Proliferative Tumor Doubling Times of Prostatic Carcinoma

Prostate cancer (PCa) has a variable biology ranging from latent cancer to extremely aggressive tumors. Proliferative activities of cancers may indicate their biological potential. A flow cytometric assay to calculate maximum proliferative doubling times (Tmax) of PCa in radical prostatectomy specimens after preoperative in vivo bromodeoxyuridine (BrdU) infusion is presented. Only 4/17 specimens had tumors large enough for flow cytometric analysis. The Tmax of tumors was similar and ranged from 0.6 to 3.6 months. Tumors had calculated doubling times 2- to 25-fold faster than their matched normal tissue. Variations in labeling index and Tmax were observed within a tumor as well as between different Gleason grades. The observed PSA doubling times (PSA-DT) ranged from 18.4 to 32.0 months, considerably slower than the corresponding Tmax of tumors involved. While lack of data for apoptotic rates is a limitation, apparent biological differences between latent versus aggressive PCa may be attributable to variations in apoptotic rates of these tumors rather than their cell proliferative rates

Biological implications of androgen dependent changes in proton‐NMR relaxation times in rat ventral prostate

The present studies were conducted in rat ventral prostate to determine if proton nuclear magnetic resonance (1H‐NMR) might be a useful tool to monitor physiologic changes in an androgen‐dependent target tissue after ablation and reconstitution. Ventral prostate mass and blood flow (86RbCl distribution) decreased markedly after castration. Although prostate water content was not affected by androgen ablation, 1H‐NMR spin‐lattice (T1) and spin‐spin (T2) relaxation times determined on excised prostate tissue were reduced by 10% and 50%, respectively. Testosterone propionate (Tp) reconstitution resulted in a prompt but transient increase in total water content, marked increases in prostate blood flow, and regrowth of the gland. 1H‐NMR studies indicated that although T1 lengthening after Tp was temporally related to changes in prostate water content, T1's remained prolonged after total prostate water content returned to control levels. Increased Gd‐DTPA‐dimeg modification of prostate T1 by Gadolinium‐DTPA‐dimethyl glucamine in androgen reconstituted rats implied that prostate extracellular water volumes were markedly increased during intervals of increased T1. Recovery of prostate T2 relaxation times after Tp was delayed with respect to changes in T1, water content, and prostate blood flow, but was temporally correlated with increase in prostate dry mass. Studies to assess Gd‐DTPA‐dimeg T2 modification showed that prostate T2 changes after androgen depletion and replacement reflected spin‐spin relaxation of water protons outside the in vivo Gd‐DTPA‐dimeg distribution volume. The results from these studies indicate that 1H‐NMR and paramagnetic probes may be useful to noninvasively monitor biologically relevant changes in cellular and extracellular water in androgen‐dependent target tissues during hormonal manipulations

Silibinin down-regulates survivin protein and mRNA expression and causes caspases activation and apoptosis in human bladder transitional-cell papilloma RT4 cells

Bladder cancer is the fourth and eighth most common cancer in men and women in the United States, respectively. Survivin, a member of inhibitor of apoptosis protein (IAP) gene family, is deregulated in a wide range of malignancies, including carcinoma of the bladder urothelium. Recent advances have identified survivin as a novel intervention target to induce apoptosis in cancer cells by phytochemicals or synthetic agents. Silibinin is a naturally occurring flavanone, isolated from milk thistle extract, and has been shown to possess cancer prevention/intervention potential against various cancers. In several animal and human studies, it is found to be safe and non-toxic. Human bladder transitional-cell papilloma RT4 cells were treated with silibinin and analyzed for survivin protein and mRNA levels by Western blotting and real-time RT-PCR, respectively. Silibinin treatment of cells for 24 h at 100 μ M dose resulted in <SUP>~</SUP> 50% decrease in survivin protein level; however, treatment at 200 μ M dose for 24 and 48 h showed a complete loss in survivin protein without any change in actin used as loading control. Employing RT-PCR analysis we also observed that silibinin causes a strong to complete decrease in survivin mRNA levels. In other studies, down-regulation of survivin by silibinin was associated with a very strong and prominent caspases-9 and -3 activation as well as PARP cleavage. Quantitative apoptotic assay showed that silibinin decreased survivin levels and caspases-PARP cleavages, in accord with a strong apoptotic death and growth inhibition of RT4 cells. Together, these findings suggest that more studies are needed to investigate in vivo effect of silibinin on survivin expression and associated biological effects in bladder cancer that could provide useful information for silibinin efficacy in the prevention/intervention of human bladder cancer