Polymorphisms of the androgen transporting gene SLCO2B1 may influence the castration resistance of prostate cancer and the racial differences in response to androgen deprivation.

BACKGROUND: Organic anion-transporting polypeptides (OATPs) encoded by SLCO mediate the cellular uptake of many compounds, including androgens. SLCO1B3 and SLCO2B1 are polymorphic, and single-nucleotide polymorphisms of those genes alter androgen transport efficiency. We aimed to investigate the association between genetic variations in SLCOs and the progression to castration-resistant prostate cancer (CRPC). METHODS: We studied the progression to CRPC for the SLCO1B3 rs4149117 and SLCO2B1 rs12422149 genotypes in 87 prostate cancer patients who received androgen deprivation therapy (ADT). Data were analyzed using the χ(2) test, Kaplan-Meier survival analysis and Cox proportional hazard model. RESULTS: SLCO3B1 genotypes were not significantly associated with the time to progression (TTP); however, patients carrying the active androgen transport SLCO2B1 genotype (GG allele) exhibited a median TTP that was 7 months shorter than that of patients with impaired androgen-transporting activity SLCO2B1 polymorphisms (GA/AA alleles) (10.0 vs 17.0 months, P=0.004). Active androgen transport genotypes of SLCO2B1 (GG allele) occurred more frequently in African and Caucasian populations than in Japanese and Han Chinese populations (P<0.001). CONCLUSIONS: These data suggest that SLCO2B1 rs12422149 variants could provide prognostic value for prostate cancer patients treated with ADT and influence ethnic differences in response to ADT. Active androgen import may be one of the underlying mechanisms of resistance to ADT, and androgen-transporting systems could provide novel biomarkers and targets for CRPC treatment.

Glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) polymorphisms and urothelial cancer risk with tobacco smoking.

The objective of this study was to examine the association between the genetic polymorphism of glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) genes and urothelial cancer risk in relation to smoking status. In this study, 325 Japanese patients with urothelial transitional cell carcinoma and 325 healthy controls were compared for frequencies of GSTM1, T1 and NAT2 genotypes. The frequencies of GSTM1 null genotype and NAT2 slow genotype were significantly higher in the cases than in the controls (adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.01-1.87, adjusted OR 3.09, 95% CI 1.69-5.63, individually). Furthermore, the risk of GSTM1 null genotype and NAT2 slow genotype was higher among smokers (adjusted OR 1.48, 95% CI 1.01-2.15, adjusted OR 4.28, 95% CI 1.96-9.36, individually). The regression analysis of cancer risk as a function of the amount of smoking showed that the susceptibility of people who had GSTM1 null genotype increased from 45 pack-years, while the susceptibility of people with NAT2 intermediate or slow genotype increased rapidly from 25 pack-years, compared with non-smokers. A multiplicative interaction between NAT2 intermediate or slow genotype and pack-years of smoking was found (P<0.001), but GSTM1 null genotype was not (P=0.06). Our results indicate that the GSTM1 null genotype and NAT2 intermediate or slow genotype are associated with an increased risk of urothelial cancer in relation to smoking amounts. Furthermore, the interaction between NAT2 intermediate or slow genotype and pack-years of smoking has a strong impact on urothelial cancer.

Significance of vitamin D receptor gene polymorphism for risk and disease severity of prostate cancer and benign prostatic hyperplasia in Japanese.

OBJECTIVE: Recent studies have demonstrated an association between vitamin D receptor (VDR) genotype and prostate cancer. Currently, there is a scarcity of data regarding the association of VDR genotype with benign prostatic hyperplasia (BPH). The purpose of this study was to investigate the TaqI VDR polymorphism in Japanese prostate cancer patients, Japanese BPH patients and Japanese controls in order to determine if an association exists between VDR genotype and the risk of developing prostate cancer and BPH as well as disease severity. METHODS: 110 prostate cancer patients, 83 BPH patients and 90 male age-matched controls were genotyped for a previously described TaqI restriction fragment length polymorphism at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of a TaqI restriction site with individuals being classified as TT, Tt or tt. RESULTS: The frequency of the genotype tt was higher in the control group (6.7%) compared to patients with prostate cancer (1.8%) and BPH (3.6%) but this was not statistically significant. However, the frequency of the genotype TT was significantly higher among prostate cancer patients with locally advanced or metastatic disease (T3/ T4/N1/M1) compared to controls (p = 0.001). In addition, the genotype TT was significantly higher among prostate cancer patients with a high Gleason grade of tumor (grade 5) compared to controls (p = 0.0001). In addition, the genotype TT was statistically higher in BPH patients with high prostate volume (volume >50 cm(3)) compared to controls (p = 0.001). CONCLUSION: These data demonstrate that VDR genotype plays an important role in determining the risk of more advanced and aggressive prostate cancer as well as prostatic enlargement in Japanese men.

