the outlined metastatic nodule was automatically calculated using commercial software (i solution DT, Seoul, Korea).
The primary tumor volumes were expressed as the mean and standard deviation. Comparison of the area of the lung nodules and tumor volumes among the experimental groups was determined by the Wilcoxon rank-sum test. The correlation between tumor volume and area of the metastatic lung nodules was evaluated by regression analysis. P- values less than 0.05 were considered statistically significant. All statistical analyses were performed with the SAS® System (SAS 14.0, SAS Institute Inc., Cary, NC., USA).
In vitro, Effect of the Selective COX-2 Inhibitor on LLC Cells
In vivo Tumor Growth
Wilcoxon rank-sum test for mean tumor volume at 20 days after tumor cell injection in control and treatment groups (p-value).
Celecoxib 25 mg/kg
Celecoxib 75 mg/kg
RT + Celecoxib 25 mg/kg
RT + Celecoxib 75 mg/kg
Celecoxib 25 mg/kg
Celecoxib 75 mg/kg
RT + Celecoxib 25 mg/kg
RT + Celecoxib 75 mg/kg
In vivo Lung Metastasis
Analysis of metastatic lung nodules according to control and treatment groups.
Areas of metastatic nodule (mean, mm2)
Celecoxib 25 mg/kg
Celecoxib 75 mg/kg
RT + Celecoxib 25 mg/kg
RT + Celecoxib 75 mg/kg
COX-2 expression has been reported in a variety of human cancers such as breast, lung, colon, cervix, liver, and prostate. Among tumors types, the intensity or distribution of COX-2 varies. However, COX-2 overexpression has been associated with tumor differentiation, tumor size, stage, and metastasis. In several cancers, patients with COX-2 overexpression have a poor prognosis [10–14]. Denkert et al. immunohistochemically evaluated COX-2 expression from breast cancer specimens. They reported more lymph node metastasis, larger tumors, poor differentiation, increased vascular invasion, and negative estrogen receptor status in patients with elevated COX-2 expression. COX-2 overexpression was reported to be of borderline significance for disease-free survival (relative risk 1.90). Sheehan et al. showed that high COX-2 expression correlates with advanced stage disease and larger tumors in patients with colorectal cancer.
COX-2 associates with tumor growth, infiltration, and metastasis in preclinical experiments. Tsujii et al. studied the phenotypic and biochemical changes associated with COX-2 expression. Rat intestinal epithelial cells were infected with a COX-2 expression vector oriented in the sense (RIE-S) or anti-sense (RIE-AS) direction. RIE-S cells demonstrated increased adhesion to extracellular matrix proteins and inhibition of apoptosis, compared with RIE-AS cells. After human colon cancer cells (Caco-2) were transfected with a COX-2 expression vector, Caco-2 cells acquired increased invasiveness compared with parental cells [15, 16]. Liu et al. showed that transgenic mice overexpressing COX-2 in the mammary gland, expressed COX-2 during pregnancy and lactation. Multiparous transgenic mice, but not virgin mice, exhibited a high incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors .
Nonsteroidal anti-inflammatory drugs (NSAID) are widely used for relief of inflammatory pain worldwide. Several population-based reports have demonstrated a 40% decrease in the death rate in persons with digestive tract cancers who regularly used aspirin, compared to those who did not. Clinical trials with NSAID in patients with Familial Adenomatous Polyposis clearly demonstrated that NSAID treatment shrunk pre-existing adenomas [18–20]. In addition, indomethacin offered palliative support to patients with advanced solid tumors, and prolonged their mean survival compared to placebo-treated patients . The mechanism of NSAID action was unknown until in 1971, when Vane proposed that NSAIDs primarily suppress inflammation by inhibiting COX and by limiting the production of PG . NSAIDs non-selectively inhibit the activities of both COX-1 and COX-2. COX-1 inhibition causes the adverse effects of NSAIDs on the gastrointestinal tract [23, 24]. In a randomized, placebo-controlled endoscopic evaluation, Scheiman et al. reported that the short-term use of nonselective COX inhibitors associated with a significantly greater ulceration rate, compared with a placebo .
The development of selective COX-2 inhibitors, with decreased potential for gastrointestinal toxicity, has stimulated additional investigations. Numerous studies on the antineoplastic effects of selective COX-2 inhibitors have been performed. Williams et al. proposed that celecoxib reduced the viability of cell lines, including LLC cells, from the induction of apoptosis and the growth of tumors in vivo, and had no effect on apoptosis or the epithelium of the normal gut . Leahy et al. reported that a reduction in proliferation and an increase in apoptosis were observed in colorectal tumor cells in response to celecoxib . Connolly et al. proposed that in vitro COX inhibitors decreased vascular endothelial growth factor production and increased apoptosis of tumor cells, as well as a reduced primary tumor weight, the number of lung metastases, and microvessel density in primary tumors in mice . Kobayashi et al. showed that selective COX-2 inhibition in colon cancer cell lines reduced the diameter of the tumor vessels as well as the number and size of the metastatic nodules in the lung. In addition, dose-dependent selective COX-2 inhibition reduced the size of metastatic tumors .
