Polyamine metabolism in prostate cancer : studies on localization, cell growth and apoptosis

The involvement of polyamines in cellular growth and differentiation has prompted many studies of their possible role in cellular neoplasia, including prostatic carcinoma and benign hyperplasia, which represent increasingly important pathologies in men. The precise role of the polyamine system in cellular physiology remains to be clarified. Insight in the exact (sub)cellular localization of polyamine metabolic enzymes might greatly contribute to the elucidation of the specific functions of polyamines in (tumor) cell growth. As described in the first part, we developed cytochemical methods for the (sub)cellular localization of ornithine decarboxylase and polyamine oxidase, which are involved in the biosynthesis and catabolism of polyamines, respectively. The second objective of this thesis was to establish the use of polyamines as determinants of malignant cellular behavior and as potential targets for chemotherapy in prostate cancer. Biochemical analysis of various human prostatic tissues showed that concentrations of the polyamine spermine were substantially lower in prostatic carcinoma compared to normal or benign prostatic tissue. We explored if magnetic resonance spectroscopy (MRS) could be used for the non-invasive determination of spermine in the prostate. Studies on prostatic biopsy samples showed that spermine can be detected and identified with MRS. Recent studies indicate that analogs of polyamines have significant antitumor activity in several human solid tumor models. We have studied the antitumor effect of the polyamine analog N1,N11-di(ethyl)norspermine (DENSpm) on prostatic cancer cells. The in vitro studies showed that all tested human prostatic cancer cells lines were sensitive to DENSpm. An in vivo study in athymic nude mice showed that DENSpm was able to inhibit tumor growth of xenografts of a human prostatic cancer cell line. In conclusion, the polyamine system provides an attractive target to study, to predict and to manipulate the cell kinetic behavior (cell growth, apoptosis) of tumor cells In addition, this study provided new tools and/or techniques for the in situ monitoring of polyamine metabolis