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Experimental Therapeutics |
Encore Pharmaceuticals Inc., Laboratory of Chemical Endocrinology, Loma Linda University, Loma Linda, California 92350 [W. J. W., D. D. L., E. D. M., D. Q.]; Division of Gastroenterology, Loma Linda Medical Center, Loma Linda, California 92350 [J. D. M.]; and Department of Cell Biology & Scott Department of Urology [N. M. G.], and Department of Pathology [R. S. B.], Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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INTRODUCTION |
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Studies in our laboratory have shown the efficacy of E-7869 (R-flurbiprofen) in reducing the number and size of adenomas in the C57BL/6J-APCMin/+ mouse, a model of familial adenomatous polyposis in man (3) . E-7869 is a single enantiomer of the commercial racemic mixture of flurbiprofen (Ansaid). Although E-7869 is an analogue of the aryl-propionic class of nonsteroidal anti-inflammatory drugs, it does not significantly inhibit COX3 -1 or COX-2. The inhibition of COX-1 and COX-2 enzymes resides only in the S-enantiomer, as demonstrated by its potent inhibition of prostaglandin synthesis (4) . However, it is possible that E-7869 may be involved in the down-regulation of COX-2 mRNA transcripts. In a recent study (5) , racemic flurbiprofen was shown to decrease COX-2 mRNA expression in PC-3 cells, even in the presence of PGE2. However, it is unclear whether one or both isomers were responsible for the reduction of the COX-2 mRNA in that study.
The inhibition of prostaglandin production may play an important role in slowing or inhibiting carcinogenesis. Prostaglandins have been shown to increase colony and cell number in numerous cancer cell lines (5 , 6) . Several papers have demonstrated an increase in PGE2 levels in colorectal carcinoma tumors compared with surrounding normal tissue (7 , 8) . Prostaglandins have also been shown to have a role in programmed cell death or apoptosis. Researchers have demonstrated that PGE2 can inhibit apoptosis and up-regulate bcl-2 expression in colon cancer cell lines (6) .
Apoptosis is a valuable physiological restraint against uncontrolled growth and differentiation. Prostate cancer, as with many cancers, is known to be a disease where the regulation of apoptosis is inhibited, allowing unchecked cellular proliferation (9) . In advanced hormone-refractory prostate cancer, although the rate of proliferation is low, the rate of apoptosis is also substantially reduced, allowing progression and growth of the cancer (10) . The presence of apoptotic bodies has also been shown to correlate with a better prognosis for certain grades of prostate cancer (11) . Therefore, identification of agents that induce apoptosis may provide an effective treatment for advanced prostate cancer.
E-7869 has been shown to significantly enhance the apoptotic index in the distal colon of rats treated with azoxymethane.4 Therefore, given the suggestion that E-7869 might act as an apoptotic agent and its putative effects on COX-2 mRNA down-regulation, we extended our studies to another epithelial adenocarcinoma model. This model, the TRAMP mouse, is an ideal model for the pharmacological evaluation of drugs to treat prostate cancer in humans. The model exhibits many similarities to human prostate cancer, including epithelial origin, progression to adenocarcinoma, and metastasis. The transgene construct in these mice is a rat probasin-SV40 large T antigen introduced into the C57BL/6 mouse (12) .
This study investigates the efficacy of E-7869 against prostate cancer in the TRAMP model. The drug was given early in the history of the disease, and treatment continued for 18 weeks. Efficacy was evaluated by measurements of primary tumor growth and differentiation as well as inhibition of metastases. We found that E-7869 reduced the progression of prostate cancer in these mice.
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MATERIALS AND METHODS |
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Chemicals.
E-7869 (R- flurbiprofen; >99.8% enantiomeric excess) was
purchased from Wyckoff Inc. (South Haven, MI). All other chemicals were
reagent grade or better.
Drug Preparation.
The E-7869 was suspended in 1% CMC by homogenization with heating
(60°C for 15 min) in a tissue homogenizer. One % CMC was used as the
vehicle control.
Groups and Treatment.
