Cancer chemopreventive effect of quassinoid derivatives. Introduction of side chain to shinjulactone C for enhancement of inhibitory effect on Epstein-Barr virus activation

A series of shinjulactone C (1) derivatives (2-8) were synthesized and evaluated for their anti-tumor promoting effects against Epstein-Barr virus early antigen activation introduced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. The succinate and 3',3'-dimethylsuccinate derivatives of 1 exhibited higher inhibitory effects than 1. From the point of view of structure-activity relationships, the succinate derivatives (2, 4) demonstrated better potency than the glutarate derivatives (3, 5-8). As substituted moieties of 3'-position became bulky, the inhibitory effects of the glutarate derivatives (7, 8) significantly decreased.     

Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors

Survivin is a new member of the inhibitors of apoptosis proteins (IAP) family, selectively overexpressed in common human cancers but not in normal adult tissues, and associated with aggressiveness of the disease and unfavorable outcomes. Recent study also found that survivin expression is associated with cell proliferation. In order to gain insight into the role of survivin in ovarian tumors, we investigated the expression of survivin in a group of epithelial ovarian tumors, and examined the relationship of its expression with cell proliferation and clinical outcome. Immunohistochemical analysis was performed in 103 cases of epithelial ovarian tumors. Twenty-six of the 103 cases were evaluated by Western blot analysis. The results showed that survivin overexpression was detected in 21.2% (7 of 33) of benign tumors, 47.8% (11 of 23) of borderline tumors, and 51.1% (24 of 47) of ovarian carcinomas. The positive ratio was significantly higher in malignant or borderline tumors than in benign tumors, and the overexpression of survivin was significantly correlated with the size of residual disease. A positive correlation between survivin expression and proliferative activity of tumor cell measured by PCNA index was found. Kaplan-Meier analysis demonstrated that the patients with survivin overexpression have a short overall survival. These findings suggest that survivin overexpression may play a pivotal role in the progression of ovarian tumors and may provide an important prognostic implication for epithelial ovarian carcinomas.     

Semisynthesis of new sarcophine derivatives with chemopreventive activity

The natural cembranolide sarcophine (3) and its lactone ring-opened analogue (10) were oxidized using selenium dioxide under different reaction temperatures to prepare hydroxylated derivatives. Nine new compounds were obtained, six of them targeted hydroxylated derivatives. The determination of regio- and stereochemistry as well as the mechanistic considerations on the selectivity observed in these reactions are discussed on the basis of 2D NMR and molecular modeling. In preliminary in vitro tests on inhibition of EBV-EA activation, compounds 10 and 12-15 have shown higher activity than the known chemopreventive agent sarcophytol A.     

An 80-year-old woman with non-resectable pulmonary adenocarcinoma that responded to concomitant use of gemcitabine and vinorelbine

An 80-year-old female with non-resectable pulmonary adenocarcinoma was treated with five courses of chemotherapy consisting of gemcitabine (GEM) 1,000 mg/m2 plus vinorelbine (VNR) 25 mg/m2 (days 1 and 8, every 4 weeks). A partial response (PR) was achieved, and her complaints abated and quality of life (QOL) improved. Although gastro-intestinal symptoms and bone marrow suppression were observed as side effects, they were within a tolerable range and did not interfere with the therapy. Anti-cancer chemotherapy for non-resectable lung cancer might be worth consideration even for elderly patients more than 80 years of age.     

Perforating pilomatricoma: transepithelial elimination or not

We present a 56-year-old woman with a perforating pilomatricoma in the left eyebrow region. Histologically, the tumor consisted mainly of basophilic cells and shadow cells, and the tumor components were being eliminated through an ulcer with damage to the epithelial structures. In past reports of perforating pilomatricoma, this elimination pattern has often been described as transepithelial elimination. In many patients with perforating pilomatricoma, elimination is accompanied by ulceration and epithelial damage. Mehregan recently stated that elimination accompanied by epidermal necrosis and superficial ulceration constituted one form of transepithelial elimination. Epidermal necrosis and ulceration generally constitute severe damage. However, when Mehregan first proposed the concept of transepithelial elimination, it was defined as a phenomenon with relatively little or no damage to the epithelial structures, differentiating it from other types of elimination. This original definition makes transepithelial elimination a unique and interesting phenomenon, and its most important feature is that there is relatively little or no damage to the epithelial structures. Therefore, the terms "epidermal necrosis" and "ulceration" should not be used in association with transepithelial elimination. Hence, in patients with perforating pilomatricoma, the elimination of tumor components from ulcers with damage to the epithelial structures, as seen in the present case, should not be described as transepithelial elimination.     

Constituents of Boronia pinnata

A novel quinolone, pinolinone (1); seven new phenylpropanoids, boropinols A (2), B (3), C (4), boropinals A (5), B (6), C (7), and boropinic acid (8); and a new lignan, boropinan (9), were isolated from the roots of Boronia pinnata, and their structures were elucidated by NMR and MS analyses. In a search for novel cancer chemopreventive agents (antitumor-promoters), we screened 10 compounds isolated from the plant for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. Boropinic acid (8) and 4'-hydroxy-3'-prenylcinnamaldehyde were observed to significantly inhibit the EBV-EA activation.     

