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Clinical Cancer Research Vol. 8, 3270-3275, October 2002
© 2002 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Prevention and Treatment of Experimental Breast Cancer with the Combination of a New Selective Estrogen Receptor Modulator, Arzoxifene, and a New Rexinoid, LG 1002681

Nanjoo Suh2, William W. Lamph2, Andrew L. Glasebrook2, Timothy A. Grese, Alan D. Palkowitz, Charlotte R. Williams, Renee Risingsong, M. Rendi Farris, Richard A. Heyman3 and Michael B. Sporn4

Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755 [N. S., C. R. W., R. R., M. R. F., M. B. S.]; Ligand Pharmaceuticals Inc., San Diego, California 92121 [W. W. L., R. A. H.]; and Lilly Research Laboratories, Indianapolis, Indiana 46285 [A. L. G., T. A. G., A. D. P.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The selective estrogen receptor modulator arzoxifene and the rexinoid LG 100268 were active not only as single agents for prevention and treatment of breast cancer in the rat model that uses nitrosomethylurea as the carcinogen but also showed striking synergy, both preventively and therapeutically, in a series of six experiments with a total of 465 rats. Mechanistic studies in cell culture reported here suggest that enhancement of stromal-epithelial interactions may contribute to this synergy. The possible clinical use of the combination of arzoxifene and LG 100268 for prevention of breast cancer in women at high risk, for treatment of women in the adjuvant setting, or for treatment of end-stage disease should now be considered.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Despite significant clinical advances that have occurred in both the prevention (1, 2, 3, 4) and treatment (5, 6, 7, 8) of breast cancer, this disease still remains a major problem in its incidence, morbidity, and mortality (9) . There is an urgent need to develop better drugs, for both prevention and treatment. The SERMs5 are one class of drugs that has already made a major impact in both prevention and treatment (10 , 11) , but more effective agents, as well as agents with fewer undesirable side effects, are needed. Moreover, because of the proven efficacy of combinations of agents for both prevention and therapy, it would be desirable to add a second class of agents to a prevention or treatment regimen that already uses a SERM. The rexinoids (12) , selective ligands for the RXRs, are a promising class of new agents for both chemoprevention and therapy of cancer (13, 14, 15, 16) . We report here the efficacy of both a new SERM, Arz (17) , as well as that of a new rexinoid, LG268 (18) , for both prevention and treatment of breast cancer in a classic rat model of this disease. Structures of both drugs are shown in Fig. 1Citation . Not only are both efficacious as single agents, but most notably, we also show a striking synergy between the two when they are used in combination.



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  		Fig. 1. Structures of Arz and LG268.

 
The SERMs tamoxifen and raloxifene have proven experimental and clinical utility for prevention of breast cancer (1, 2, 3) , and tamoxifen is a clinically proven agent for therapy of disease (10 , 11) . Likewise, the pan-RAR/RXR agonist 9-cis-retinoic acid and its analogue, Targretin (which is more specific, although not totally so, for binding to RXR), have proven utility for prevention and treatment of experimental breast cancer (13, 14, 15, 16 , 19, 20, 21) . Moreover, animal studies have previously shown that combinations of SERMs, such as either tamoxifen or raloxifene, together with either 9-cis-retinoic acid or Targretin are more effective as preventive agents than regimens involving single drugs alone (14 , 19 , 20) .

Most recently, we have found that the new SERM Arz is markedly superior to older drugs such as tamoxifen or raloxifene, either in terms of efficacy or safety, in an experimental model for prevention of breast cancer (17) . Likewise, the rexinoid Targretin is superior to its parent molecule, 9-cis-retinoic acid, in prevention of breast cancer in either ER-positive or ER-negative animal models (13 , 22) . However, Targretin has some minimal binding to RARs, which can potentially cause some undesirable toxicity (13) . Thus, the newer rexinoid, LG268, which is more potent (18) and specific for binding solely to the RXRs and not to the RARs, has theoretical advantages when compared with Targretin.

With the known efficacy of combinations of SERMs with either 9-cis-retinoic acid or Targretin (14 , 19 , 20) , we therefore wished to study the effects of the combination of the two newer agents, Arz and LG268. In the present experiments, we have used combinations of both drugs in protocols that measure either prevention or treatment of breast cancer in the well-established model that uses NMU as a carcinogen, which causes ER-positive carcinomas in rats (23) . Our first experiments measured the effects of combinations of Arz plus LG268 for prevention of progression of early lesions (administration of drugs 1 week after carcinogen dosing) or their efficacy in treatment of small tumors shortly after the tumors became palpable. With the success of these protocols, we then started experiments in which administration of drugs was delayed either beyond early stages of carcinogenesis (prevention protocols) or until tumors were extremely large, on the verge of ulceration (treatment protocols). In all cases, dramatic synergy between Arz and LG268 has been found.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents.
Reagents were from Sigma Chemical Co. unless otherwise noted. Arz (17 , 24) and LG268 (18) were synthesized at Lilly Research Laboratories. Antibody to TGF-ß (1D-11, which recognizes all three isoforms of TGF-ß), was obtained from Genzyme; anti-iNOS antibody was from Santa Cruz Biotechnology.