Sixty 12-week-old TRAMP mice were randomized into control or treatment
groups using the Monte Carlo method. The mice in the HSF groups were
fed Teklad mouse/rat chow, which contains 4.2% total fat and 2.4%
saturated fat. The mice in the LSF groups were fed Dyets AIN 93-G chow,
which contains 7% total fat and 1.05% saturated fat. The animals in
all groups were treated by oral gavage with either 1% CMC (vehicle
control), 15 mg/kg E-7869 (LSF only), or 20 mg/kg E-7869 once daily
between 8 a.m. and 11 a.m.. Each animal was weighed weekly,
and the administered dose was adjusted accordingly. The animals were
treated for 18 weeks. Necropsy was performed at 30 weeks of age.
Necropsy and Histology.
At the time of necropsy, each mouse was anesthetized with an i.p.
injection of 50 mg/kg ketamine and 10 mg/kg xylazine. A laparotomy was
performed to expose all major organs, and the animal was exsanguinated
by cardiac puncture. The hematocrit was measured, and the remaining
blood (
500–700 µl) was placed in a 1.5-ml microcentrifuge tube.
Plasma was obtained by centrifugation (13,000 x g for 5 min) and stored at -20°C for drug analyses. All
major organs were inspected for frank toxicity or evidence of
metastases. Necropsy notes were collected on all animals. These notes
included quantitative and qualitative descriptions of the prostate,
lymph nodes, and any tissues showing any visible abnormality.
Photographs were made for documentation of the animals and their
urogenital systems in situ. A PCR assay, as described below,
was performed on any animals that did not display any obvious disease.
Four animals that were originally included in the study were removed
after this PCR assay revealed that they were wild-type mice.
The urogenital system (seminal vesicles, prostate lobes, and bladder) was removed and placed in a Petri dish containing PBS (137 mM NaCl, 3 mM KCl, 4 mM Na2HPO4, and 1.5 mM KH2PO4) to prevent desiccation. The bladder was emptied, and the tissues were gently blotted to remove excess PBS; then the entire urogenital system was weighed. Under a dissecting microscope, the different lobes of each prostate were separated and placed in labeled biopsy cassettes. Periaortic lymph nodes were identified (lower lumbar region of aorta, distal to femoral artery bifurcation) and removed, then placed in Petri dishes containing PBS. The lymph nodes were gently blotted to remove excess PBS and then weighed. The lymph nodes were then placed on biopsy foam pads inside biopsy cassettes.
The following specimens were collected for histology: periaortic lymph nodes; lung tissue; seminal vesicles; and ventral, dorsolateral, and anterior prostate. Any tissues containing visible metastases or other abnormalities were also collected for histological evaluation. All tissue samples were placed in 4:1 water:Zn-buffered formalin for 12–24 h, after which the formalin solution was replaced with 70% ethanol (v/v). The tissue samples were dehydrated and embedded in paraffin. Sections (5 µm) were cut from paraffin-embedded tissues and mounted on ProbeOn-Plus slides (Fisher Scientific) as described by Greenberg et al. (13) . Histological sections were analyzed with a standard H&E stain. The sections were evaluated by a pathologist and blinded to the treatment groups for the incidence and degree of pathology within the tissue samples. The urogenital tissues were graded on a 1–6 scale: noncancerous lesions were graded 1, 2, or 3 indicating normal tissue, low PIN, and high PIN, respectively. Grades 4, 5, or 6 indicated well-, moderately, and poorly differentiated cancerous lesions. The periaortic lymph node and lung tissues were graded as to the presence (+) or absence (-) of metastases.
Analysis of Drug Levels.
Plasma samples were taken 2–4 h
(Cmax) after the final drug dose for
the determination of plasma drug levels and inversion of R-
to S-flurbiprofen. The extraction and analysis procedures
were previously described (3)
.
PCR Analysis.
The PCR method for identification of TRAMP animals derived from our
breeding colony was adapted from Greenberg et al.
(14)
. Our TRAMP mice were an inbred strain obtained by
crossing against C57BL/6J mice. Animals were genotyped by
allele-specific PCR using 5 mm of tail tissue. A DNA isolation kit
(Pharmacia Biotech) was used for DNA extraction, and the DNA pellet was
dissolved in a hydration solution supplied with the DNA isolation kit.
