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Positron (β + ) emitting radionuclides have been used for positron emission tomography (PET) imaging in diagnostic medicine since its development in the 1950s. Development of a fluorinated glucose analog, fluorodeoxyglucose, labelled with a β + emitter fluorine-18 ( 18 F-FDG), made it possible to image cellular targets with high glycolytic metabolism. These targets include cancer cells based on increased aerobic metabolism due to the Warburg effect, and thus, 18 F-FDG is a staple in nuclear medicine clinics globally. However, due to its attention in the diagnostic setting, the therapeutic potential of β + emitters have been overlooked in cancer medicine. Here we show the first in vitro evidence of β + emitter cytotoxicity on prostate cancer cell line LNCaP C4-2B when treated with 20 Gy of 18 F. Monte Carlo simulation revealed thermalized positrons (sub-keV) traversing DNA can be lethal due to highly localized energy deposition during the thermalization and annihilation processes. The computed single and double strand breakages were ~ 55% and 117% respectively, when compared to electrons at 400 eV. Our in vitro and in silico data imply an unexplored therapeutic potential for β + emitters. These results may also have implications for emerging cancer theranostic strategies, where β + emitting radionuclides could be utilized as a therapeutic as well as a diagnostic agent once the challenges in radiation safety and protection after patient administration of a radioactive compound are overcome.

Prostate-specific antigen (PSA) gene expression is regulated by androgen receptor (AR) through androgen response elements (AREs) in the promoter region of the PSA gene. A single nucleotide polymorphism with guanine (G) to adenine (A) substitution is identified at position -158 in the ARE of the PSA gene. The purpose of this study was to investigate the allelic differences in the PSA promoter activity in vitro and the relation to several clinical factors of prostate cancer patients in the Japanese population. No significant differences of promoter activity in luciferase assay and binding activity of androgen receptor were noted between the two alleles in vitro. The PSA -158 G/A polymorphism was determined by PCR amplification and restriction digestion assays in 101 organ-confined prostate cancer (PC) patients who underwent radical prostatectomy and 52 controls with benign prostatic hyperplasia. The results revealed that homozygosity for the A allele in Japanese is less common (only 8.5%) than in ethnic populations. There were no significant differences in serum PSA value at the time of diagnosis, differentiation of cancer, pathological stage, cancer volume or ratio of serum PSA/ cancer volume. However, cancer volume after neoadjuvant endocrine therapy was significantly smaller in GG genotype than in AA + AG genotypes. Our data indicate that the PSA -158 G/A polymorphism has no effect on the PSA promoter activity in vitro and no association with the serum PSA level in Japanese men, however suggest that the patients with GG genotype of ARE1 may be more sensitive to androgen ablation therapy. Taken together, the ARE1 polymorphism in the PSA gene promoter may be one of the biomarkers for response to androgen deprivation therapy.

Carcinogenesis of the prostate involves androgen influences, and associations between genetic polymorphisms of androgen receptor and metabolizing enzymes and prostate cancer risk have been reported. Roles for non-androgenic hormones are not well defined, but they also may have an impact judging from epidemiological and animal experimental alphalambda zeta of data. The purpose of the study was to determine whether hormone-related polymorphisms are associated with prostate cancer risk. A case-control study was performed with 147 Japanese prostate cancer patients and 266 urological controls. Polymorphisms of target genes [cytochrome P450 (CYP) 1B1, Leu432Val; debrisoquine hydroxylase, (CYP2D6)*4; aromatase (CYP19), Arg264Cys; estrogen receptor (ER)alpha-Xx (Xba I) and Pp (Pvu II); ERbeta-Rr (Rsa I); progesterone receptor (PR) Alu in intron 7] were examined by PCR-based methods. The capital and small letters signify the absence and presence of restriction sites, respectively. Odds ratios (OR) were adjusted for age using multiple logistic regression analysis with SPSS Medical Pack. Among the seven examined genetic polymorphisms, significant associations between CYP1B1 Leu432Val (OR 4.80; 95% confidence interval (CI), 1.21-19.05) and Alu in intron 7 of PR (OR 4.17; 95%CI, 1.26-13.85) were found. As for combined effects, the CYP1B1 polymorphisms (Leu/Val+Val/Val) together with heterozygosity for Alu in the PR were more frequent among prostate cancer patients (1.45%) than controls (0.41%), although without significance (OR, 3.99; 95%CI, 0.36-44.8). The combination of ERalpha (P/p+p/p) polymorphisms with heterozygosity for Alu in the PR demonstrated an OR of 4.56 (95%CI, 1.01-20.6). This pilot study showed that CYP1B1 and PR polymorphisms, alone or in combination, might be associated with prostate cancer risk. They might, therefore, have potential as a tool for identifying high-risk individuals.