Prevention and Treatment of Mammary Cancer in Rats.
Procedures used have been described in our previous publications (14 , 17 , 19 , 20 , 25) . The use of weanling rats in the NMU model is described in Ref. 26 . Statistical analysis of in vivo experiments was performed with nonparametric methods, using the Wilcoxon matched pairs test.

Induction of TGF-ß in Stromal Cells.
Swiss-3T3 cells were plated at a density of 3.0 x 105 cells/100-mm dish and grown for 18 h in DMEM/10% fetal bovine serum. The cells were then washed twice in serum-free medium, which was replaced with 0.1% BSA/DMEM. Arz and/or LG268 was then added, as was the anti-TGF-ß antibody 1D-11 (0.1 mg/ml). Media were then conditioned for 24 h, treated at 80°C for 8 min to activate latent TGF-ß (27) , and used as the medium for CCL-64 mink lung epithelial cells (28) grown in monolayer culture. These cells were treated with the conditioned media for 24 h, pulsed for 2 h with tritiated thymidine, and then evaluated for thymidine uptake into DNA.

Suppression of iNOS Induction in Stromal Cells.
Primary REFs were isolated from 14–17-day gestation Fischer rats (29) , plated at a density of 3.0 x 105 cells/100-mm dish, grown for 18 h at 37°C in DMEM/F12K with 10% fetal bovine serum, and then treated with LPS alone to induce iNOS (controls), with combinations of LPS and either Arz or LG268, or with both Arz and LG268 for 24 h. Total protein was isolated from the cells and run on Western blots. The blots were probed with the N-20 polyclonal iNOS antibody and exposed to film.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Prevention of Progression of Early Lesions by the Combination of Arz plus LG268.
Table 1Citation confirms the extremely high potency of the new SERM Arz as a preventive agent in the rat breast cancer model that uses NMU as the carcinogen (17) . Arz has chemopreventive activity that is statistically significant at doses as low as 1 mg/kg diet (approximately 0.05 mg/kg body weight). Table 1Citation also shows for the first time the high chemopreventive activity of LG268 in this breast cancer model. In all experiments reported in Table 1Citation , animals were always treated with either Arz or LG268 beginning 1 week after the administration of NMU, so that effects on initiation of carcinogenesis have been eliminated from the experimental design.


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  		Table 1 Prevention of breast cancer by Arz in combination with LG268

 
For our studies on the effects of combinations of Arz plus LG268, we have deliberately chosen very low doses of each agent to measure potential synergistic activity. Thus, as shown in Table 1Citation , neither Arz at 0.5 mg/kg diet nor LG268 at 30 mg/kg diet is effective in reducing tumor burden in a statistically meaningful manner; however, the combination of the two agents at these very low doses causes meaningful reduction in tumor burden. If the dose of LG268 is increased to 100 mg/kg diet, an even more impressive effect is seen with the combination of Arz plus LG268, with tumor burden at autopsy being as low as <1% of control values.

Prevention of Breast Cancer after Delayed Administration of Arz and LG268.
Table 2Citation shows that even when administration of the combination of Arz plus LG268 is delayed as long as 5 weeks after injection with NMU, combining the two agents has a highly significant preventive effect, which again can be quantified most effectively in terms of tumor burden at autopsy (12 weeks after NMU). In these experiments, in which dosing with chemopreventive agents was delayed until rats had advanced premalignant lesions (palpable tumors can be detected in some animals within 6–7 weeks after dosing with NMU), it was necessary to use higher doses of both Arz and LG268 than were found to be effective in Table 1Citation , in which animals were placed on preventive agents beginning 1 week after treatment with the carcinogen.


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  		Table 2 Prevention of breast cancer after delayed administration of Arz and LG268

 
Treatment of Early Invasive Breast Cancer with the Combination of Arz plus LG268.
Because combinations of Arz and LG268 were so effective in chemoprevention, we next determined whether they would be useful for treatment of grossly visible breast tumors, which are known to be adenocarcinomas in the NMU rat model (23) . Rats were given the standard dose of carcinogen and palpated weekly for appearance of tumors, whose size was measured with calipers. When tumors were relatively small but had reached a minimal size of 10 x 10 mm, rats bearing such tumors were randomly assigned to treatment or control groups and then placed on special diets containing either Arz, LG268, combinations of the two agents, or control vehicle. Individual tumors were noted and measured weekly with calipers before autopsy 3 weeks later.