Effects of gold banded lily (Lilium auratum Lindl) or Chinese milk vetch (Astragalus sinicus L) on spontaneous mammary tumourigenesis in SHN mice.

Some guanidino compounds have been found to inhibit spontaneous mammary tumourigenesis in mice. In the present study, the effects of chronic treatment with Gold Banded Lily (Lilium auratum LindI) or Chinese Milk Vetch (Astragalus sinicus L), which contains L-arginine or L-canavanine, on spontaneous mammary tumourigenesis were examined in SHN mice. Free access to drinking water containing hot water extract of each natural product at a concentration of 0.5% significantly inhibited the development, but not growth, of mammary tumour. The mechanism of the protective role of each natural product in mammary tumours remains to be clarified; however, there were no significant long-term deleterious side-effects of chronic treatment with either product estimating from body weight change, food and water intakes and plasma component levels. Thus, the present findings suggest that these natural products containing guanidino compounds may act as prophylactic agents for mammary and other types of tumours.

Diagnosis of retrovesical ectopic and hyperplastic prostate tissue by transrectal needle biopsy.

We report on an ectopic prostate in a 50-year-old man. Transabdominal ultrasonography, pelvic computed tomography, and pelvic magnetic resonance imaging revealed a heterogeneous tumor 8 cm in diameter in contact with the posterior wall of the urinary bladder. The tumor was histologically confirmed to be a benign prostatic hyperplasia. This is the 3rd case of retrovesical ectopic prostatic tissue which was diagnosed by transrectal needle biopsy.

Effects of coffee cherry, the residue left after removal of the beans from the coffee fruit, on mammary glands, automatic behavior and related parameters in mice.

To clarify the mechanisms of the anti-mammary tumor activity of coffee cherry (CC), the residue left after the removal of beans from the fruit, the effects in SHN mice of CC on plasma and urine component levels, mammary gland growth, spontaneous motor activity and several related parameters were examined. Hot water extract of CC was given to 2-month-old mice in drinking water (0.5%) for 60 days. The treatment prevented the elevation of plasma and urine levels of alanin amino-transferase and asparate aminotransferase, indicating that CC can protect against metabolic abnormality, which is a cause of the high mammary tumor susceptibility of SHN mice. It also resulted in an inhibition of the formation of precancerous mammary hyperplastic alveolar nodules. Neither food and water intake nor spontaneous motor activity was affected by CC. The findings provide novel information on the mechanism of the protective effect of CC on mammary tumorigenesis and confirm the usefulness of CC as a safe chemopreventive agent of mammary and other types of tumors.

Clinical and pathological significance of vitamin D receptor gene polymorphism for prostate cancer which is associated with a higher mortality in Japanese.

The purpose of this study was to investigate the TaqI vitamin D receptor (VDR) polymorphism in both Japanese prostate cancer patients and Japanese noncancer controls in order to determine if an association exists between VDR genotype with clinical and pathological risk of prostate cancer patients. This study involved 115 patients with prostate cancer and 133 male age-matched noncancer controls genotyped for a previously described TaqI restriction fragment length polymorphism (RFLP) at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of TaqI restriction site with individuals being classified as TT, Tt, or tt. The genotype tt was higher among the control group (6.0%) compared to the patients with prostate cancer (1.8%), but not so (OR=0.28; 95%o CI, 0.06-1.33; p=0.081). In addition, the genotype TT was statistically higher among patients with locally advanced or metastatic disease (T3/T4/NI/M1) compared to controls (OR=2.52; 95%o CI, 1.21-5.27; p=0.009). Lastly, the genotype TT was statistically higher among patients with poorly differentiated adenocarcinoma compared to controls (OR=5.38; 95%o CI, 1.57-18.50; p=0.002). These data demonstrate that VDR genotype plays an important role in determining the risk of more clinically advanced and pathologically aggressive prostate cancer which is associated with a higher mortality rate in Japanese men.

NAT2 gene polymorphism as a possible marker for susceptibility to bladder cancer in Japanese.

