Mikinobu Ohtani

Effects of a Soybean Isoflavone Mixture on Carcinogenesis in Prostate and Seminal Vesicles of F344 Rats

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti‐carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2′‐dimethyl‐4‐aminobi‐phenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2‐week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6‐week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN‐76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.

Expression of antitumor response role of attachment and viability of bacillus calmette—guérin to bladder cancer cells

Background. Antitumor effects of Bacillus Calmette‐Guérin (BCG) against superficial urinary bladder cancer is known to be strong when BCG is directly infused into the bladder cavity. For expression of that effect, attachment of BCG to tumor cells is reported to be essential as the first step. Our study was conducted to elucidate the significance of attachment of BCG to tumor cells in inducing the antitumor effect.

A NEW TUMOR MARKER FOR BLADDER CANCER

Biochemical assay and immunohistochemical staining of neutral endopeptidase were performed on bladder cancer cells. In superficial bladder cancer the enzyme activity and immunohistochemical intensity of staining were high, while invasive bladder cancer showed only a low level of activity. This finding suggests that neutral endopeptidase is expressed at a certain stage of cell differentiation, during the neoplastic process in the bladder. Gene expression is assumed to be closely correlated with this mechanism. From the results of this study neutral endopeptidase will serve as a new tumor marker for bladder cancer as well as acute lymphatic leukemia.

Detection and cloning of a protein recognized by anti-human prostate-specific antigen (PSA) antibody in the rat ventral prostate

Prostate‐specific antigen (PSA), a 33 kDa glycoprotein produced in the epithelium of the human prostate, has become established as a useful tumor marker for prostate cancer in man. Since reports of homologous proteins in animals other than primates have been lacking, the present investigation was carried out to identify any PSA‐like protein in rats. Immunoblot analysis using a specific monoclonal anti‐human PSA antibody detected a 32 kDa immunoreactive protein in the ventral lobe of the rat prostate, but not in other lobes or in other tissues. Positive immunostaining was observed only for the luminal surface of the glandular epithelium and the intraductal fluid in the ventral prostate. Sequence analysis of a cDNA for the rat PSA‐like protein, cloned by immunoscreening of an expression cDNA library prepared from the ventral lobe, revealed identity to the rat submaxillary gland S3 kallikrein. Human PSA also belongs to the kallikrein family. Thus, this protein produced in the rat ventral prostate was suggested to be a possible counterpart of human PSA.

Validity of Short-term Examination for Antipromoters of Bladder Carcinogenesis

Various compounds were screened for antipromoter activity in bladder carcinogenesis in rats with a view to using them clinically to inhibit postoperative intravesical ectopic tumor growth of superficial papillary bladder cancer. Their inhibitions of the effect of sodium saccharin in maintaining increased agglutinability of bladder cells by concanavalin A were examined in 4‐week tests. The compounds found to inhibit the effect of saccharin were α‐tocopherol, ascorbic acid, aspirin, all‐trans aromatic retinoid, α‐difluoromethylornithine, sodium cyanate and p, p′‐diaminodiphenylmethane. Considering the toxicities of some of these chemicals, ascorbic acid and α‐difluoromethylornithine were concluded to be the most promising for future clinical trials.

Effects of intravesical instillation of antitumor chemotherapeutic and immunotherapeutic agents on bladder lesion development in rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effects of 12 weeks of intravesical instillation of bleomycin, cisplatinum and picibanyl on development of urinary bladder tumors and preneoplastic lesions were examined in rats pretreated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) for four weeks. Upon sacrifice at week 36, histopathological examination revealed a significantly reduced incidence of PN hyperplasia and a tendency for decreased papilloma generation in rats given cisplatinum. However, the other treatments were not associated with any effect on carcinogen-induced lesion development. The results demonstrate that cisplatinum has a potential for postinitiation inhibition of rat bladder carcinogenesis.