Between 1994 and 2001, 80 patients underwent radical prostatectomy without adjuvant therapy for clinical stage B and C prostate cancer. The patients were not treated with adjuvant therapy before biochemical prostate specific antigen (PSA) failure. Of all 80 patients, 35 patients (43.8%) received neoadjuvant hormonal therapy prior to radical prostatectomy (the neoadjuvant therapy group), 45 patients (56.2%) underwent prostatectomy alone (the surgery alone group). Retrospective analysis to evaluate the effects of neoadjuvant therapy was performed from clinicopathological findings and the biochemical PSA failure-free rate. Of all patients, 58 (72.5%) were in clinical stage B and 22 (27.5%) were in clinical stage C. Of 58 patients in clinical stage B, 19 (32.8%) underwent prostatectomy combined with neoadjuvant therapy. Of the 22 patients in clinical stage C, 17 (77.3%) underwent prostatectomy combined with neoadjuvant therapy. Pathologically, 37 (46.3%) were in stage B, 38 (47.5%) in stage C and 2 (2.5%) in stage D1. Three patients in the neoadjuvant therapy group had no malignant findings in specimens of prostatectomy. In comparison with the clinical stage, pathologically 8 (22.9%) showed overstaging, 4 (5.0%) understaging and 23 (28.8%) accurate staging in the neoadjuvant therapy group, respectively, 0 (0.0%), 20 (44.4%), and 25 (55.6%) in the surgery alone group. In clinical stage B and C, there was no significant difference in the biochemical PSA failure-free rate between the neoadjuvant therapy group and the surgery alone group. On the other hand, in pathological stages B, the 5-year PSA failure-free rate was 63.2% in the neoadjuvant therapy group, but 100% in the surgery alone group. Although neoadjuvant therapy may have some effect on downstaging, our retrospective analysis suggests that it has no significant effect on PSA failure-free rate.

Background: In our previous study, the gene encoding the human X-box binding protein 1 (hXBP-1) was isolated as a down-regulated gene in advanced prostate cancers using cDNA-representational difference analysis (RDA). In the present investigation, we characterized alterations of hXBP-1 in prostate cancer specimens., Methods: Expression patterns of hXBP-1 in a series of human prostate cancers were examined by Northern blotting, mRNA in situ hybridization or immunohistochemistry. Loss of heterozygosity (LOH) analysis using microsatellite markers and gene mutation analysis in the hXBP-1 region were also performed., Results: Expression of hXBP-1 was localized in epithelial and adenocarcinoma cells of the prostate. An inverse correlation between hXBP-1 expression and histological differentiation was found in a series of prostate cancers without hormonal therapy. Majority of refractory cancer cases exhibited weak hXBP-1 expression. No allelic loss or gene mutations were found in the hXBP-1 region and its open reading frame, respectively, in the prostate cancer examined., Conclusions: These results suggest that reduction of hXBP-1 expression may be a useful marker for prostate adenocarcinoma differentiation and progression., (Copyright 2002 Wiley-Liss, Inc.)

Background: The purpose of this study was to identify preoperative variables that would be useful in objectively selecting prostate cancer patients for nerve-sparing prostatectomy., Methods: Twenty-six patients with clinical T1c-T2c cancers were evaluated for cancerous involvement in the region of the neurovascular bundles (NVB) from prostatectomy specimens. Preoperative prostate-specific antigen (PSA) and pathologic features in systematic biopsy specimens also were reviewed., Results: A total of eight (31%) patients had cancerous involvement in the region of the NVB, including four on the right side, three on the left side and one on both sides. The percentage of each biopsy specimen occupied by the cancer was scored from zero to four and defined as the positive biopsy score. Preoperative PSA (P = 0.046), mean positive biopsy score (total sum of positive biopsy score divided by number of biopsy specimens; P = 0.001), number of cores containing cancer (P = 0.011), percentage of cores involved (P = 0.036) and maximum positive biopsy score (P < 0.001) were significant for predicting cancerous involvement in the NVB region using univariate analysis. However, only the mean positive biopsy score was independently significant according to multivariate analysis. To predict cancerous involvement in the region of each NVB, we found that ipsilateral mean positive biopsy score (total sum of corresponding positive biopsy score divided by number of ipsilateral biopsy specimens), number of cores involved on the ipsilateral side, percentage of cores involved on the ipsilateral side and maximum positive biopsy score on the ipsilateral side were significant predictive variables: the ipsilateral mean positive biopsy score being most appropriate for clinical practice., Conclusion: Ipsilateral mean positive biopsy score in systematic biopsy specimens can be an appropriate variable for selecting patients with localized prostate cancer for nerve-sparing prostatectomy.