BACKGROUND: N-acetyltransferase (NAT) is known to metabolize the carcinogen arylamine. The polymorphism of the NAT2 gene is an important determinant of individual susceptibility to bladder cancer. There are significant interethnic differences in NAT2 allele frequencies. The relationship between NAT2 genotypes and bladder cancer in a Japanese population was investigated. METHODS: A case control study on 85 bladder cancer patients and 146 control subjects was conducted. NAT2 alleles were differentiated by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) methods using originally created PCR primers and genomic DNA extracted from peripheral white blood cells. The NAT2 genotypes were determined by the combination of three known NAT2 mutant type alleles (M1, M2, M3) and the wild type allele. RESULTS: NAT2 slow genotypes were associated with bladder cancer risk (odds ratio adjusted for age and gender, 4.23; 95% confidence interval [CI], 1.76-10.81). Among those with NAT2 slow genotypes/smoker, there was a significantly increased risk of 7.80 (95% CI, 1.66-57.87) when the NAT2 rapid genotypes/non-smoker were considered the reference group. This suggested a possible interaction between NAT2 slow genotypes/smoking status and bladder cancer risk. It was also shown that bladder cancer patients with NAT2 slow genotypes were more likely to have a high grade tumor (G3) or an advanced stage tumor (pT2-pT4) [corrected]. However, no association between NAT2 genotypes and the survival rate of invasive bladder cancer patients was recognized. CONCLUSION: It was demonstrated that the NAT2 slow acetylation genotype is an important genetic determinant for bladder cancer in a Japanese population.

Results of conservative treatment of upper urinary tract transitional cell carcinoma.

BACKGROUND: The treatment preserving the kidney for upper urinary tract tumor is still controversial. The indications and results of conservative treatment remain to be elucidated. Experiences of this type of treatment are reported. METHODS: Between April 1981 and March 1998, 14 patients with upper urinary tract transitional cell carcinoma were treated with renal preserving methods. Five were elective and nine were imperative cases. Treatments performed were partial nephrectomy, partial ureterctomy with or without adjuvant chemotherapy, endoscopic tumor resection and topical bacillus Calmette-Guerin instillation in one, 10, two and one patient, respectively. RESULTS: Crude and cause-specific 5 year-survival rates were 91.7 and 100%, respectively. Of 14 patients, five had bladder recurrences, but ipsilateral local recurrence developed in only one patient. Two patients died from metastasis of transitional cell carcinoma 61 and 89 months after initial treatment. The lesions of carcinoma in situ were well controlled with topical bacillus Calmette-Guerin therapy. CONCLUSION: The results of conservative treatment for upper urinary tract tumor were satisfactory and local excision can be indicated for low grade, solitary tumors located in the distal ureter.

Human glutathione S-transferase P1 polymorphism and susceptibility to smoking related epithelial cancer; oral, lung, gastric, colorectal and urothelial cancer.

The A/G polymorphism at nucleotide 313 in the glutathione S-transferase P1-1 (GSTP1) gene was examined in patients with different types of smoking-related cancers (oral, lung, gastric, colorectal and urothelial cancers) and healthy control individuals. This polymorphism results in an amino acid substitution from isoleucine to valine at residue 105, which reduces catalytic activity of the enzyme. In control individuals, 23.8% of individuals had GSTP1 AG or GG genotype. This rose to 37.3% [n = 83, odds ratio = 1.93 (1.05-3.58), P = 0.035] in oral cancer patients. No increase in the frequency of the GSTP1 AG or GG genotype was obtained in lung, gastric, colorectal or urothelial cancers in this Japanese population. After grouping by smoking status, no consistent difference was observed between smoking patients and corresponding control individuals for the frequency of the GSTP1 A/G polymorphism for any cancer. However, a moderate risk (odds ratio = 2.78; 95% confidence interval 1.06-7.51) was associated with this polymorphism in the non-smoking group of oral cancer patients. The results suggest the GSTP1 polymorphism at nucleotide 313 may be associated with susceptibility to oral squamous cell carcinoma in the Japanese population.

Effects of simultaneous treatment with hydroxyapatite and coffee cherry, the residue left after the removal of coffee beans, on spontaneous mammary tumourigenesis and related parameters in SHN mice.