Prognostic value of intratumoral natural killer cells in gastric carcinoma

BACKGROUND: Natural killer (NK) cells are a group of effector cells that act nonspecifically against tumor cells. The correlation between intratumoral NK cell infiltration and clinicopathologic features remains unclear. METHODS: The authors selected 146 patients with gastric carcinoma who underwent gastrectomy at Kagoshima University Hospital between 1985-1995. Immunohistochemical staining with the CD57 antibody was performed for the evaluation of NK cell infiltration. A total of 25 areas containing CD57 positive cells were selected and the number of NK cells were counted (magnification, x200). The patients were divided into 2 groups: patients with a high level of NK infiltration (n = 39) (>25 NK cells/25 high-power fields [HPF]) and patients with a low level of NK infiltration (n = 107) (<25 NK cells/25 HPF). Intratumoral lymphocytic infiltration also was counted in 25 areas at a magnification of x200. Patients were classified into a high infiltrating lymphocyte (IL) group (n = 69) (>150 cells/HPF) and a low IL group (n = 77) (<150 cells/HPF). The Kaplan-Meier curve was used to analyze surgical outcome. Multivariate analyses were performed to evaluate prognostic factors. RESULTS: Patients with a high level of NK infiltration had a higher rate of early gastric carcinoma, fewer metastases to the lymph nodes (P < 0.01), and less lymphatic invasion (P < 0.05) than patients with a low level of NK infiltration. NK cell infiltration also was found to correlate with depth of invasion, clinical stage, and venous invasion. There was no correlation between NK cells and lymphocytic infiltration (P = 0.07; correlation coefficient = 0.15). The 5-year survival rate of patients with a high rate of NK infiltration was 78%, which was significantly better than that of patients with a low level of NK infiltration (P < 0.01). Multivariate analysis did not show NK cell infiltration to be a significant prognostic factor. Combination analysis of the number of NK cells and lymphocytic infiltration was shown to be an independent prognostic factor (P = 0.02; hazard ratio = 1.32). CONCLUSIONS: Patients with a high level of NK infiltration were found to have a better prognosis than those with a low level of NK infiltration. Combination analysis with lymphocytic infiltration may provide useful information regarding the immunologic condition of patients with gastric carcinoma.     

Persistence of the benefits of a structured psychiatric intervention for breast cancer patients with lymph node metastases

The aim of this study was to investigate the persistence of clinical effectiveness of a 5 week structured group intervention program for Japanese breast cancer patients. A total of 47 patients with breast cancer completed the full program. The results of the Profile of Mood States (POMS) scores were compared before, immediately after, and 6 months after the intervention program. As analysed by POMS scores, the clinical effectiveness of a structured group intervention program persisted for 6 months for patients without nodal metastases. In contrast, the intervention program did not show a lasting effect for patients with nodal metastases. This study demonstrated the short-term effectiveness of structured interventions among Japanese cancer patients, but persistence of the effects of intervention was found only among patients without nodal metastases. For patients with nodal metastases, additional intervention would be needed.     

Cancer chemopreventive activity of an iridoid glycoside, 8-acetylharpagide, from Ajuga decumbens

In the course of our continuing search for novel cancer chemopreventive agents from natural sources, several kinds of Labiatae plants were screened. Consequently, the iridoid glycoside derivative, 8-acetylharpagide (8-AcHarp), was obtained from the flowering whole plant of Ajuga decumbens as an active constituent. This glycoside exhibited the remarkable inhibitory effect on two-stage carcinogenesis test of mouse skin tumors induced by nitric oxide (NO) donor, (+/-)-(E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexen eamide (NOR 1) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. Further, 8-AcHarp exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test of mouse hepatic tumor using N-nitrosodiethylamine (DEN) as an initiator and phenobarbital (PB) as a promoter.     

In vivo chemosensitivity of human malignant cystosarcoma phyllodes xenografts

Malignant cystosarcoma phyllodes (MCSP) is a rare breast tumor. Chemotherapeutic regimens for treatment of MCSP have not been established. We previously established an MCSP xenograft line MC-3-JCK. In this study, we established a new MCSP xenograft line, MC-10-JCK, by serial transplantation in nude mice. We studied the chemosensitivity of these two MCSP tumor xenografts to anticancer drugs in vivo. We also examined the expression of multidrug resistance-related proteins such as p-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) by immunohistochemical analysis. These two xenografts were sensitive to doxorubicin, vincristine and cyclophosphamide in vivo. Immunohistochemically, clinical specimens and xenografts were negative for Pgp and MRP expression. These results are consistent with the chemosensitivity of human MCSP to lipophilic anticancer compounds.