Immunological protection induced by bacillus Calmette-Guérin treatment in a murine bladder tumor model

Background: It has been previously reported that MBT‐2 tumor growth is completely inhibited when mice are inoculated with bacillus Calmette–Guérin (BCG). In this study it was examined whether or not vaccination with a mixture of BCG and MBT‐2 cells also induces immunological protection against murine bladder tumors.

The effect of dose intensity on M-VAC therapy for advanced urothelial cancer

M-VAC therapy (methotrexate, vinblastine, Adriamycin, and cisplatin) has improved the treatment results of urothelial cancer patients. However, it is sometimes complicated by drug toxicities, including bone marrow suppression. We analyzed the relative dose intensity in each patient undergoing M-VAC chemotherapy in relation ot the chemotherapeutic effect and survival. In addition, the role of granulocyte colony-stimulating factor (G-CSF) in the dose intensity of M-VAC therapy was analyzed. Between June 1988 and March 1993, 29 patients with advanced urothelial cancer were treated with M-VAC therapy in our institution. Of 18 patients with evaluable lesions, 2 (11.1%) showed a complete response (CR) and 7 (38.9%) showed a partial response (PR), and the overall response rate was 50.0%. The median follow-up period for these 18 patients was 14.6 months and the median survival was 8.7 months, with 12 of the 18 patients being alive at the time of analysis. The relative dose intensity (RDI) for these 18 patients was 0.81 for methotrexate, 0.80 for vinblastine, 0.92 for Adriamycin, and 0.91 for cisplatin, for a mean RDI of 0.87. There was no correlation between the chemotherapeutic effect and the RDI. When we calculated the RDI for all 29 patients who underwent M-VAC therapy, G-CSF increased the RDI of Adriamycin significantly. The results of this retrospective study indicate that a dose intensity for M-VAC therapy in the range of 0.61–1.00 is unlikely to correlate with the chemotherapeutic effect, although G-CSF contributes to increasing the RDI of Adriamycin.

The feasibility and effectiveness of robot-assisted radical cystectomy after neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer

Objectives The aim of this study was to compare 29 muscle-invasive bladder cancer patients who received neoadjuvant chemotherapy (NAC) followed by immediate robot-assisted radical cystectomy (RARC) with those who underwent minimum-incision endoscopic RC (MIE-RC). Methods We retrospectively reviewed the charts of 430 consecutive patients who underwent RC and bilateral pelvic node dissection (PLND) between May 1994 and July 2016. Our study focused on patients with MIBC who had histologically confirmed stage T2-T4aN0M0 urothelial carcinoma of the bladder and received NAC prior to surgery. Accordingly, 225 patients were included in this analysis, of whom, 29 underwent RARC (RARC group) and 196 underwent MIE-RC (MIE-RC group). The primary endpoints in this study were the positive surgical margin (PSM) rate and lymph node (LN) count. Results In the RARC group, 20 patients underwent RARC with intracorporeal urinary diversion and nine patients underwent RARC with extracorporeal urinary diversion. The median surgical duration for RC and bilateral PLND was 125 min in the RARC group and 98 min in the MIE-RC group (P < 0.001). The rate of PSM was 0% in the RARC group and 0.5% in the MIE-RC group. The median LN counts were 15 in the RARC group and 18 in the MIE-RC group. No intra-operative complication or mortality was associated with RARC or MIE-RP. All complications were grade 2 according to the Clavien-Dindo classification. Conclusions Our initial experience with NAC followed by RARC appears to be favorable, with acceptable operative and perioperative clinical outcomes when compared with those of MIE-RC.

Evaluation of the invasive potential of superficial bladder cancer by adenosine triphosphate measurement

In order to predict the malignant potential of superficial bladder cancer, in 121 patients with this malignancy adenine nucleotide levels (adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate) and energy charge in bladder cancer cells were determined. The nucleotides were analyzed according to the method of Bücher, and the energy charge was calculated by applying the formula of Atkinson. It was clearly pointed out that superficial bladder tumors, which became invasive and/or metastatic, had higher levels of adenylate compounds than those which became not. Our results show that a high correlation exists between adenine nucleotide content and tumor progression.