We have found that the chronic administration of the diet containing 5% hydroxyapatite (HAP) derived from bovine or swine bone or drinking water containing 0.5% extract of coffee cherry (CC), the residue left after the removal of coffee beans, induced a marked inhibition of spontaneous mammary tumourigenesis in SHN mice, while the effects decreased with age. In the present study, the combined effects of HAP and CC on mammary tumourigenesis and related parameters were examined. The inhibitory effects of HAP or CC alone on the development and/or the growth of mammary tumours were reduced by HAP + CC. Decreased food and water intake and retarded body growth caused by CC were ameliorated by HAP. Enhancement by HAP or CC of the excretion of the urine components was mostly nullified by HAP + CC. Parameters such as normal mammary gland growth and uterine adenomyosis on which neither HAP nor CC had an effect also did not respond to HAP + CC. These findings suggest that the target is important when administering natural products in combination if the agents are to manifest their effects, additive, synergistic, antagonistic or otherwise.

Effects of glutathione S-transferase (GST) M1 and GSTT1 genotypes on urothelial cancer risk.

The M1 member of the mu class of the glutathione S-transferase (GSTM1) gene is present in about 50% of individuals. GSTT1, a member of the theta class, which has been recently shown to be polymorphic, is expressed in 35-90% of individuals. In this study, 145 Japanese patients with urothelial transitional cell carcinoma and 145 healthy controls, frequency-matched for age and gender, were compared for frequencies of GSTM1 and GSTT1 genotypes. The urothelial cancer risk increased due to the GSTM1 null genotype (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.05-2.79). On the other hand, the OR tended to decrease due to the GSTT1 null genotype, although not significantly. Among individuals of the GSTM1 null genotype, those of the GSTT1-positive genotype had a two-fold risk (OR 2.62, 95% CI 1.36-5.05) compared with the GSTT1 null genotype (OR 1.25, 95% CI 0.62-2.51). A significant interaction between the GSTM1 genotype and smoking status was found; the GSTM1 null genotype was associated with an increased risk of urothelial cancer among smokers (OR 1.98, 95% CI 1.10-3.57).

Inhibition by guanidino compounds of the growth of spontaneous mammary tumours in SHN mice.

The D-form of lombricine extracted from the earthworm was previously found to inhibit the growth of spontaneous mammary tumours of mice. In the present study, the anti-mammary tumour effects of guanidino compounds, of which structures resembled those of lombricine, i.e., guanidinesulfate (Guanidine), 2-guanidinoethanol sulfate (2-GEt), 4-guanidino-1-butanol sulfate (4-GBt), guanidinoethylphosphate (GEP), opheline (OPHE) and the L-form of lombricine (L-Lom), were investigated in relation to their structures. In Experiment I, each guanidino compound was suspended in olive oil at the concentration of 0.3 mg/0.05 ml, and was injected subcutaneously for 10 days to SHN mice bearing spontaneous mammary tumours. 2-GEt, GEP, OPHE and L-Lom markedly inhibited mammary tumour growth, but Guanidine and 4-GBt did not. In Experiment II, the the compounds examined, 2-GEt and GEP, also significantly inhibited mammary tumour growth when given in drinking water (0.003%) for 10 days, while the effects were much weaker than those of the injected compounds. These results indicate that the existence and the length of the ethylene group are important to antitumour activity and that the site of the antitumour activity in guanidino compounds is the guanidinoethyl group. These compounds are also suggested to be more effective when administered subcutaneously rather than intragastrically.

Effects of guan-mu-tong (Caulis aristolochiae manshuriensis) in combination with other natural products on normal and preneoplastic mammary gland growth in mice.

The effects of combined treatment with Guan-mu-tong (Gmt: Caulis aristolochiae manshuriensis) and other major components of Shi-Liu-Wei-Liu-Qi-Yin (SLWLQY), a Chinese herbal medicine prescribed for breast diseases, on normal and preneoplastic mammary gland growth were investigated. SHN virgin mice were divided into 6 groups at 3 months of age and treated with the samples in drinking water as shown in Table 2 for 8 weeks. Each sample was extracted repeatedly with hot water, dried in vacuo and dissolved with tap water at the concentration indicated in Table 2. Normal and preneoplastic mammary gland growth and thymidylate synthetase activity in the mammary gland were inhibited by Gmt alone; but its effect was affected slightly by the further addition of other products. However, the excretion of urinary components, which is abnormally low in SHN mice, was gradually enhanced by the addition of other products to Gmt and was highest by SLWLQY. The elongated estrous/metestrous stage of the estrous cycle induced by Gmt+Zq was returned to the control level by further addition of other products and by SLWLQY. The normal parameters in this strain during this age period such as body weight change, food and water intake and immune system were affected little by all treatments. All these findings strongly suggest that one of the principles of prescribing Chinese herbal medicines is to normalize the physical conditions, which, in turn, contributes to therapy and protection from diseases.