Aminopeptidase N (AP-N) degrades collagen type IV and is proposed to play a role in tumor invasion. However, the precise functions of AP-N in tumor cells and the relationship of AP-N to prostate cancer remains unclear. In our study, we examined a possible role for zinc in the regulation of AP-N enzymatic activity in relation to tumor cell invasion in human prostate. AP-N purified from human prostate was irreversibly inhibited by low concentrations of zinc (Ki = 11.2 microM) and bestatin. AP-N, which has zinc in the active center, was also inhibited by the chelating agents, EDTA, o-phenanthroline and EGTA. EDTA was shown to remove zinc from the enzyme. When the effects of zinc and bestatin on invasion of PC-3 cells were investigated in vitro using a Transwell cell-culture chamber, zinc and bestatin effectively suppressed cell invasion into Matrigel at the concentration range of 50-100 microM. These results strongly suggest that the suppression of PC-3 cell invasion by zinc is based on the inhibition of AP-N activity by zinc. We also evaluated the expression of AP-N to investigate the relationship with the progression of prostate disease in human cancerous prostate. AP-N was found to be located at the cytoplasmic membranes of prostate gland epithelial cells and to be expressed more in prostate cancer, while the expression of prostate-specific antigen (PSA), which is a useful marker for prostate cancer, was shown in normal and cancer tissues, suggesting that AP-N is potentially a good histological marker of prostate cancer. Thus, highly expressed AP-N in human cancerous prostate probably plays an important role in the invasion and metastasis of prostate cancer cells., (Copyright 2001 Wiley-Liss, Inc.)

Although different histological grading systems of prostatic cancer refer to well-described characteristics, results are hard to reproduce. The aim of this study was to obtain morphometric data that would enable objective and reproducible grading of prostatic cancers by stereological estimation of mean nuclear volume (MNV). The clinical records and tissue specimens from 100 patients who were newly diagnosed as having prostatic cancer from 1973 to 1990 and who were followed up for 5 years or longer were retrospectively examined. We analysed the relationship between MNV and clinical stage, Gleason score and histological grading according to the World Health Organization (WHO) classification. To evaluate prognostic predictors, a multivariate analysis of factors associated with cause-specific survival was performed. We found a good correlation between the MNV and clinical stage and between the MNV and histological grading. There was no correlation between MNVs and Gleason scores. Multivariate analysis revealed that the MNV was the only predictor of survival time (coefficient 0.005; P < 0.0001; hazard ratio 1.005). We consider that the MNV is an excellent predictor of the prognosis in patients with prostatic cancer. Moreover, stereological estimation of MNV is a simple, quick, inexpensive and reliable morphometric procedure that enables the quantitative analysis of the histological and biological character of prostatic cancer.

The results of a mass screening examination for prostate cancer conducted from 1989 to 1993 at a local town, Kawagoe-cho, in Mie Prefecture were evaluated. Among the 216 examinees, 4 were found to have prostate cancer. The most accurate examination was the prostate specific antigen (PSA), which was followed by digital examination and transrectal ultrasound. The applicants for the prostate cancer screening accounted for only 8% of the Kawagoe-cho male residents over 40 years old. An educational campaign of prostate disease in the area must be started to increase the number of applicants. We concluded that the most effective modality for the screening program was a combination of PSA and digital examination in the field study, and transrectal ultrasound accompanied by systemic biopsy results in the second tool for screening.

To evaluate the correlation between the histological grade and the prognosis, we reviewed 100 cases of prostatic cancer according to the Japanese General Rules of Prostatic Cancer (JGRPC) and Gleason grading system. The study led to the following results: (1) There was a close relation between the JGRPC grade and Gleason score (GS). (2) The JGRPC grade and Gleason score were equally concerned with the clinical stage. (3) There were significant differences in survival rate between well and moderately, well and poorly differentiated groups by the JGRPC grading system, and between GS 2-4 and GS 5-7, GS 2-4 and GS 8-10 groups by Gleason score. (4) In proportion to the JGRPC grade, the cancer death rate increased linearly in each stage. (5) When the patients were grouped according to their JGRPC grades of main lesion and accompanied lesion, the cancer death rate increased in the cases with lower differentiated elements. We conclude that the JGRPC grading system is easily comprehensible, and equal with the Gleason grading system to predict the prognosis of prostatic cancer.

The serum levels of gamma-Seminoprotein (gamma-Sm) were determined by enzyme immunoassay in 77 patients with prostatic cancer (30 untreated and 47 treated), 44 patients with benign prostatic hypertrophy and 12 patients with prostatitis. Serum levels of gamma-Sm in each disease were as follows; untreated prostatic cancer 23.2 +/- 18.3 ng/ml (positive rate 93%), treated prostatic cancer 4.7 +/- 8.3 (positive rate 25.5%), benign prostatic hypertrophy 3.6 +/- 3.3 (positive rate 23.7%), prostatitis 2.0 +/- 2.0 (positive rate 7.7%). Serum gamma-Sm levels in prostatic cancer were higher in advanced stage but relatively low in poorly differentiated adenocarcinoma. We consider that the level of serum gamma-Sm is a useful tumor marker as well as prostatic acid phosphatase (PAP) in diagnosis and follow-up of the patients with prostatic cancer.