A PCR premix solution containing Taq polymerase, dNTPs,
sense and antisense gene primers, and MgCl2 was
added to template DNA in a total volume of 50 µl. The PCR products
were separated after electrophoresis in a 1.8% agarose gel. The gel
was stained with ethidium bromide, viewed by UV light, and photographed
with a direct screen camera.
Statistical Analysis.
The central tendency and variability were determined using descriptive
statistics for the different data variables. The normality of data were
determined through graphical representation and the Shapiro-Wilk test,
with P < 0.05 representing a nonnormal data
set. Based on the normality of data, an ANOVA or Kruskal-Wallis test
was used for statistical analysis. Dunnett’s test and the
nonparametric Dunnett’s test were used for multiple comparisons of the
data, with a significance level set at 
= 0.05.
Statistical analysis of histological specimens used Fisher’s exact
test to determine significance (P < 0.05).
Analyses were conducted using Analyze-it for Microsoft Excel 95/97
(Analyze-it Software Ltd., Leeds, United Kingdom) and Microsoft Excel
(Microsoft Corp., Seattle, WA).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The urogenital and lymph node weights were highly variable in both
vehicle control groups (LSF and HSF) and in the lower (15 mg/kg) E-7869
dose (Fig. 1)
. By contrast, both 20-mg/kg E-7869 groups had much less variability
and significantly lower tissue wet weights. For animals treated with 20
mg/kg E-7869 on the LSF diet, the range of urogenital weights was
1.0 g, whereas the range was 4 g for the vehicle control animals
on the same diet. Similarly, animals treated with 20 mg/kg E-7869 on
the HSF diet also displayed a range of urogenital weights of 1.0 g,
whereas the vehicle controls ranged 3.5 g (Fig. 1)
. The lymph node
weights displayed even greater differences between weight ranges for
the 20-mg/kg-treated animals and the vehicle control animals on both
diets.
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55–60% compared with
their respective controls (Table 1)
. The animals in the 15-mg/kg E-7869
group given the HSF diet demonstrated a similar significant reduction
(48%) with average urogenital weights of 0.90 g versus
1.74 g in the vehicle control animals (Table 1)
. Conversely,
15-mg/kg E-7869 treatment in the group fed the HSF diet failed to show
a significant reduction in the lymph node wet weights. The mean lymph
node weight for 15-mg/kg-treated animals was 7.9 mg, whereas for the
corresponding vehicle control animals, it was 5.3 mg (Table 1)
.
Hematocrit and Body Weight.
To assess the toxicity of the drug treatment in the TRAMP mouse, we
measured hematocrits at necropsy and body weight changes throughout
treatment. There was a significant hematocrit reduction in all
treatment groups versus their respective vehicle controls
(Table 2)
. The drug did not appear to have an effect on body weight on either
diet. However, the animals on the LSF diet showed a greater overall
weight gain than mice fed the HSF diet. All animals receiving the HSF
diet (treated or untreated) had an average of a 2% weight gain,
whereas the LSF group had a >10-fold greater increase in their average
weight over the course of the study (Table 2)
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Compared with vehicle controls, the incidence of metastases was
significantly reduced in the 20-mg/kg treatment group given the HSF
diet. The metastasis incidence for the vehicle controls fed the HSF
diet was 8 of 20 tissue samples (40%), whereas only 1 of 16 samples
(6%) from animals treated with 20 mg/kg E-7869 developed any evidence
of metastasis (Table 3)
. Animals treated with 15 mg/kg E-7869 failed to
show any reduction in metastases in the HSF diet group.
The 20-mg/kg E-7869 treatment also gave a reduction in the incidence in metastases in the LSF diet group. Within this group, 12 tissues were examined for incidence of metastases, and none had any evidence of metastatic disease. However, in the vehicle control group, only 2 of 20 tissues examined (10%) had any evidence of metastases.
The lower incidence of carcinoma in the prostate lobes and metastatic
sites for animals treated with 20 mg/kg E-7869 suggests an overall
reduction in the total cancer prevalence. Two of 6 animals (33%) in
the 20-mg/kg E-7869 (LSF) treatment group had no histologically
demonstrable cancer (Table 3)
. Similarly, in the 20-mg/kg E-7869 (HSF)
treatment group, 1 of 7 animals had no detectable cancer. All vehicle
control animals in this study had histological evidence of carcinoma.