As seen in Fig. 2Citation , tumors in the control animals grew rapidly and reached a total volume of approximately 14 cm3 before autopsy. The size and weight of all tumors were confirmed at autopsy, as shown in Table 3Citation . Fig. 2Citation and Table 3Citation show that although both Arz and LG268 have some efficacy in controlling the growth of these small tumors, the combination of the two agents is much more effective than either agent alone. These results have been obtained in two completely independent experiments involving a total of 221 rats; these experiments gave essentially identical results. The data from the two experiments have been pooled in Fig. 2Citation and Table 3Citation .



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  		Fig. 2. Arz and LG268 synergize in treatment of early invasive breast cancer in rats. Diets were fed to rats with tumors greater than 10 x 10 mm at the start of the experiment. Tumors were measured weekly with calipers. {blacksquare}, control; •, Arz, 20 mg/kg diet; {blacktriangleup}, LG268, 60 mg/kg diet; {circ}, combination of Arz and LG268.

 

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  		Table 3 Arz and LG268 synergize in treatment of early invasive breast cancer in rats

 
Treatment of Advanced Invasive Breast Cancer with the Combination of Arz plus LG268.
After obtaining the results in the previous section, we next evaluated the effects of the drugs in treatment of more advanced carcinomas, which had reached a minimum size of 20 x 20 mm and were on the verge of ulcerating. Treatment with the drugs was started at this point, and again the size of individual tumors was measured weekly with calipers. All rats were autopsied after 5 weeks of treatment with drugs. Results are shown in Fig. 3Citation and Table 4Citation , which report the pooled data from two independent experiments involving 131 rats. Again it can be seen that there is dramatic synergy between Arz and LG268 in shrinking very large tumors to the point that many were barely palpable in as short a time as 3 weeks after beginning treatment. Statistical analysis, shown in Table 4Citation , indicates that adding treatment with LG268 to treatment with Arz alone confers a highly significant benefit.



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  		Fig. 3. Arz and LG268 synergize in treatment of advanced invasive breast cancer in rats. Diets were fed to rats with tumors greater than 20 x 20 mm at the start of the experiment. Tumors were measured weekly with calipers. {blacksquare}, control; •, Arz, 60 mg/kg diet; {blacktriangleup}, LG268, 200 mg/kg diet; {circ}, combination of Arz and LG268.

 

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  		Table 4 Arz and LG268 synergize in treatment of advanced invasive breast cancer in rats

 
Effects of the Combination of Arz plus LG268 on Stromal Cells in Culture.
Although some of the effects of Arz and LG268 we have noted above are undoubtedly direct actions on either premalignant or malignant epithelial cells, it is also possible that some effects may also be mediated by stromal cells that regulate the tumor microenvironment (30 , 31) . We have therefore conducted a few preliminary experiments to investigate whether some stromal-epithelial interactions might be germane to the synergy we have observed between Arz and LG268. We have used Swiss-3T3 cells, REFs, and NRK fibroblasts as surrogate models for the actual mixed population of stromal cells in a tumor. In Fig. 4Citation , we show that after treatment of Swiss-3T3 cells with Arz or LG268 alone, the conditioned media derived from these cells do not significantly inhibit the growth of mink lung epithelial cells (CCL-64), which are known to be highly sensitive to TGF-ß (28) . However, when Arz and LG268 are used in combination on Swiss-3T3 cells, the medium conditioned by this treatment inhibits the growth of CCL-64 cells by as much as 61% of control values. Furthermore, this inhibition is totally reversed by the addition of the monoclonal anti-TGF-ß antibody, 1D-11, which inactivates all three isoforms of TGF-ß. Results similar to those we have just described with Swiss-3T3 cells have also been found when we treated either REFs or NRK cells with the combination of Arz and LG268 and then treated CCL-64 cells with the respective conditioned media (data not shown).



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  		Fig. 4. Arz and LG268 synergize to increase TGF-ß production by Swiss-3T3 cells. Swiss-3T3 cells were treated with 1 µM LG268 and/or 0.01–0.1 µM Arz, and the media were conditioned for 24 h. Conditioned media were then placed upon CCL-64 cells for an additional 24 h, and inhibition of CCL-64 growth by TGF-ß was measured by thymidine incorporation. The anti-TGF-ß antibody 1D-11 completely reversed CCL-64 inhibition of growth by Swiss-3T3-conditioned media.

