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Experimental Therapeutics |
-Difluoromethylornithine in TRAMP Mice1
Departments of Dermatology [S. G., N. A., H. M.], Urology [S. R. M.], and Pathology [G. T. M.], Case Western Reserve University, Cleveland, Ohio 44106, and Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030 [N. M. G.]
Development of effective chemopreventive agents for human consumption
requires conclusive evidence of their efficacy in animal models that
have relevance to human diseases. Transgenic adenocarcinoma mouse
prostate (TRAMP) is an excellent model of prostate cancer that mimics
progressive forms of human disease inasmuch as 100% of males develop
histological PIN by 8–12 weeks of age that progress to adenocarcinoma
with distant site metastases by 24–28 weeks of age. In these animals,
ornithine decarboxylase (ODC) activity (>3-fold) as well as protein
expression (>4-fold) was found to be markedly higher in the
dorsolateral prostate as compared with the nontransgenic littermates,
suggesting their suitability to determine the chemopreventive effect of
-difluoromethylornithine (DFMO), an enzyme-activated irreversible
inhibitor of ODC, against prostate cancer. Using male TRAMP mice, we
studied the effect of oral consumption of DFMO on development of
prostate carcinogenesis and surrogate end point biomarkers related to
prostate cancer progression. In two independent experiments, each
consisting of 8 animals on test, the cumulative incidence of prostatic
cancer development at 28 weeks of age in 16 untreated TRAMP mice was
100% (16 of 16), whereas 94% (15 of 16) and 69% (11 of 16) of the
animals exhibited distant site metastases to lymph nodes and lungs,
respectively. Oral consumption of 1% DFMO (w/v) in the drinking water
to TRAMP mice from 8 to 28 weeks of age resulted in a significant
decrease in (a) weight (59%) and volume (66%) of
prostate, (b) genitourinary weight (63%), and
(c) ODC enzyme activity (52%) in the dorsolateral
prostate. Importantly, in none of the DFMO-fed TRAMP mice were any
distant metastases to lymph node and lungs observed. Furthermore, DFMO
treatment resulted in the marked reduction in the protein expression of
proliferation cell nuclear antigen, ODC, and probasin in the
dorsolateral prostate. The protein expression of antimetastases
markers, i.e., E-cadherin and - and ß-catenin, was
found to be restored in DFMO-fed animals as compared with the
non-DFMO-fed mice. These chemopreventive effects of DFMO were further
confirmed by immunohistochemical analysis of the dorsolateral prostate.
Histological analysis of the dorsolateral prostate of DFMO-fed animals
displayed marginal epithelial stratification, a small number of
cribriform structures, elongated hyperchromatic epithelial nuclei, and
a significant increase in apoptotic index. Non-DFMO-fed animals, on the
other hand, displayed extensive epithelial stratification with profound
cribriform structures accompanied with marked thickening, remodeling,
and hypercellularity of the fibromuscular stroma. In nontransgenic
littermates fed with DFMO, no significant alterations in the above
parameters were evident. These data demonstrate that ODC represents a
promising and rational target for chemoprevention of human prostate
cancer and that TRAMP mice are excellent models for screening of novel
drugs and chemopreventive regimens for potential human use.
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