This data suggests that treatment with E-7869 had a profound ability to
inhibit the progression of cancer in these animals.
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DISCUSSION |
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Any therapy that could prevent or control metastatic prostate cancer would have immediate clinical importance. Unfortunately, once metastatic prostate cancer has developed, virtually all men develop androgen-independent disease. Once the disease has become hormone refractory, most treatment is palliative; the median life span of these patients is <12 months (15) . A virtue of the TRAMP model is its similarity to human disease in the progression to metastatic prostate cancer. The ability of E-7869 to reduce the incidence of metastatic disease in this model suggests that it may be able to control metastatic prostate cancer in man.
The ability of E-7869 to prevent metastases appears to be dose-related.
A 10-mg/kg dose of E-7869 showed minimal activity in the TRAMP mouse
model (data not shown). The 15-mg/kg dose group appears to have
marginal activity in preventing metastasis suggested by the rise in
incidence (Table 3)
. The 20-mg/kg dose group, on either diet, had a
combined 1 of 28 (3.5%) tissues demonstrating any evidence of
metastatic disease. This dose-effect relationship suggests that a
higher dose of E-7869 might prove even more effective.
In TRAMP mice, 15% of R-flurbiprofen is converted to
S-flurbiprofen at 2–4 h after administration (data not
shown); this result is consistent with earlier studies in Min mice
(3)
. It is now recognized that the inhibition of COX-1
results in alterations in the regulation of mucosal blood flow and
mucous and bicarbonate secretion; these changes can lead to
gastrointestinal ulceration and bleeding (16
, 17)
. The
decrease in the hematocrits in all treated groups (Table 2)
indicates
that some R-to-S inversion was probably causing gastrointestinal
ulceration. Although the TRAMP animals were not inspected for ulcers,
previous studies in our laboratory have shown clearly that the
S-enantiomer is ulcerogenic in the mouse (3
, 18)
. The inversion of E-7869 makes this drug somewhat toxic in
mice and limits our ability to increase the dose. This limitation
prevents us from determining whether the dose-response relationship can
be sustained at higher doses. Fortunately, this limitation is unlikely
to be a problem in humans because the R-to-S inversion rate is
substantially lower (<1%) in man (19)
. Thus, there may
be a larger therapeutic window for E-7869 in human trials for the
treatment of prostate or other cancers.
In animal colon cancer models, the COX-2 pathway has been used as a
therapeutic target for many selective inhibitors. Several potent COX-2
inhibitors have shown a decrease in the degree of malignancy in animal
models (20
, 21)
. S-flurbiprofen is a potent
inhibitor of the COX-1 and COX-2 enzymes, whereas
R-flurbiprofen (E-7869) has a 150- and 600-fold lower
affinity for the COX-1 and 2 enzymes, respectively (4)
. As
seen with other COX-2 inhibitors (22)
,
S-flurbiprofen has some anticancer effect in the Min mouse
model. The adenoma inhibition is not, however, solely the result of
COX-2 inhibition by the S-enantiomer.
R-flurbiprofen was far more effective than one would expect
simply from the activity of S-flurbiprofen arising from the
10–15% inversion in the Min mouse (3)
. As previously
stated, it is unclear if R-flurbiprofen alone or both
enantiomers contribute to the antineoplastic effects demonstrated in
our animal studies. R-flurbiprofen (E-7869) may
down-regulate COX-2 mRNA through effects on other factors indirectly
associated with COX-2 transcription. The R-enantiomer of
ibuprofen, another arylpropionic acid, has been shown to inhibit the
activation of nuclear factor 
B (23)
. The PPAR has been
shown to negatively regulate COX-2 activity without affecting the
COX-1 enzyme (24)
. Ibuprofen has also been shown to bind
to PPAR and PPAR
(25)
. The activation of PPAR by
certain nonsteroidal anti-inflammatory drugs has also been shown to
decrease the malignancy of prostate and breast cancer in
vivo (26
, 27)
.