 
Because TGF-ß is one of the most potent inhibitors of the induction of iNOS (32) , we also investigated the effects of Arz and LG268 on induction of iNOS by LPS in stromal cells. We found that the combination of Arz and LG268 synergistically decreased iNOS expression by 98% (as measured by Western blots of iNOS protein) in REF cells, whereas the compounds have little effect on iNOS expression when used alone (See Fig. 5Citation ). Again, this effect was reversed by the 1D-11 antibody.



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  		Fig. 5. Western analysis showing synergy between Arz and LG268 in decreasing iNOS expression in primary REFs. All REFs were treated with LPS to induce iNOS, and some cultures were also treated simultaneously with 1 µM LG268 and/or 0.1 µM Arz for 24 h, and total protein was isolated. The Western blot was subsequently probed with a polyclonal iNOS antibody. Again, the anti-TGF-ß antibody 1D-11 reversed suppression of iNOS expression by Arz and LG268.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The principal conclusion that emerges from more than 6 years of study of both prevention and treatment of experimental breast cancer with either Arz or LG268, as well as the combination of both these agents, is that the use of these agents in combination is always superior to their use singly. This conclusion is valid for prevention of progression of either early or advanced premalignant lesions or treatment of either early or advanced invasive lesions. These conclusions are based on the study of 465 rats in six separate protocols. At the doses of Arz and LG268 we have used, we have observed essentially no gross toxicity in the rats that have been treated for as long as 2 months with these agents, either alone or in combination. Feeding of chemopreventive agents in the diet is a simple and effective method for dosing animals. Thus, we have found that feeding Arz at 20 mg/kg diet gives plasma levels of drug in excess of 10 nM; the IC50 for suppression of growth of human MCF-7 breast cancer cells in culture is <1 nM (17) . The rat model in our studies, with NMU as carcinogen, has been used for more than 30 years and is widely regarded as highly relevant to the genesis of ER-positive breast cancer in women (23) . Most notably, three agents that have been shown to have positive results in clinical trials of chemoprevention of breast cancer, namely, tamoxifen, raloxifene, and fenretinide, are all potent preventive agents in the NMU rat model (1, 2, 3, 4) .

The mechanism of action of the synergy between Arz and LG268 clearly needs further study, and the results reported here represent only a first attempt to implicate stromal-epithelial interactions in this synergy. The established mechanism of Arz as a classical SERM clearly needs to be considered (17) . Furthermore, LG268, a rexinoid whose receptors, RXR-{alpha}, RXR-ß, and RXR-{gamma}, heterodimerize with numerous other members of the nuclear receptor superfamily (33) , has the potential to interact with numerous other pathways of regulation of growth and differentiation of both preneoplastic and neoplastic cells. Our data, which suggest that the combination of Arz and LG268 activates TGF-ß signaling, raise further possibilities that induction of terminal differentiation, induction of apoptosis, or suppression of epithelial cell growth (all of which are known to be mediated by TGF-ß) may contribute to the results we have observed here in the rats (34 , 35) . It would thus appear unlikely that there is a single mechanism that is responsible for the synergy we have seen, which is probably the result of the concerted action of several signaling pathways. Such concerted action of multiple pathways may be clinically useful, in that it is clear that development of carcinoma in men and women often involves dysregulation of multiple genes, and in this setting, the use of combinations of agents has a definite rationale. Our data suggest that the possible use of the combination of Arz and LG268 for either prevention of breast cancer in women at high risk or treatment of women in the adjuvant setting or with end-stage disease should now be considered.


   ACKNOWLEDGMENTS
 
We thank Megan Padgett for expert assistance with the preparation of the manuscript and John McPherson and Bruce Pratt for supplying 1D-11 antibody.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 M. B. S. is an Oscar M. Cohn Professor, and breast cancer research in his laboratory was partially supported by United States Army Medical Research Materiel Command under Grant DAMD17-99-1-9168. Back

2 N. S., W. W. L., and A. L. G. contributed equally to this work. Back

3 Present address: X-Ceptor Therapeutics, San Diego, CA 92121. Back

4 To whom requests for reprints should be addressed, at Department of Pharmacology, Dartmouth Medical School, Remsen 524, Hanover, NH 03755. Phone: (603) 650-6557; Fax: (603) 650-1129; E-mail: michael.sporn{at}dartmouth.edu Back

5 The abbreviations used are: SERM, selective estrogen receptor modulator; RAR, retinoic acid receptor; RXR, retinoid X receptor; Arz, arzoxifene; LG268, LG 100268; TGF-ß, transforming growth factor ß; REF, rat embryo fibroblast; iNOS, inducible nitric oxide synthase; NMU, nitrosomethylurea; ER, estrogen receptor; LPS, lipopolysaccharide. Back

Received 4/ 4/02; revised 6/18/02; accepted 6/20/02.


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Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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