JNCI Journal of the National Cancer Institute

JNCI Journal of the National Cancer Institute 1999 91(17):1501-1504; doi:10.1093/jnci/91.17.1501
© 1999 by Oxford University Press

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Journal of the National Cancer Institute, Vol. 91, No. 17, 1501-1504, September 1, 1999
© 1999 Oxford University Press

BRIEF COMMUNICATION

Enhancement of Tumor Response to -Radiation by an Inhibitor of Cyclooxygenase-2 Enzyme

Luka Milas, Kazushi Kishi, Nancy Hunter, Kathryn Mason, Jaime L. Masferrer, Philip J. Tofilon

Affiliations of authors: L. Milas, K. Kishi, N. Hunter, K. Mason, P. J. Tofilon, Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston; J. L. Masferrer, Pharma Research and Development, Searle, Monsanto, St. Louis, MO.

Correspondence to: Luka Milas, M.D., Ph.D., Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 066, Houston, TX 77030-4095 (e-mail: lmilas{at}mdanderson.org).

Prostaglandins are arachidonate metabolites produced in virtually all mammalian tissues and possess diverse biologic capabilities, including vasoconstriction, vasodilatation, stimulation or inhibition of platelet aggregation, and immunomodulation, primarily immunosupression (1-4). They are implicated in the promotion of development and growth of malignant tumors (4-7). They are also involved in the response of tumor and normal tissues to cytotoxic agents such as ionizing radiation (8). Prostaglandin production is mediated by two cyclooxygenase enzymes: cyclooxygenase-1 and cyclooxygenase-2. Cyclooxygenase-1 is constitutively expressed and is ubiquitous, and cyclooxygenase-2 is induced by diverse inflammatory stimuli (7,9).

Nonsteroidal anti-inflammatory drugs (NSAIDs) or agents inhibit cyclooxygenase enzymes and consequently can prevent, inhibit, or abolish the effects of prostaglandins. Increasing evidence shows that NSAIDs can inhibit the development of cancer in both experimental animals and in humans (7), can reduce the size of established tumors (6-8), and can increase the efficacy of cytotoxic anticancer agents (8). Our own investigations have demonstrated that the NSAID indomethacin prolongs tumor growth delay and increases the tumor cure rate in mice after radiotherapy (8,10,11).

Commonly used NSAIDs, including indomethacin, inhibit both cyclooxygenase-1 and cyclooxygenase-2. However, treatment with these agents may be limited by toxicity to normal tissue, particularly by ulcerations and bleeding in the gastrointestinal tract ascribed to the inhibition of cyclooxygenase-1. Recently developed selective cyclooxygenase-2 inhibitors exert potent anti-inflammatory activity but cause fewer unwanted side effects (7,9,12,13). These compounds may thus be safer than those NSAIDs that are in common use. A recent report (7) shows that cyclooxygenase-2-specific inhibitors can prevent carcinogenesis in experimental animals, but their efficacy in enhancing in vivo tumor response to radiation has not been established.

By use of the mouse sarcoma NFSA, we investigated the potential of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-l-yl]benzenesulfonamide (SC-'236), a selective cyclooxygenase-2 inhibitor (14,15) (supplied by Searle, G. D. & Co., Skokie, IL), to enhance response of tumor to local -irradiation. All studies reported had institutional approval and all guidelines for appropriate animal treatment were followed.

We have reported earlier (6) that the NFSA sarcoma is a nonimmunogenic and prostaglandin-producing tumor that spontaneously developed in C3Hf/Kam mice. This tumor exhibits an increased radioresponse if indomethacin is given prior to tumor irradiation (10,11). In experiments described in this communication, solitary tumors were generated in the right hind legs of mice by the injection of 3 x 10⁵ viable NFSA tumor cells. When tumors were 8 mm in diameter, they were locally irradiated with 25-80 Gy single-dose -radiation. Treatment with SC-'236 (6 mg/kg body weight, given in the drinking water) was started when tumors were approximately 6 mm in diameter, and the treatment was continued for 10 consecutive days. In some experiments, tumor irradiation was performed 3-8 days after initiation of the treatment with SC-'236. The end points of the treatment were tumor growth delay (days) and TCD₅₀ (tumor control dose 50, defined as the radiation dose yielding local tumor cure in 50% of irradiated mice 120 days after irradiation).

