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.



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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 13-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.
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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.

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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.
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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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