Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952.

Optimization of novel azetidine compounds, which we had found as colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors, provided JTE-952 as a clinical candidate with high cellular activity (IC50 = 20 nM) and good pharmacokinetics profile. JTE-952 was also effective against a mouse collagen-induced model of arthritis (mouse CIA-model). Additionally, the X-ray co-crystal structure of JTE-952 with CSF-1R protein was shown to be a Type II inhibitor, and the kinase panel assay indicated that JTE-952 had high kinase selectivity.

Glucose Tolerance-Improving Activity of Helichrysoside in Mice and Its Structural Requirements for Promoting Glucose and Lipid Metabolism.

An acylated flavonol glycoside, helichrysoside, at a dose of 10 mg/kg/day per os for 14 days, improved the glucose tolerance in mice without affecting the food intake, visceral fat weight, liver weight, and other plasma parameters. In this study, using hepatoblastoma-derived HepG2 cells, helichrysoside, trans-tiliroside, and kaempferol 3-O-ß-D-glucopyranoside enhanced glucose consumption from the medium, but their aglycones and p-coumaric acid did not show this activity. In addition, several acylated flavonol glycosides were synthesized to clarify the structural requirements for lipid metabolism using HepG2 cells. The results showed that helichrysoside and related analogs significantly inhibited triglyceride (TG) accumulation in these cells. The inhibition by helichrysoside was more potent than that by other acylated flavonol glycosides, related flavonol glycosides, and organic acids. As for the TG metabolism-promoting activity in high glucose-pretreated HepG2 cells, helichrysoside, related analogs, and their aglycones were found to significantly reduce the TG contents in HepG2 cells. However, the desacyl flavonol glycosides and organic acids derived from the acyl groups did not exhibit an inhibitory impact on the TG contents in HepG2 cells. These results suggest that the existence of the acyl moiety at the 6'' position in the D-glucopyranosyl part is essential for glucose and lipid metabolism-promoting activities.

Discovery of conformationally constrained tetracyclic compounds as potent hepatitis C virus NS5B RNA polymerase inhibitors.

We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.

[A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting].

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.

A case of occult contralateral breast cancer incidentally detected by contrast-enhanced MRI; report of a case with review of literature.

We encountered a case of occult contralateral breast cancer, previously undetected by conventional imaging such as mammography (MMG) and ultrasonography (US), but incidentally detected by contrast-enhanced magnetic resonance imaging (CE-MRI). We present it here with a review of the literature. A 67-year-old Japanese woman was referred to our hospital in October 2000 because of a 1.5 cm right breast lump detected in a medical checkup. MMG, US and fine needle aspiration cytology revealed a cancerous lesion during the right breast. No mass lesion was palpable nor was any detected by MMG or US in the left breast. Bilateral breast CE-MRI was performed for more detailed evaluation. Consequently, an occult contralateral breast cancerous lesion was detected incidentally by CE-MRI, with the images showing rapid initial enhancement of time to signal intensity curves. Before surgery, bilateral breast lesions were diagnosed as invasive ductal carcinoma by open biopsy. She underwent bilateral breast conserving surgery with bilateral axillary lymph node dissection. The postoperative course was uneventful and no recurrence has been noted as of January 18th, 2004. CE-MRI of the contralateral breast should be of value as a routine screen in those patients with a known or suspected malignancy in one breast considering the limits of breast cancer detection by such conventional modalities as MMG and US.

Survival and clinical evaluation of salvage operation for cervical lymph node recurrence in esophageal cancer.

BACKGROUND/AIMS: Although extended lymphadenectomy for thoracic esophageal cancer is widely practiced in Japan, solitary supraclavicular lymph node recurrence (SCLR) has often become a problem. This study was designed to evaluate the survival and clinical benefit of salvage cervical lymphadenectomy. METHODOLOGY: Between 1989 and 2001, 153 patients underwent esophagectomy for esophageal cancers. SCLR was identified in 5 (3.7%) patients and these five patients were examined retrospectively. RESULTS: Surgical treatment was performed intensively for all patients. Two patients showed longterm survival for 7 years 3 months and 4 years, respectively. Four patients belonged to the good prognostic group but the other patient had poor prognosis from the viewpoint of both the pathological metastatic lymph node number and disease-free interval (DFI). There were no local recurrences but were a recurrent laryngeal nerve palsy in three patients associated with treatment. CONCLUSIONS: Salvage cervical lymphadenectomy for SCLR should be performed positively by selecting each case carefully. Indication must be weighed against increased morbidity considering such indicators as the extent of metastatic lymph node numbers and DFI.

Prognostic and clinical evaluation of patients with T2 gastric cancer.

