Yoshiki Sugimura

NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese.

AbstractMethods. The cases were 102 patients with esophageal cancer, 143 with stomach cancer, 74 with colon cancer, 72 with rectal cancer, 192 with lung cancer, 237 with breast cancer, 56 with prostate cancer, and 108 with malignant lymphoma. Controls consisted of outpatients from two sources: 241 noncancer outpatients who underwent gastroscopy and 399 first-visit outpatients, expected to include about 20% with cancer. Genotyping was conducted by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Results. The TT genotype with null enzyme activity was found in 19.9% of the 241 noncancer gastroscopy examinees, 16.5% of the 399 first-visit outpatients, 12.7% of the esophageal cancer patients, 16.8% of the stomach cancer patients, 13.5% of the colon cancer patients, 9.7% of the rectal cancer patients, 17.7% of the lung cancer patients, 14.3% of the breast cancer patients, 16.1% of the prostate cancer patients, and 15.7% of the malignant lymphoma patients. The odds ratios (ORs) of the genotypes were not significant for any cancers combined or for any site of cancer, except for lung cancer (OR, 0.66; 95% confidence interval [CI], 0.46–0.96 for CT relative to CC). The OR of current smoking for cancers of the esophagus and lung combined was different between the CC genotype (OR, 2.06; 95% CI, 1.06–3.98) and TT genotype (OR, 5.11; 95% CI, 1.37–19.05), although the difference was not significant. Conclusion. This study suggests that the CC genotype of the NQO1 C609T polymorphism is associated with the risk of lung cancer, and that the TT genotype increases the risk of smoking for cancers of the esophagus and lung.

Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion

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 μM) 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 μM. 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.

ALTERED METHYLATION OF MULTIPLE GENES IN CARCINOGENESIS OF THE PROSTATE

The methylation status of 7 genes was examined in four cell lines, 36 samples of benign prostatic hyperplasia (BPH), 20 samples of prostatic intraepithelial neoplasia (PIN) and 109 samples of prostate cancer (PCa), using methylation‐specific PCR (MSP): the pi‐class glutathione S‐transferase (GSTP1), retinoic acid receptor beta 2(RARβ2), androgen receptor (AR), death‐associated protein kinase (DAPK), tissue inhibitor of metalloproteinase‐3 (TIMP‐3), O6‐methylguanine DNA methyltransferase (MGMT), and hypermethylated in cancer‐1 (HIC‐1). The frequencies of methylation in PCa were 88% for GSTP1, 78% for RARβ2, 36% for DAPK, 15% for AR, 6% for TIMP‐3, and 2% for MGMT, whereas the values were 11% for AR and DAPK, 6% for TIMP‐3, 3% for GSTP1, and 0 for RARβ2 and MGMT in BPH. Aberrant methylation of the GSTP1 and RARβ2 genes was detected in 30% and 20% of PIN, respectively. Most samples of BPH and PCa were positive for HIC‐1 methylation. Regarding accumulation of methylated cancer‐related genes, there were significant correlations between PCa and BPH as well as PIN and BPH. In the present study, a high frequency of aberrant promoter methylation of the GSTP1 and RARβ2 genes was noted in PCa. Our findings suggest that methylation of cancer‐related genes may be involved in carcinogenesis of the prostate.

Adjuvant methotrexate, vinblastine, adriamycin, and cisplatin chemotherapy has potential to prevent recurrence of bladder tumors after surgical removal of upper urinary tract transitional cell carcinoma

Objectives:  To evaluate the efficacy of adjuvant platinum based chemotherapy in upper urinary tract urothelial cancer following surgical resection in terms of survival benefit and inhibition of bladder cancer recurrence.

Midterm results of radiofrequency ablation versus nephrectomy for T1a renal cell carcinoma.

PurposeThe aim of this study was to retrospectively evaluate midterm results of renal radiofrequency (RF) ablation compared to the results after nephrectomy in patients with T1a renal cell carcinoma (RCC).Materials and methodsA total of 115 patients with a single RCC measuring ≤4 cm (T1a) were included; 51 patients underwent RF ablation, 54 patients radical nephrectomy, and 10 patients partial nephrectomy. The survival and the percent decreases in glomerular filtration rate (GFR) were compared among the three treatments.ResultsAlthough overall survival after RF ablation (75.0% at 5 years) was lower than those after radical and partial nephrectomy, the RCC-related survival (100% at 5 years) was comparable to those following radical nephrectomy (100% at 5 years) and partial nephrectomy (100% at 3 years). The disease-free survival (DFS) after RF ablation (98.0% at 5 years) was also comparable to those after radical nephrectomy (95.0% at 5 years) (P = 0.72) and partial nephrectomy (75.0% at 3 years) (P = 0.13). The percent decrease in the GFR at last follow-up in the RF ablation group (median 7.9%) was significantly lower than that in the radical nephrectomy group (median 29.0%) (P < 0.001) and comparable to that in the partial nephrectomy group (median 11.5%) (P = 0.73).ConclusionRF ablation provides RCC-related and DFS comparable to that found after nephrectomy with little loss of renal function.

Percutaneous radiofrequency ablation with transarterial embolization is useful for treatment of stage 1 renal cell carcinoma with surgical risk: results at 2-year mean follow up.

Objectives:  Despite laparoscopic partial nephrectomy and laparoscopic cryotherapy being performed lately, an even less invasive treatment would be desirable in high‐risk patients. Under local anesthesia with i.v. sedation, we were able to perform percutaneous radiofrequency ablation (RFA) combined with renal arterial embolization for unresectable stage 1 (T1NoMo) renal cell carcinoma (RCC). We evaluated the feasibility, safety and therapeutic effects of this technique after a 2‐year mean follow up.