The effect of dietary fat in the modulation of prostate tumor growth
has been documented in numerous studies (28, 29, 30)
. Most of
the studies were concerned with high dietary fat intake, such as the
traditional Western diet, which derives 40% of energy from total
fat. In this study, the AIN-93G diet yields 16.7% of its energy from
fat, whereas the Teklad diet yields 9.7% of its energy from fat.
Although the Teklad diet derives less of its energy from fat, it
contains a larger amount of saturated fat, 2.4% versus
1.05% in the AIN-93G diet. With these same diets, we previously have
shown that the LSF diet was associated with greater effects of
R-flurbiprofen in the APCMin/+ mouse;
mice on the HSF developed more adenomas (3)
. In prostate
cancer, saturated fat has been shown to be associated with advanced
prostate cancer risk (31)
. Although there is a difference
in the saturated fat composition between these two diets, it did not
seem to influence the wet weights of the urogenital tissues or lymph
nodes (Table 1)
. All E-7869 treatment groups, except the 15-mg/kg
group, demonstrated significant reductions in lymph node wet weights
when compared to their respective controls. The use of tissue wet
weights as a measurement of tumorigenicity may lack the resolution
necessary to discern small changes in dietary fat composition.
Therefore, a finer scale of observation would be necessary to
distinguish any differences in tumorigenicity relative to the fat
content in the diet.
In the studies reported here, the histological analysis demonstrated a
remarkable difference in the metastatic effect between the diets. In
the HSF group, the animals receiving vehicle control had primary tumors
in 19 of 40 tissues (48%) and metastases in 8 of 20 tissues (40%;
Table 3
). The vehicle control animals in the LSF diet group also had a
high prostate tumor incidence (58%), but they had a dramatically lower
incidence of metastasis (10%). In the absence of any other treatment,
the difference in the metastatic incidence between the HSF group (40%)
versus the LSF group (10%), although not statistically
significant, is quite remarkable. The reduced metastatic potential seen
in vehicle control animals on the LSF diet prevents the 20-mg/kg E-7869
group from demonstrating significance, although no metastases were
found in any of the treated animals (Table 3)
. These data suggest that
metastatic potential or invasiveness of the cancer was considerably
diminished due to a difference in the saturated fat content of the
diet.
All animals fed the LSF diet gained significantly more weight
than the animals fed the HSF diet (Table 2)
. Considering only the
vehicle controls, to exclude drug-associated events, the possible
explanation for the disparity in the weight gain appears to have two
components. Because the low saturated diet actually contains twice the
amount of total fat as does the higher saturated fat diet (7%
versus 4.2%), differences in body weights between control
animals given the two diets could be due simply to the overall total
fat content. However, given the reduced metastatic potential of this
model when animals received the LSF diet (Table 3)
, these animals may
also be generally less compromised by disease than those animals that
received the HSF diet.
In conclusion, we have evidence that E-7869 (R-flurbiprofen), the non-COX-inhibiting enantiomer of flurbiprofen, can significantly reduce urogenital and periaortic lymph node wet weights in the TRAMP mouse model. A diet lower in saturated fat was associated with a decreased incidence of metastasis in the TRAMP mouse. Furthermore, in the model, daily oral dosing with E-7869 reduces the incidence of cancer in the prostate and in metastatic sites.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Adventist Health Systems Loma Linda
(to W. J. W., D. D. L., E. D. M., D. D. Q., and J. D. M.),
National Cancer Institute Grant CA58204 Specialized Program of Research
Excellence [S.P.O.R.E.], and CapCure (to R. J. B. and
N. M. G.). A preliminary report of these results was presented at the
meeting for the Prevention and Cure of Prostate Cancer (AACR; Indian
Wells, CA), December 1998 and at the annual meeting of the AACR
(Philadelphia, PA), April 1999. 