Treatment of mice with SC-'236 alone significantly inhibited tumor growth (inset in Fig. 1, A). Tumor diameter doubling time, based on tumor growth from 6 to 12 mm in diameter, was increased from 7.3 days (95% confidence interval [CI] = 6.4-8.1 days) to 14.8 days (95% CI = 11.5-18.1 days) (P<.0001). The effect of SC-'236 was evident already within 1 day from the start of the treatment.

View larger version (81K): [in this window] [in a new window]   Fig. 1. A) Effect of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-'236) alone (insert) or in combination with local tumor irradiation on tumor growth. Solitary tumors were generated in the muscles of the right hind legs of mice by injection of 3 x 105 viable NFSA tumor cells. Treatment with SC-'236 (6 mg/kg body weight) or vehicle (0.05% Tween 20 and 0.95% polyethylene glycol) given in the drinking water was started when tumors were approximately 6 mm in diameter, and the treatment was continued for 10 consecutive days. Water bottles were changed every 3 days. To obtain tumor growth curves, three mutually orthogonal diameters of tumors were measured daily with a vernier caliper, and the mean values were calculated. The inset in Fig. 1, A, plots the growth of tumors treated with vehicle () or SC-'236 (); the groups consisted of eight mice each, respectively. Vertical bars represent 95% confidence intervals.  Local tumor irradiation with single -ray doses of 30, 40, or 50 Gy was given when these tumors reached 8 mm in diameter. Irradiation to the tumor was delivered from a dual-source 137Cs irradiator at a dose rate of 6.31 Gy/minute. During irradiation, unanesthetized mice were immobilized on a jig and the tumor was centered in a circular radiation field 3 cm in diameter. Regression and regrowth of tumors were followed at 1–3-day intervals until the tumor diameter reached approximately 14 mm. Panel A plots the growth curves to illustrate the effect of SC-'236 on tumor growth when combined with a radiation dose of 30 Gy. Day 0 designates the time of tumor irradiation; it should be noted, however, that tumors in the groups receiving SC-'236 reached the size of 8 mm (day 0) at a later time than tumors treated with the vehicle. Groups consisted of five to eight mice each. Two of eight mice in the SC-'236-only group died of unknown causes. = vehicle, = SC-'236, • = 30 Gy, and () = SC-'236 plus 30 Gy. Vertical bars represent 95% confidence intervals. B) The effect of SC-'236 on dose-dependent and radiation-induced delay in tumor growth. The magnitude of tumor growth delay as a function of radiation dose with or without treatment with SC-'236 was plotted to determine the enhancement of tumor response to radiation. This requires that tumor growth delay after radiation be expressed only as the absolute tumor growth delay, i.e., the time in days for tumors treated with radiation to grow from 8 to 12 mm in diameter minus the time in days for untreated tumors to reach the same size. It also requires that the effect of the combined SC-'236-plus-irradiation treatment be expressed as the normalized tumor growth delay. Normalized tumor growth delay is defined as the time for tumors treated with both SC-'236 and radiation to grow from 8 to 12 mm in diameter minus the time in days for tumors treated with SC-'236 alone to reach the same size. Absolute tumor growth delay (•) and normalized tumor growth delay () along with their 95% confidence intervals were plotted for all three radiation doses used in this experiment (30, 40, and 50 Gy). The enhancement factor was 3.64 (95% confidence interval = 3.42-3.86), obtained by use of a likelihood analysis to fit the ratio of the slopes of the two lines. While no tumors were cured by any of the three radiation doses given alone, tumors in one of six, in two of six, and in three of eight animals were cured when SC-'236 treatment was combined with radiation treatment at 30, 40, and 50 Gy, respectively. Two of eight mice in the group that received SC-'236 plus 40 Gy died of unknown causes. The mice whose tumors were cured and the mice that died were not included in tumor growth delay analysis. C) The effect of SC-'236 on tumor cure by radiation. The entire procedure for treatment with SC-'236 and local tumor irradiation was the same as that described in Fig. 1, A and B. Here, the single doses of -radiation ranged from 25 to 80 Gy. Mice were checked for the presence of tumor at the irradiated site at 2- to 7-day intervals for up to 120 days, at which time TCD50 values were calculated. TCD50 values (tumor control dose 50 designates a radiation dose yielding 50% control [regression] of local tumor) were computed by use of the logistic model (24). • = radiation only and = SC-'236 plus radiation. Horizontal bars represent 95% confidence intervals at the TCD50 dose level. Five of 60 mice that received SC-'236 plus radiation died of unknown causes. The dead mice were excluded from TCD50 analysis. TCD50 assays contained 57 mice that received radiation only and 55 mice that received a combination of SC-'236 and radiation.