In our study, we used western blot analysis to confirm that a COX-2 inhibition increased COX-2 expression. The effect of celecoxib on the delay of tumor growth was dose-dependent, regardless of irradiation. High dose celecoxib (75 mg/kg celecoxib daily) significantly reduced the tumor volume, compared to control and low dose celecoxib groups. The rate of lung metastasis was decreased by about 25% in the high dose celecoxib group, compared to the control group. In addition, the area of metastatic lung nodules decreased significantly in the high dose celecoxib group.
With irradiation, COX-2 expression increased in tumors and associated with increased PGE2 levels. Steinauer et al. observed a dose-dependent increase in COX-2, following irradiation. PGE2 levels in irradiated cells were higher than in controls, and decreased when combined with a COX-2 inhibitor . The mechanisms underlying the radiation-enhancing effects of COX-2 inhibitors include (1) an accumulation of cells in the G2/M phases of the cell cycle which are considered to be sensitive to irradiation; (2) a reduction of PG-induced immunosuppressive activity caused by antitumor immunologic responses capable of potentiating tumor responses to radiation; and (3) direct effects on tumor neovascularization [7, 30, 31]. Shin et al. reported that celecoxib's radiation-enhancing effect was observed in COX-2 expressing cells but was not observed in COX-2 non-expressing cells. The radiation-enhancing effects disappeared in cells treated with COX-2-specific siRNA . LLC cells express COX-2 . In this study, we confirmed COX-2 expression by western blotting. Unlike Steinauer et al., irradiation, regardless of the dosage, did not increase COX-2 expression. However, PGE2 levels increased with irradiation in a dose-dependent manner. Tumor growth was delayed as a result of irradiation, especially in mice treated by irradiation and high dose celecoxib, where tumor growth was markedly delayed. The area of metastatic lung nodules was significantly smaller in mice treated by irradiation, regardless of celecoxib dose, than in the control group. Lung metastases were detected in only 25% of the mice treated by irradiation plus high dose celecoxib, as compared to 100% of the control mice.
The surgical removal of a primary tumor or radiation in order to eradicate a primary tumor can result in rapid growth and metastasis [33, 34]. Camphausen et al. reported that a single or hypofractionated irradiation protocol for the eradication of primary LLC cells increased the number of surface lung metastases in irradiated animals, as compared to controls. However, in our study, the number of lung metastases decreased from 100% in control mice to 50% in mice treated with irradiation alone. The differences between these two studies may be due to the doses used, i.e., whether it was a curative dose or not. We did not irradiate the primary tumor for eradication because we were studying the effects of a selective COX-2 inhibitor as a radiation sensitizer for the inhibition of tumor growth and pulmonary metastasis.
In conclusion, a high dose oral treatment of celecoxib significantly inhibited tumor growth, compared to a low dose treatment. In mice treated with radiotherapy and a high dose celecoxib, delay of tumor growth and reduction of pulmonary metastases were more prominent than in the mice treated with celecoxib or radiotherapy alone. However, further studies are needed to evaluate the effect of selective COX-2 inhibitors combined with conventional fractionation or hypofractionation radiotherapy on various cancer cell lines with regard to the delay of tumor growth and inhibition of metastasis.
This work was supported by a grant from "Department of medical sciences, the graduate school, Ajou University" in 2003.
- Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991, 21: 109-122.View ArticleGoogle Scholar
- Marks LB: The impact of organ structure on radiation response. Int J Radiat Oncol Biol Phys. 1996, 34: 1165-1171.View ArticleGoogle Scholar
- Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998, 16: 1310-1317.Google Scholar
- Girinsky T, Rey A, Roche B, Haie C, Gerbaulet A, Randrianarivello H, Chassagne D: Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome. Int J Radiat Oncol Biol Phys. 1993, 27: 1051-1056.View ArticleGoogle Scholar
- Koki AT, Masferrer JL: Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer Control. 2002, 9: 28-35.Google Scholar
- Choy H, Milas L: Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?. J Natl Cancer Inst. 2003, 95: 1440-1452.View ArticleGoogle Scholar
- Milas L, Furuta Y, Hunter N, Nishiguchi I, Runkel S: Dependence of indomethacin-induced potentiation of murine tumor radioresponse on tumor host immunocompetence. Cancer Res. 1990, 50: 4473-4477.Google Scholar
- Williams CS, Mann M, DuBois RN: The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 1999, 18: 7908-7916. 10.1038/sj.onc.1203286.View ArticleGoogle Scholar
- Kobayashi H, Gonda T, Uetake H, Higuchi T, Enomoto M, Sugihara K: JTE-522, a selective COX-2 inhibitor, interferes with the growth of lung metastases from colorectal cancer in rats due to inhibition of neovascularization: a vascular cast model study. Int J Cancer. 2004, 112: 920-926. 10.1002/ijc.20523.View ArticleGoogle Scholar
