Significance of chemoprevention for prostate cancer development: Experimental in vivo approaches to chemoprevention

Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Pathology International (Impact Factor: 1.69). 02/2008; 58(1):1-16. DOI: 10.1111/j.1440-1827.2007.02182.x
Source: PubMed


Prostate cancer is the most common tumor in men in Western countries and mortality in Asian countries from the disease appears to be constantly increasing. Characteristics include (i) frequent discovery of latent carcinoma, even in countries with low incidences of clinical cancer; (ii) very long time to clinically significant cancer; (iii) few patients under 50 years of age (primarily a disease of elderly men); (iv) strong influences of environmental factors such as food; (v) temporal effectiveness of androgen deprival therapy; and (vi) no effective therapeutic approaches once hormone-refractory neoplasms have developed. Therefore prostate cancer is particularly indicated for preventive efforts, especially chemoprevention. Several large-scale chemoprevention trials have in fact been conducted and some have found suppressive effects. However, not all have been proven to have benefit. Experimental preclinical investigations, particularly using animal models, are recommended to find better chemopreventive agents with less adverse effects. Data using rat models have generated very interesting findings from which mechanism-based strategies can be proposed. In the present report the importance of chemoprevention of prostate cancer will be discussed using the data on human and rat prostate cancer development.

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    ABSTRACT: Prostate cancer, the most prevalent non-cutaneous cancer in men, is associated with increased age. This suggests that dietary chemopreventive measures could be effective in delaying the onset or decreasing the severity of the disease. We utilized the Lobund-Wistar rat nitrosomethylurea induced, testosterone promoted (NMU-T) model of male sex accessory gland cancer to test the potential chemopreventive effects of myo-inositol and limonene on tumor incidence and associated protease activities. Tumors were found to arise in the seminal vesicles and dorsal and anterior prostate lobes. There were also some tumors that appeared to arise in both the seminal vesicles and anterior prostate, and in some cases the tissue of origin was not clear. The distribution of tumors as to site of origin in limonene or myo-inositol treated animals did not vary from that of the starch fed control animals, and the number of animals presenting with metastases did not vary significantly between treatment groups. There was a statistically significant delay in onset of tumors in myo-inositol, but not limonene fed rats, at 10 months post-induction of carcinogenesis; however, at 12 and 15 months this was not significant. The ventral prostate and seminal vesicles expressed pro-MMP-2 and plasminogen activator (PA) activities. Based on sensitivity to amiloride, the PA activities were predominately urokinase (uPA) in the ventral prostate and a mixture of tissue-type activator (tPA) and uPA in the seminal vesicles of non-treated rats. Sex accessory gland tumors, and metastases, expressed increased levels PA and pro- and active forms of MMP-2 and -9. The PA activities of the tumors were a mixture of uPA and tPA. There was no difference in the levels of these protease activities based on the tissue of tumor origin, nor in tumor vs metastasis. These studies indicate that MMP and PA activities play a role in sex accessory gland tumor biology and that dietary supplementation with myo-inositol can delay but not ultimately prevent the development of such tumors.
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    ABSTRACT: Nontoxic naturally occurring metabolite of estrogen namely 2-methoxyestradial (2ME2) found in serum and urine has been shown to be antitumorigenic in various tumor models including the prostate. A recent study conducted in breast cancer cells showed growth stimulatory effect of 2ME2 when used at low concentrations (10-750 nM). Studies from our laboratory has demonstrated prostate tumor preventive ability of 50 mg/kg 2-ME2. In this study we show that concentrations of 2-ME2 as low as 1 µM is sufficient to inhibit proliferation and induce apoptosis in androgen responsive LNCaP cells. In addition oral administration of doses lower than 50 mg/kg prevented prostate tumor development in LNCaP xenograft model. The observed tumor growth inhibition was associated with induction of apoptosis, increased expression of Wee1 kinase and p34cdc2. In addition administration of 25 mg/kg 2-ME2 prevented tumor development significantly that is associated with reduction in serum PSA levels.
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