Effects of aristoloside, a component of guan-mu-tong (Caulis aristolochiae manshuriensis), on normal and preneoplastic mammary gland growth in mice.

Aristoloside, an extract of Guan-mu-tong (Gmt; Caulis aristolochiae manshuriensis) showing a marked anticancer potential, was dissolved with tap water (0.05%) and given to 4 month-old SHN mice for 30 days as drinking water. The treatment induced the inhibition of preneoplastic mammary gland growth and the stimulation of the excretion of urinary component. Ovarian follicles were dominant and the oestrous stage was elongated by the treatment. Aristoloside had little affect on normal mammary gland growth and serum levels of prolactin and free fatty acid. All findings were in agreement with those obtained from studies on chronic treatment with Gmt, and aristoloside is thus strongly suggested as being one of the major components of Gmt.

[Clinical study of occupational uroepithelial cancer].

We studied 438 persons who were engaged in the production and use of aromatic amines (benzidine sulfate, beta-naphthylamine, alpha-naphthylamine and dianisidine). Among these 438 persons, 88 new cases of occupational uroepithelial cancer had occurred from 1949 to 1995. The incident rate of occupational uroepithelial cancer was 20.1%. The average exposure period of these 88 cases to the aromatic amines was 7.40 years (range, 0.75-26.75), and the incidence rate of tumors increased with the length of exposure to aromatic amines. The average latent period was 26.79 years (range, 1.33-48.50), and the average age of first onset was 52.59 (range, 24-79). Recently it has been determined that the longer the latent period, the older the age of first onset. Of these 88 cases, the tumor sites were bladder in 67 cases (76.1%) and upper urinary tract (renal pelvis and/or ureter) in 5 cases (5.7%). The other 16 cases (18.2%) were the bladder and upper urinary tract. The screening examination for chemical workers using urinary cytology was begun in 1962. In our cases, urine cytology was a useful method for diagnosing occupational uroepithelial cancer. As for initial treatment of the 88 cases, transurethral surgery was most frequently performed, that is on 58 cases (65.9%). However, eight cases (9.1%) had to undergo a total nephroureterectomy, and six cases (6.8%) had a total cystectomy. Recurrence was observed in 61 cases (69.3%) out of the 88 patients with an average of 1.81 times. The other organic cancers developed in 39 cases (8.9%) out of 438 workers who were exposed to aromatic amines and in 8 cases out of 88 patients (9.1%). Prognosis of the 88 patients is that, the number of alive and dead is 51 (58.0%) and 37 (42.0%) respectively on December 31, 1995. Twenty-eight patients (31.8%) died of uroepithelial cancer, and five patients (5.7%) died of other organic cancers. The survival rates of 5, 10, 15 and 20 years was 87.9%, 74.0%, 65.9% and 56.3%, respectively. From these results, patients with occupational uroepithelial cancer and workers who are exposed to aromatic amines should undergo long term observation.

Further study on the effects of coffee cherry on spontaneous mammary tumourigenesis in mice: effects of methanol extract.

To examine the effective components in the antitumourigenic role of water extract of coffee cherry (CC), and the residue after removal of beans, the dry matter of coffee cherry was extracted repeatedly by 60% methanol and further divided into water-soluble and -insoluble fractions (CC-W and CC-M, respectively). Free access to CC-W (0.25% in tap water) markedly inhibited mammary tumour development in SHN virgin mice, while it had no effect on the growth of normal and preneoplastic mammary glands and established tumours. Associated with this, urinary excretion of some components and intrathymic T cell differentiation were stimulated by the treatment with the CC. CC-W had little affect on the endocrine system, including serum prolactin level, oestrous cycles and endocrine organs, but retarded ovarian degeneration in mice developing mammary tumours. The finding in CC-W were generally similar to those in CC. Fat emulsion of CC-M, which was only checked for mammary tumour growth owing to the limited amount available, showed no effect at the dose level used (0.25% in drinking water). Finally, the previous and the present findings taken together strongly suggest that the effective components of coffee cherry are in the water-soluble fraction.

A case of prostate carcinoma metastasizing to renal cell carcinoma.

Metastasis of one cancer to another cancer is extremely rare. The most frequent metastasizing tumor is a lung carcinoma, and the most common recipient tumor is a renal cell carcinoma. We report herein a case of prostate carcinoma metastasizing to a renal cell carcinoma, which has previously been reported only four times.