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Experimental Therapeutics, Preclinical Pharmacology |
Breast Center, Baylor College of Medicine, Houston, Texas 77030 [K. W., H. T. K., S. G. H., S. K. M., P. H. B.]; Department of Medicine, Division of Medical Oncology [J. L. R., D. M.], and Department of Pharmacology [J. G. K.], The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284; Department of Retinoid Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121 [W. W. L., M. M. G., M. A. S.]; and Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892 [J. E. G.]
Retinoids
have been investigated as potential agents for the prevention and
treatment of human cancers. These compounds play an important role in
regulating cell growth, differentiation, and apoptosis.
9-cis-Retinoic acid (9cRA) is a naturally occurring
ligand with a high affinity for both the retinoic acid receptors and
the retinoid X receptors. We hypothesized that treatment with 9cRA
would prevent mammary tumorigenesis in transgenic mice that
spontaneously develop mammary tumors. To test this hypothesis,
C3(1)-SV40 T antigen (Tag) mice, which develop mammary tumors by the
age of 6 months, were treated daily p.o. with vehicle or two different
dose levels of 9cRA (10 or 50 mg/kg) from 5 weeks to 6 months of age.
Tumor size and number were measured twice each week, and histological
samples of normal and malignant tissue were obtained from each mouse at
time of sacrifice. Our results demonstrate that 9cRA suppresses mammary
tumorigenesis in C3(1)-SV40 Tag-transgenic mice. Time to tumor
development was significantly delayed in treated mice; median time to
tumor formation for vehicle-treated mice was 140 days
versus 167 days for mice treated with 50 mg/kg 9cRA
(P = 0.05). In addition, the number of tumors per
mouse was reduced by >50% in mice treated with 9cRA (3.43 for
vehicle, 2.33 for 10 mg/kg 9cRA, and 1.13 for 50 mg/kg 9cRA,
P 
0.002). Histological analysis of the mammary
glands from vehicle and treated mice demonstrated that 9cRA treatment
also did not affect normal mammary gland development.
Immunohistochemical staining of normal and malignant breast tissue and
Western blot analysis demonstrated that SV40 Tag expression was not
affected by treatment with retinoids. Single doses of 10 and 50 mg/kg
resulted in peak plasma concentrations of 3.4 and 6.71
µM, respectively. Daily doses of 9cRA for 28 days
resulted in plasma concentrations of 0.86 and 1.68 µM,
respectively, concentrations consistent with that seen in humans
treated with 9cRA in clinical trials. These results demonstrate that
9cRA suppresses mammary carcinogenesis in transgenic mice without any
major toxicity and suggest that retinoids are promising agents for the
prevention of human breast cancer.
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