BACKGROUND/AIMS: Little is known about the clinicopathological features of intermediate-stage T2 gastric cancer, defined as tumors invading the muscularis propria or subserosa. METHODOLOGY: Of 808 patients with gastric cancer, 210 patients (25.9%) who underwent gastrectomy for T2 gastric cancer were selected for this retrospective study. The clinicopathologic findings of these patients were analyzed retrospectively from their hospital records. RESULTS: Of all 808 patients with gastric cancer, 73 patients (9.0%) had tumors invading the muscularis propria (mp). The remaining 137 patients (16.9%) had tumors invading the subserosa (ss). Compared with ss gastric cancer, mp gastric cancer was associated with smaller tumor size, an absence of lymphatic spreading, and hematogenous and late recurrence [disease-free interval: 654.5 days (mp) vs. 365.5 days (ss)]. Univariate analysis of cases with curative operations showed that lymphatic invasion, and lymph node metastasis were significant prognostic factors in patients with T2 gastric cancer. Further examination by multivariate analysis demonstrated that pN2 or higher as classified by both the JCGC (Japanese Classification of Gastric Cancer) and the TNM lymph node staging systems was a predictor of poor prognosis. CONCLUSIONS: JCGC and TNM lymph node staging systems were the most reliable prognostic factors for T2 gastric cancer. Close follow-up should be required for patients with stage pN2 or higher gastric cancer. Long-term follow-up should be required for mp cancers, in particular.

[Early phase II dose-finding study of exemestane in postmenopausal patients with advanced/recurrent breast cancer].

Exemestane was administered orally to postmenopausal women with advanced/recurrent breast cancer at a dose of 10 mg/day or 25 mg/day once daily for more than 8 weeks in order to evaluate the drug's anti-tumor effects and safety in a dose-finding study. The response rate (CR + PR) in the 10 mg and 25 mg group was 25.0% (8/32) and 31.4% (11/35), respectively, demonstrating no significant differences between the two groups, yet a higher efficacy rate was observed in 25 mg group. The efficacy rate in hormone-treatment-resistant patients within the 10 mg and 25 mg groups was 14.3% (3/21) and 26.1% (6/23), respectively, demonstrating more than a 20% response rate in 25 mg group. Incidences of the adverse events of which relevance to the drug could not be excluded were 30.6% (11/36) in the 10 mg group. 13.9% (5/36) in the 25 mg group and 22.2% (16/72) in the total group. The major adverse events were, hot flashes, numbness of the limbs, nausea, headache etc. Abnormal findings in clinical laboratory tests were as follows: ALP increase; GOT increase; GPT increase; gamma-GTP increase; total cholesterol increase; urinary sediment present. Abnormal findings in endocrine function were as follows: aldosterone decrease; testosterone.cortisol.DHEA-S decrease. But discontinuation due to abnormal laboratory findings was not found. No abnormal findings in physical tests were observed. A significant decrease in plasma estrogen concentration at week 4 was observed in both the 10 mg and 25 mg groups compared with baseline. These low levels were maintained throughout the study period. On the basis of these results, the efficacy of exemestane 25 mg/day was verified to be slightly higher than 10 mg/day. In addition the safety profile had no major adverse events to notice. In these patients with advanced/recurrent breast cancer, 25 mg/day was recommended as the most appropriate dose to be used clinically.

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells.

The aryl hydrocarbon receptor (AhR) has been shown to play important roles in the immune system, and contributions of AhR ligands to the differentiation and functions of Th17/Treg cells have recently been established. However, it has not been fully clarified whether AhR plays roles in B cell differentiation and functions. The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly potent AhR agonist, was reported to suppress the production of immunoglobulin M (IgM) in a transformed mouse B cell line. However, TCDD exhibits high toxicity toward cells and has unknown activities except for its action as an AhR agonist. In the present study, we tried to clarify how an endogenously generated AhR agonist affects mouse B cell differentiation and functions in terms of the direct effects on the expression of Ig subclasses in purified mouse B cells stimulated with an anti-CD40 antibody and interleukin-4. The AhR agonist 2-(1'H-indole-3'- carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), which is derived via tryptophan metabolism, suppressed the expression of not only IgM, but also IgG1 and IgE. ITE was also found to suppress the expression of secreted-type Ig mRNAs and plasma cell-specific genes. These findings indicate that the endogenous AhR agonist suppresses B cell differentiation into Ig-secreting plasma cells.

Further studies on hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors toward improved replicon cell activities: benzimidazole and structurally related compounds bearing the 2-morpholinophenyl moiety.

Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem.2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC(50)=7.6 nM).

Predictive value of the time-intensity curves on dynamic contrast-enhanced magnetic resonance imaging for lymphatic spreading in breast cancer.

PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (CE-MRI) has emerged as a promising diagnostic modality in various breast cancer treatments. However, little is known about the correlation between the pattern of time to signal intensity curves (TIC) on the CE-MRI and clinicopathologic features. This study was designed to investigate these correlations and evaluate the predictive value of TIC on CE-MRI in order to identify high-risk patients. METHODS: Between 2001 and 2003, 101 lesions were evaluated to detect malignancy on CE-MRI in 101 women who were suspected of having breast tumors based on either clinical findings or conventional imaging studies. Moreover, the clinicopathologic findings were compared with the pattern of TIC for the 69 surgically treated malignant lesions. RESULTS: In detecting malignancy, the sensitivity, specificity, and accuracy were 78.7%, 88.5%, and 81.2%, respectively, in the 101 breast lesions. Especially for the 69 surgically treated malignant lesions, in comparison with breast cancer tumors with the benign pattern of TIC, the breast cancer tumors with a malignant pattern were found more frequently in lymphatic invasion (P < 0.01) and lymph node metastasis (P < 0.005), although no statistical correlation regarding the histological type, tumor size, vascular invasion, extensive intraductal component, hormone receptor status, or pathological stage was noted between the two groups. According to a logistic regression model, lymph node metastasis was found to be a significant independent variable. CONCLUSION: The pattern of TIC could be used to predict lymphatic spreading associated with lymph node metastasis prior to surgery as well as to detect malignancy. Therefore, a more detailed evaluation should be made to identify the presence of lymphatic spreading in patients with a malignant pattern of TIC.

Pulmonary embolism in a living-related kidney transplantation donor.

Living-related renal transplantation is the optimal therapy for patients with end-stage renal disease (ESRD). Normally, complications are rare in living-related donor nephrectomy. However, we experienced a case of pulmonary embolism (PE). The incidence of PE in living donor nephrectomy is rare, but the total incidence of PE in surgical operations has recently increased. The patient in the case reported here was diagnosed relatively early and recovered with appropriate treatment. It is very important for surgeons to realize that serious complications such as PE can develop in any case of living donor nephrectomy.

Elevated expression levels of NCOA3, TOP1, and TFAP2C in breast tumors as predictors of poor prognosis.

BACKGROUND: Amplification of DNA in certain chromosomal regions plays a crucial role in the development and progression of human malignancies, specifically when protooncogenic target genes within those amplicons are overexpressed. Comparative genomic hybridization studies have revealed frequent amplification at 20q in primary breast tumors. The aim of the current study was to identify specific genes in the 20q amplicon that were likely to have clinical significance. METHODS: The authors examined 38 primary breast tumors by using a quantitative real-time reverse transcription-polymerase chain reaction assay to determine expression levels of 18 potential targets for amplification events involving 20q. Potential correlations between elevated expression of the genes in question and clinicopathologic parameters or clinical outcomes were analyzed. RESULTS: Elevated expression of NABC1 was significantly associated with positive estrogen (P < 0.001) and progesterone (P = 0.027) receptors in breast tumors, and high expression of PTK6 was significantly correlated with positive estrogen receptor status (P = 0.022) and postmenopausal status (P = 0.008). Patients whose tumors showed elevated expression of NCOA3 (AIB1) had significantly shorter disease-free (P = 0.017) and overall (P = 0.0021) survival times after surgery than did other patients with breast tumors. Reduced disease-free survival, but not reduced overall survival, was associated with high expression of TOP1 (P = 0.035) and TFAP2C (P = 0.035). CONCLUSIONS: TOP1, TFAP2C, and (particularly) NCOA3 may be prognostic indicators for patients with breast tumors.

Comparison of intraductal spread on dynamic contrast-enhanced MRI with clinicopathologic features in breast cancer.

OBJECTIVE: Contrast-enhanced magnetic resonance imaging (CE-MRI) has emerged as a new diagnostic technology in various breast cancer treatments. However, little is known about the correlation between intraductal spread on CE-MRI and clinicopathologic features. This study was designed to evaluate these correlations for the surgical planning of breast cancer. METHODS: Twenty-six breast cancer lesions (in 26 female patients) treated by breast conserving surgery between March 2001 and March 2003 were evaluated retrospectively. CE-MRI was performed with a 1.5 T unit using a dedicated bilateral breast coil. RESULTS: In detecting intraductal spread of breast cancer, the sensitivity, specificity and accuracy of CE-MRI were 82.4%, 60.0% and 77.3%, respectively. On mammography (MMG), these were 21.1%, 100.0% and 42.3%, respectively. Therefore, CE-MRI has a higher sensitivity and accuracy, although with a lower specificity than MMG. Compared with breast cancer lesions without intraductal spread on CE-MRI, lesions with intraductal spread on CE-MRI were found more frequently in larger-sized tumors (P = 0.0088). CONCLUSION: Preoperative evaluation for intraductal spread by CE-MRI should be more useful than by MMG for breast cancer. When making the surgical decision regarding excision range, particular attention should be paid to this consideration for patients with larger-sized cancer tumors.