 
SC-'236 treatment dramatically increased the effect of tumor irradiation, as shown by both tumor growth delay (Fig. 1, A and B) and tumor cure rate (Fig. 1, C). The growth delay after the combined treatment was more than the sum of growth delays caused by either irradiation alone or SC-'236 alone (Fig. 1, A). Tumors in control mice required 4.6 days (95% CI = 3.9-5.4 days) to grow from 8 to 12 mm in diameter. Mice treated with SC-'236 required 7.1 days (95% CI = 5.0-9.2 days) (P = .003), mice treated with 30 Gy required 13.6 days (95% CI = 10.5-16.7 days), and mice treated with both agents required 43.5 days (95% CI = 30.8-56.2 days) (P = .001 compared with radiation-only group). The efficacy of irradiation was enhanced by a factor of 3.64 (95% CI = 3.42-3.86), determined from the curves in Fig. 1, B, which plot the magnitude of tumor growth delay as a function of radiation dose with or without treatment with SC-'236 (see legend to Fig. 1, A and B). This compound also greatly enhanced the tumor cure rate after irradiation (Fig. 1, C): The TCD₅₀ value was reduced from 69.2 Gy (95% CI = 65.7-72.7 Gy) in the radiation-only group to 39.2 Gy (95% CI = 31.1- 44.6 Gy) in the combination-treatment group. The enhancement factor was 1.77 (95% CI = 1.51-1.98), obtained by dividing the TCD₅₀ value of the radiation-alone group by the combination-treatment group. The 95% CIs were obtained by use of Fieller's theorem (16).

Because prostaglandins are known to stimulate angiogenesis (17), the possibility that SC-'236 inhibited tumor angiogenesis was investigated. In an intradermal assay for angiogenesis developed in our laboratory (18), mice received intradermally injections of 10⁶ tumor cells, and blood vessels at the injection site were counted after 2, 4, 6, 8, and 10 days. SC-'236 (6 mg/kg) was given in the drinking water for 9 consecutive days, starting 1 day after tumor cell injection. Fig. 2 shows that neovascularization preceded measurable tumor growth and that SC-'236 statistically significantly reduced the number of newly formed vessels (see legend to Fig. 2 for more details). This reduction was associated with tumor growth retardation.