- Sheehan KM, Sheahan K, O'Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, Murray FE: The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA. 1999, 282: 1254-1257. 10.1001/jama.282.13.1254.View ArticleGoogle Scholar
- Graffney DK, Holden J, Davis M, Zempolich K, Murphy KJ, Dodson M: Elevated cyclooxygenase-2 expression correlates with diminished survival in carcinoma of the cervix treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2001, 49: 1213-1217.View ArticleGoogle Scholar
- Buskens CJ, van Rees BP, Sivula A, Reitsma JB, Haglund C, Bosma PJ, Offerhaus GJ, van Lanschot JJ, Ristimaki A: Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology. 2002, 122: 1800-1807. 10.1053/gast.2002.33580.View ArticleGoogle Scholar
- Kim YB, Kim GE, Cho NH, Pyo HR, Shim SJ, Chang SK, Park HC, Suh CO, Park TK, Kim BS: Overexpression of cyclooxygenase-2 is associated with a poor prognosis in patients with squamous cell carcinoma of the uterine cervix treated with radiation and concurrent chemotherapy. Cancer. 2002, 95: 531-539. 10.1002/cncr.10684.View ArticleGoogle Scholar
- Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, Kristiansen G, Reles A, Siegert A, Guski H, Hauptmann S: Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer. 2003, 97: 2978-2987. 10.1002/cncr.11437.View ArticleGoogle Scholar
- Tsujii M, DuBois RN: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995, 83: 493-501. 10.1016/0092-8674(95)90127-2.View ArticleGoogle Scholar
- Tsujii M, Kawano S, DuBois RN: Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA. 1997, 94: 3336-3340. 10.1073/pnas.94.7.3336.View ArticleGoogle Scholar
- Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hla T: Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem. 2001, 276: 18563-18569. 10.1074/jbc.M010787200.View ArticleGoogle Scholar
- Waddell WR, Loughry RW: Sulindac for polyposis of the colon. J Surg Oncol. 1983, 24: 83-87. 10.1002/jso.2930240119.View ArticleGoogle Scholar
- Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW: Aspirin use and risk of fatal cancer. Cancer Res. 1993, 53: 1322-1327.Google Scholar
- Fossilien E: Molecular pathology of cyclooxygenase-2 in neoplasia. Ann Clin Lab Sci. 2000, 30: 3-21.Google Scholar
- Lundholm K, Gelin J, Hyltander A, Lonnroth C, Sandstrom R, Svaninger G, Korner U, Gulich M, Karrefors I, Norli B: Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors. Cancer Res. 1994, 54: 5602-5606.Google Scholar
- Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971, 231: 232-235.View ArticleGoogle Scholar
- Fosslien E: Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system. Ann Clin Lab Sci. 1998, 28: 67-81.Google Scholar
- Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR: Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-cxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA. 1999, 96: 7563-7568. 10.1073/pnas.96.13.7563.View ArticleGoogle Scholar
- Scheiman JM, Cryer B, Kimmey MB, Rothstein RI, Riff DS, Wolfe MM: A randomized, controlled comparison of ibuprofen at the maximal over-the-counter dose compared with prescription-dose celecoxib on upper gastrointestinal mucosal injury. Clin Gastroenterol Hepatol. 2004, 2: 290-295. 10.1016/S1542-3565(04)00057-6.View ArticleGoogle Scholar
- Williams CS, Watson AJ, Sheng H, Helou R, Shao J, DuBois RN: Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res. 2000, 60: 6045-6051.Google Scholar
- Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL: Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res. 2002, 62: 625-631.Google Scholar
- Connolly EM, Harmey JH, O'Grady T, Foley D, Roche-Nagle G, Kay E, Bouchier-Hayes DJ: Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer. Br J Cancer. 2002, 87: 231-237. 10.1038/sj.bjc.6600462.View ArticleGoogle Scholar
- Steinauer KK, Gibbs I, Ning S, French JN, Armstrong J, Knox SJ: Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cells. Int J Radiat Oncol Biol Phys. 2000, 48: 325-328.View ArticleGoogle Scholar
- Furuta Y, Hunter N, Barkley T, Hall E, Milas L: Increase in radioresponse of murine tumors by treatment with indomethacin. Cancer Res. 1988, 48: 3008-3013.Google Scholar
- Milas L, Kishi K, Hunter N, Mason K, Masferrer JL, Tofilon PJ: Enhancement of tumor response to gamma-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst. 1999, 91: 1501-1504. 10.1093/jnci/91.17.1501.View ArticleGoogle Scholar
- Shin YK, Park JS, Kim HS, Jun HJ, Kim GE, Suh CO, Yun YS, Pyo H: Radiosensitivity enhancement by celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, via COX-2-dependent cell cycle regulation on human cancer cells expressing differential COX-2 levels. Cancer Res. 2005, 65: 9501-9509. 10.1158/0008-5472.CAN-05-0220.View ArticleGoogle Scholar
- O'Relly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediated the suppression of metastases by Lewis lung carcinoma. Cell. 1994, 79: 315-328. 10.1016/0092-8674(94)90200-3.View ArticleGoogle Scholar
- Camphausen K, Moses MA, Beecken WD, Khan MK, Folkman J, O'Reilly MS: Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res. 2001, 61: 2207-2211.Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.