Significance of chemoprevention for prostate cancer development: experimental in vivo approaches to chemoprevention.
ABSTRACT 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: Argyrophilic staining of the nucleolar organizer regions (AgNOR) was studied in 30 cases of benign prostatic hyperplasias (BPH), 17 cases of latent prostate carcinomas, 50 cases of clinical carcinomas and seven cases of metastatic lesions from prostate carcinomas. The criteria for these comparisons were the number of positive-staining dots per nucleus, the area of the dots, and a relative score determined by multiplying the number of positive-staining dots in the nuclei by the areas of the dots. Overall, there were no significant differences in these three parameters between BPH and latent carcinomas. Among latent carcinomas, however, significantly higher AgNOR scores were observed for infiltrative lesions than for non-infiltrative lesions. AgNOR dot number, area and score increased as tumors became less differentiated, with no significant differences detected in metastatic versus non-metastatic carcinomas. These results suggest that some latent tumors are similar in biological behavior, such as cell proliferation, to clinical carcinoma.Pathology International 05/1994; 44(4):297-302. · 1.72 Impact Factor
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ABSTRACT: We previously demonstrated that an angiotensin II receptor blocker (ARB) had the potential to inhibit cell proliferation of prostate cancer. In this study, we examined whether an ARB could elicit an antiproliferative effect on hormone-refractory prostate cancer, clinically. Twenty-three patients with advanced hormone-refractory prostate cancer who had already received secondary hormonal therapy using dexamethasone, and who were no longer receiving conventional therapy, were enrolled. All of the patients received candesartan 8 mg once daily per os and, simultaneously, androgen ablation. Change in prostate-specific antigen (PSA) was determined as the primary endpoint. The secondary end-point was change in performance status (PS). To investigate angiotensin II type 1 (AT1) receptor expression in prostate cancer tissue, real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed, using specimens, from untreated patients with prostate cancer. Eight patients (34.8%) showed responsive PSA changes; six showed a decrease immediately after starting administration and two showed a stable level of PSA. Six men with a PSA decline of more than 50% showed an improvement in PS. The mean time to PSA progression (TTPP) in responders was 8.3 months (range, 1-24 months). Half of the patients showed stable or improved PS during treatment. With regard to toxic effects, only one patient showed hypotension during treatment. The RT-PCR showed that AT1 receptor expression in well-differentiated adenocarcinoma was higher than that in poorly differentiated adenocarcinoma. These data showed that an ARB had potential biological effects on prostate cancer, suggesting the usefulness of the cytostatic activity of such agents on recurrent prostate cancer.International Journal of Clinical Oncology 01/2006; 10(6):405-10. · 1.73 Impact Factor
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ABSTRACT: Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.The Prostate 02/1992; 20(4):339-53. · 3.84 Impact Factor