View larger version (27K): [in this window] [in a new window]   Fig. 2. Effect of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-'236) on tumor angiogenesis. A triangular skin flap was constructed on the right abdominal region of the mice anesthetized with Nembutal (0.06 mg/g body weight) by making a skin incision along the midline of the abdomen and extending it to the right groin. The skin flap was separated from the subcutaneous tissue by a gentle pull laterally and then an area with the fewest tiny blood vessels possible was searched for by use of a dissecting microscope with a magnification of x20. After the number of blood vessels was recorded at the tumor cell injection site, 106 NFSA cells were injected intradermally in a volume of 0.03 mL of phosphate-buffered saline with the use of a 30-gauge needle. The skin flap was then brought back to the midline and closed with the use of surgical clips. One day after the injection of tumor cells, the mice began receiving treatments with SC-'236 in the drinking water, which continued daily for 9 consecutive days. The number of blood vessels as well as the tumor size was determined at 2-day intervals, starting 2 days after tumor cell injection and continuing until 8 or 10 days after tumor cell injection. This was performed under a dissecting microscope (magnification x20) in anesthetized animals in which the skin flap at each of the above days was reopened by removing the surgical clips and pulling the flap laterally. Tumor volume was calculated by use of the formula for calculating elliptical mass (1/6 x a x b x c; a, b, and c designate tumor diameters for length, width, and depth, respectively). Open symbols = treated with vehicle; closed symbols = treated with SC-'236. Groups contained five mice each. Vertical bars are 95% confidence intervals. The differences in the number of vessels between the control and SC-'236treated group are statistically significant for the 4-, 6-, and 8-day points (P = .003 for day 4, P = .004 for day 6, and P = .02 for day 8; two-tailed Student's t test). The details of the intradermal assay of tumor angiogenesis were described earlier (18). Newly formed vessels were counted on tumor surface and peritumorally within approximately 1 mm from the tumor border. The x20 magnification-dissecting microscope allowed measurements of vessels as small as 0.01 mm in diameter, but vessels of smaller diameter were counted as well if visualized as distinct vessels. The repeated opening of the skin flap had no influence on angiogenesis.

 
The NFSA tumor is relatively radioresistant (19); it is strongly infiltrated by inflammatory mononuclear cells, primarily macrophages (19), which secrete factors that stimulate tumor cell proliferation (19). Furthermore, this tumor produces a number of prostaglandins, including prostaglandin E₂ and prostaglandin I₂ (6). SC-'236 dramatically enhanced the tumor response to radiation, as evidenced by the increase in tumor growth delay and the augmentation of tumor curability. The enhancement factors were 3.64 and 1.77, respectively, greater than the enhancement factors of 1.4 and 1.26 for radiation plus indomethacin and radiation alone, respectively (10).

Although the mechanisms responsible for the SC-'236-induced potentiation of the NFSA tumor response to radiation remain to be elucidated, they likely involve the inhibition of prostaglandin synthesis (8,10,11). Prostaglandin-mediated effects at both the microenvironmental and cellular levels have been implicated in the modulation of such response. Prostaglandin E₂ and prostaglandin I₂ protect jejunum crypt cells (8,20), and prostaglandin I₂ protects B16 melanoma cells from radiation damage (21). Thus, a decrease in prostaglandins arising from the cyclooxygenase-2 inhibition may have caused the loss of radioprotection. Inhibition of prostaglandin synthesis was also reported to induce an accumulation of cells in the G₂ + M phases of the cell cycle (6), which are generally considered to be the most sensitive to ionizing radiation; thus, this effect may also play a role in the SC-'236-induced radiosensitization. Another possibility is that, with the inhibition of prostaglandin synthesis, prostaglandin-induced immunosuppressive activity was diminished and antitumor immunologic responses were able to potentiate tumor response to radiation (11). Finally, prostaglandins are vasoactive agents and are thus likely to regulate tumor blood flow and perfusion. As shown in Fig. 2, SC-'236 inhibited the vascularization of the NFSA tumor. In a separate study (22), another specific inhibitor of cyclooxygenase-2, celecoxib, exerted a potent inhibition of fibroblast growth factor-induced corneal angiogenesis in rats. Recently, it was reported that the combination of radiation with other antiangiogenic compounds produces an additive or greater than additive effect on the growth of human tumor xenografts (23). A similar situation may exist for inhibitors of prostaglandin synthesis. Although the mechanism remains to be defined, the results presented here are, to our knowledge, the first to show that treatment with a specific inhibitor of cyclooxygenase-2 can potentiate tumor response to radiation. Thus, this class of compounds has the potential for improving the efficacy of radiotherapy.

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Manuscript received March 22, 1999; revised June 25, 1999; accepted July 8, 1999.