Radiofrequency Ablation Combined with Renal Arterial Embolization for the Treatment of Unresectable Renal Cell Carcinoma Larger Than 3.5 cm: Initial Experience

The purpose of the study was to evaluate the feasibility, safety, and therapeutic effects of the combination of renal arterial embolization and radiofrequency (RF) ablation to reinforce the anticancer effect on renal cell carcinomas (RCCs) measuring 3.5 cm or larger. This study was undertaken to evaluate this combined therapy on large RCCs-based tumor geometry. Eleven patients with 12 RCCs 3.5 cm or larger in diameter (3.5–9.0 cm) underwent combined therapy. Two were exophytic tumors, and the remaining 10 tumors had components extending into the renal sinus fat. Tumor vessels were selectively embolized in nine patients and the renal artery was completely embolized in two patients with polyvinyl alcohol or ethanol mixed with iodized oil. RF ablation was percutaneously done under the computed tomographic (CT)–fluoroscopic guidance. Response to treatment was evaluated by dynamic contrast-enhanced CT and magnetic resonance (MR) imaging. Tumor enhancement was eliminated after a single RF session in nine tumors (75%), after two sessions in two tumors (17%), and after four sessions in one tumor (8%). Both exophytic tumors (100%) and 7 of 10 tumors having components in the renal sinus fat (70%) were completely ablated with a single RF session. All tumors remained controlled during a mean follow-up period of 13 months and showed significant reduction in tumor sizes (5.2 ± 1.7 cm to 3.6 ± 1.4 cm, p < 0.001). A delayed abscess developed in the ablated lesion in a patient, which was percutaneously drainaged. Combined therapy as described in this report is a feasible, relatively safe, and promising treatment method for large RCCs regardless of tumor geometry.

Growth factors as mediators of androgen action during the development of the male urogenital tract

SummaryStudies on the developing prostate and SV suggest that androgens act via mesenchymal AR to elicit synthesis and secretion of various autocrine and paracrine factors that regulate epithelial and stromal growth and differentiation. Clearly, the global regulation of epithelial growth and ductal branching morphogenesis is a complex multifactorial process involving the interplay of many diffusible factors (both positive and negative regulators), extracellular matrix molecules, cell-surface receptors for growth factors, receptors for extracellular matrix molecules, and matrix-degrading enzymes. Future progress will certainly be dependent upon the utilization of appropriate, biologically relevant models to examine the respective roles of various growth factors in the growth and development of androgen target organs.

Endocrine Disrupter Bisphenol A Increases In Situ Estrogen Production in the Mouse Urogenital Sinus

The balance between androgens and estrogens is very important in the development of the prostate, and even small changes in estrogen levels, including those of estrogen-mimicking chemicals, can lead to serious changes. Bisphenol A (BPA), an endocrine-disrupting chemical, is a well-known, ubiquitous, estrogenic chemical. To investigate the effects of fetal exposure to low-dose BPA on the development of the prostate, we examined alterations of the in situ sex steroid hormonal environment in the mouse urogenital sinus (UGS). In the BPA-treated UGS, estradiol (E2) levels and CYP19A1 (cytochrome P450 aromatase) activity were significantly increased compared with those of the untreated and diethylstilbestrol (DES)-treated UGS. The mRNAs of steroidogenic enzymes, Cyp19a1 and Cyp11a1, and the sex-determining gene, Nr5a1, were up-regulated specifically in the BPA-treated group. The up-regulation of mRNAs was observed in the mesenchymal component of the UGS as well as in the cerebellum, heart, kidney, and ovary but not in the testis. The number of aromatase-expressing mesenchymal cells in the BPA-treated UGS was approximately twice that in the untreated and DES-treated UGS. The up-regulation of Esrrg mRNA was observed in organs for which mRNAs of steroidogenic enzymes were also up-regulated. We demonstrate here that fetal exposure to low-dose BPA has the unique action of increasing in situ E2 levels and CYP19A1 (aromatase) activity in the mouse UGS. Our data suggest that BPA might interact with in situ steroidogenesis by altering tissue components, such as the accumulation of aromatase-expressing mesenchymal cells, in particular organs.

Naftopidil, a selective α-1 adrenoceptor antagonist, inhibits growth of human prostate cancer cells by G1 cell cycle arrest

α‐1 adrenoceptor antagonists are generally prescribed for benign prostate hyperplasia with lower urinary tract symptoms. Naftopidil, a selective α‐1 adrenoceptor antagonist, is frequently used in Japan because it has fewer side effects. Here we demonstrate for the first time that naftopidil has growth inhibitory effect in androgen‐sensitive and ‐insensitive human prostate cancer cell lines. The concentrations causing 50% inhibition (IC50) of cancer cell growth were 22.2 ± 4.0 μM in androgen‐sensitive LNCaP cells and 33.2 ± 1.1 μM in androgen‐insensitive PC‐3 cells. FACS analysis revealed that cell growth inhibition by naftopidil was due to the arrest of the G1 cell cycle. Expressions of p27kip1 and p21cip1 were significantly increased in LNCaP cells treated with naftopidil. In PC‐3 cells, naftopidil induced p21cip1 but not p27kip1. In vivo, oral administration of naftopidil to nude mice inhibited the growth of PC‐3 tumors as compared to vehicle‐treated controls. These results suggest that naftopidil may be useful in the chemoprevention of prostate cancer and the intervention of hormone refractory prostate cancer.