2 To whom requests for reprints should be
addressed, at Encore Pharmaceuticals Inc., Chairman and CSO, Laboratory
of Chemical Endocrinology, Loma Linda University, MC1512, Loma Linda,
CA 93254. Phone: (909) 558-4903; Fax: (909) 796-0290; E-mail: WWechter{at}compuserve.com
3 The abbreviation used are: COX, cyclooxygenase;
PGE2, prostaglandin E2; TRAMP, transgenic
adenocarcinoma mouse prostate; PIN, prostatic intraepithelial
neoplasia; CMC, carboxymethylcellulose; LSF, low saturated fat; HSF,
high saturated fat; PPAR, peroxisome proliferator-activated receptor.
4 G. Young, personal communication.
Received 10/ 4/99. Accepted 2/18/00.
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REFERENCES |
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but not PPAR activators. Nature (Lond.)., 393: 790-793, 1998.[Medline]
and are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem., 79: 81-94, 1997.
(troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res., 58: 3344-3352, 1998. and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in BNX mice. Proc. Natl. Acad. Sci. USA, 95: 8806-8811, 1998.
-3 fatty acids on the DU-145 transplantable human prostatic tumor. Anticancer Res., 7: 1173-1180, 1987.[Medline]
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A. L. Lovering, J. P. Ride, C. M. Bunce, J. C. Desmond, S. M. Cummings, and S. A. White Crystal Structures of Prostaglandin D2 11-Ketoreductase (AKR1C3) in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin Cancer Res., March 1, 2004; 64(5): 1802 - 1810. [Abstract] [Full Text] [PDF]
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 R. E. Hill, D. M. de Avila, K. P. Bertrand, N. M. Greenberg, and J. J. Reeves Immunization Against Luteinizing Hormone-Releasing Hormone Fusion Proteins Does Not Decrease Prostate Cancer in the Transgenic Adenocarcinoma Mouse Prostate Model Experimental Biology and Medicine, July 1, 2003; 228(7): 818 - 822. [Abstract] [Full Text] [PDF]
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J. C. Desmond, J. C. Mountford, M. T. Drayson, E. A. Walker, M. Hewison, J. P. Ride, Q. T. Luong, R. E. Hayden, E. F. Vanin, and C. M. Bunce The Aldo-Keto Reductase AKR1C3 Is a Novel Suppressor of Cell Differentiation That Provides a Plausible Target for the Non-Cyclooxygenase-dependent Antineoplastic Actions of Nonsteroidal Anti-Inflammatory Drugs Cancer Res., January 15, 2003; 63(2): 505 - 512. [Abstract] [Full Text] [PDF]
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A. Suttie, A. Nyska, J. K. Haseman, G. J. Moser, T. R. Hackett, and T. L. Goldsworthy A Grading Scheme for the Assessment of Proliferative Lesions of the Mouse Prostate in the TRAMP Model Toxicol Pathol, January 1, 2003; 31(1): 31 - 38. [Abstract] [PDF]
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A. Nyska, A. Suttie, S. Bakshi, L. Lomnitski, S. Grossman, M. Bergman, V. Ben-Shaul, P. Crocket, J. K. Haseman, G. Moser, et al. Slowing Tumorigenic Progression in TRAMP Mice and Prostatic Carcinoma Cell Lines Using Natural Anti-Oxidant from Spinach, NAO--A Comparative Study of Three Anti-Oxidants Toxicol Pathol, January 1, 2003; 31(1): 39 - 51. [Abstract] [PDF]
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 M. F. Leitzmann, M. J. Stampfer, J. Ma, J. M. Chan, G. A. Colditz, W. C. Willett, and E. Giovannucci Aspirin Use in Relation to Risk of Prostate Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1108 - 1111. [Abstract] [Full Text] [PDF]
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S. J. Baek, L. C. Wilson, C.-H. Lee, and T. E. Eling Dual Function of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Inhibition of Cyclooxygenase and Induction of NSAID-Activated Gene J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 1126 - 1131. [Abstract] [Full Text] [PDF]
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D. Boutemmine, N. Bouchard, D. Boerboom, H. E. Jones, A. K. Goff, M. Dore, and J. Sirois Molecular Characterization of Canine Prostaglandin G/H Synthase-2 and Regulation in Prostatic Adenocarcinoma Cells in Vitro Endocrinology, March 1, 2002; 143(3): 1134 - 1143. [Abstract] [Full Text] [PDF]
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