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				B. B.Y. Ma, R. G. Bristow, J. Kim, and L. L. Siu Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents J. Clin. Oncol., July 15, 2003; 21(14): 2760 - 2776. [Abstract] [Full Text] [PDF]

				P. Wachsberger, R. Burd, and A. P. Dicker Tumor Response to Ionizing Radiation Combined with Antiangiogenesis or Vascular Targeting Agents: Exploring Mechanisms of Interaction Clin. Cancer Res., June 1, 2003; 9(6): 1957 - 1971. [Abstract] [Full Text] [PDF]

				J. M. Wallace Nutritional and Botanical Modulation of the Inflammatory Cascade--Eicosanoids, Cyclooxygenases, and Lipoxygenases-- As an Adjunct in Cancer Therapy Integr Cancer Ther, March 1, 2002; 1(1): 7 - 37. [Abstract] [PDF]

				M. J. Thun, S. J. Henley, and C. Patrono Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues J Natl Cancer Inst, February 20, 2002; 94(4): 252 - 266. [Abstract] [Full Text] [PDF]

				J. Portnow, S. Suleman, S. A. Grossman, S. Eller, and K. Carson A cyclooxygenase-2 (COX-2) inhibitor compared with dexamethasone in a survival study of rats with intracerebral 9L gliosarcomas Neuro-oncol, January 1, 2002; 4(1): 22 - 25. [Abstract] [PDF]

				H. Pyo, H. Choy, G. P. Amorino, J.-s. Kim, Q. Cao, S. K. Hercules, and R. N. DuBois A Selective Cyclooxygenase-2 Inhibitor, NS-398, Enhances the Effect of Radiation in Vitro and in Vivo Preferentially on the Cells That Express Cyclooxygenase-2 Clin. Cancer Res., October 1, 2001; 7(10): 2998 - 3005. [Abstract] [Full Text] [PDF]

				R. D. Blumenthal, C. Waskewich, D. M. Goldenberg, W. Lew, C. Flefleh, and J. Burton Chronotherapy and Chronotoxicity of the Cyclooxygenase-2 Inhibitor, Celecoxib, in Athymic Mice Bearing Human Breast Cancer Xenografts Clin. Cancer Res., October 1, 2001; 7(10): 3178 - 3185. [Abstract] [Full Text] [PDF]

				C. Petersen, S. Petersen, L. Milas, F. F. Lang, and P. J. Tofilon Enhancement of Intrinsic Tumor Cell Radiosensitivity Induced by a Selective Cyclooxygenase-2 Inhibitor Clin. Cancer Res., June 1, 2000; 6(6): 2513 - 2520. [Abstract] [Full Text]

				T. Hida, K.-i. Kozaki, H. Muramatsu, A. Masuda, S. Shimizu, T. Mitsudomi, T. Sugiura, M. Ogawa, and T. Takahashi Cyclooxygenase-2 Inhibitor Induces Apoptosis and Enhances Cytotoxicity of Various Anticancer Agents in Non-Small Cell Lung Cancer Cell Lines Clin. Cancer Res., May 1, 2000; 6(5): 2006 - 2011. [Abstract] [Full Text] [PDF]

				, , , , , J. , P. , and Preferential Enhancement of Tumor Radioresponse by a Cyclooxygenase-2 Cancer Res., March 1, 2000; 60(5): 1326 - 1331. [Abstract] [Full Text] [PDF]

				O. Gallo Re: Enhancement of Tumor Response to {gamma}-Radiation by an Inhibitor of Cyclooxygenase-2 Enzyme J Natl Cancer Inst, February 16, 2000; 92(4): 346 - 346. [Full Text] [PDF]

				L. Milas, K. A. Mason, and P. J. Tofilon RESPONSE: Re: Enhancement of Tumor Response to {gamma}-Radiation by an Inhibitor of Cyclooxygenase-2 Enzyme J Natl Cancer Inst, February 16, 2000; 92(4): 346a - 347a. [Full Text] [PDF]

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