Phase II study of concurrent administration of doxorubicin and docetaxel as first-line chemotherapy for metastatic breast cancer

OBJECTIVE: To evaluate the efficacy and toxicity of concurrent administration of doxorubicin and docetaxel, without prophylactic use of granulocyte colony-stimulating factor, as first-line chemotherapy in patients with metastatic breast cancer (MBC). METHODS: This multi-institutional study enrolled 40 women; 37 were assessable for efficacy and all 40 patients were evaluated for toxicity. Treatment consisted of 50 mg/m(2) doxorubicin and 60 mg/m(2) docetaxel on day 1 every 3-4 weeks. RESULTS: Patients received a total of 251 cycles of chemotherapy (median, 5 cycles; range, 1-13 cycles). Of the 37 patients assessable for efficacy, 2 had a complete response and 24 had partial responses, which accounted for a 70% objective response rate (95% confidence interval, 53-84%). The median time to treatment failure was 30.1 weeks (range, 3.3-80.7 weeks). Grade 4 neutropenia was observed in 88% of patients and was the most frequent haematological toxicity. Febrile neutropenia was seen in 40% of patients, but no severe infections were observed. Non-haematological toxicity was generally tolerable. There were 2 grade 4 adverse events, which included 1 bleeding duodenal ulcer and 1 hypersensitivity reaction, but grade 3 episodes were infrequent. None of the patients developed congestive heart failure or asymptomatic decrease of left ventricular ejection fraction to less than 50%. Fluid retention syndrome 相似文献   

Clinical Review of the Japanese Experience with Boron Neutron Capture Therapy and A Proposed Strategy Using Epithermal Neutron Beams

Our concept of boron neutron capture therapy (BNCT) is selective destruction of tumor cells using the heavy-charged particles yielded through ¹⁰ B(n, )⁷ Li reactions. To design a new protocol that employs epithermal neutron beams in the treatment of glioma patients, we examined the relationship between the radiation dose, histological tumor grade, and clinical outcome. Since 1968, 183 patients with different kinds of brain tumors were treated by BNCT; for this retrospective study, we selected 105 patients with glial tumors who were treated in Japan between 1978 and 1997. In the analysis of side effects due to radiation, we included all the 159 patients treated between 1977 and 2001.With respect to the radiation dose (i.e. physical dose of boron n-alpha reaction), the new protocol prescribes a minimum tumor volume dose of 15Gy or, alternatively, a minimum target volume dose of 18Gy. The maximum vascular dose should not exceed 15Gy (physical dose of boron n-alpha reaction) and the total amount of gamma rays should remain below 10Gy, including core gamma rays from the reactor and capture gamma in brain tissue.The outcomes for 10 patients who were treated by the new protocol using a new mode composed of thermal and epithermal neutrons are reported.     

HIV-1 integrase inhibitory substances from Coleus parvifolius

For the purpose of discovering anti-HIV-1 agents from natural sources, water and EtOH extracts of 50 Thai plants were screened for their inhibitory activity against HIV-1 integrase (IN), an enzyme essential for viral replication. Of these plants, an EtOH extract of Coleus parvifolius Benth. (aerial parts) showed potent activity against HIV-1 IN with an IC50 value of 9.2 microg/mL. From this extract, 11 compounds were isolated and identified as luteolin 5-O-beta-d-glucopyranoside (1), luteolin (2), luteolin 7-methyl ether (3), luteolin 5-O-beta-d-glucuronide (4), 5-O-beta-d-glucopyranosyl-luteolin 7-methyl ether (5), rosmarinic acid (6), rosmarinic acid methyl ester (7), daucosterol (8), a mixture of alpha- and beta-amyrin (9, 10) and phytol (11). Of these compounds, rosmarinic acid methyl ester (7), rosmarinic acid (6), luteolin (2) and luteolin 7-methyl ether (3) exhibited inhibitory activities against HIV-1 IN with IC50 values of 3.1, 5.0, 11.0 and 11.0 microM, respectively. Among rosmarinic acid derivatives, the HIV-1 IN inhibitory activity increased in turn for a dimer (IC50 = 5.0 microM), a trimer (IC50 = 1.4 microM), and a tetramer (IC50 = 1.0 microM).     

A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway

We identified IFI16 as a BRCA1-associated protein involved in p53-mediated apoptosis. IFI16 contains the Pyrin/PAAD/DAPIN domain, commonly found in cell death-associated proteins. BRCA1 (aa 502-802) interacted with the IFI16 Pyrin domain (aa 1-130). We found that IFI16 was localized in the nucleoplasm and nucleoli. Clear nucleolar IFI16 localization was not observed in HCC1937 BRCA1 mutant cells, but reintroduction of wild-type BRCA1 restored IFI16 nuclear relocalization following IR (ionizing radiation). Coexpression of IFI16 and BRCA1 enhanced DNA damage-induced apoptosis in mouse embryonic fibroblasts from BRCA1 mutant mice expressing wild-type p53, although mutant IFI16 deficient in binding to BRCA1 did not induce apoptosis. Furthermore, tetracycline-induced IFI16 collaborated in inducing apoptosis when adenovirus p53 was expressed in DNA-damaged p53-deficient EJ cells. These results indicate a BRCA1-IFI16 role in p53-mediated transmission of DNA damage signals and apoptosis.     

BH4-domain peptide from Bcl-xL exerts anti-apoptotic activity in vivo

The Bcl-2 family of proteins regulates apoptosis chiefly by controlling mitochondrial membrane permeability. It has previously been shown that the BH4 domain of Bcl-2/Bcl-xL is essential for the prevention of apoptotic mitochondrial changes, including the release of cytochrome c and apoptotic cell death. We have previously reported that BH4 peptide fused to the protein transduction domain of HIV-1 TAT protein (TAT-BH4) significantly inhibits etoposide-induced apoptosis in a cell line. This time, we investigated whether TAT-BH4 peptide was cytoprotective in ex vivo and in vivo rodent models. Intraperitoneal injection of TAT-BH4 peptide greatly inhibited X-ray-induced apoptosis in the small intestine of mice and partially suppressed Fas-induced fulminant hepatitis. In addition, this peptide markedly suppressed heart failure after ischemia-reperfusion injury in isolated rat heart, probably by preventing mitochondrial dysfunction. These findings demonstrate that TAT-BH4 peptide exerts anti-apoptotic activity both in vivo and ex vivo, and imply that it may be a useful therapeutic agent for diseases involving mitochondrial dysfunction and apoptosis.     

MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-kappaB activation

Bcr-Abl tyrosine kinase, a chimeric oncoprotein responsible for chronic myelogenous leukemia, constitutively activates several signal transduction pathways that stimulate cell proliferation and prevent apoptosis in hematopoietic cells. The antiapoptotic function of Bcr-Abl is necessary for hematopoietic transformation, and also contributes to leukemogenesis. Herein, we show for the first time that cell transformation induced by Bcr-Abl leads to increased expression and kinase activity of MEK kinase 1 (MEKK1), which acts upstream of the c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and NF-kappaB signaling pathways. Inhibition of MEKK1 activity using a dominant-negative MEKK1 mutant (MEKK1km) diminished the ability of Bcr-Abl to protect cells from genotoxin-induced apoptosis, but had no effect on the proliferation of Bcr-Abl-transformed cells. Expression of MEKK1km also reduced NF-kappaB activation, and inhibited antiapoptotic c-IAP1 and c-IAP2 mRNA expression in response to the genotoxin. By contrast, neither JNK nor ERK activation was affected. These results indicate that MEKK1 is a downstream target of Bcr-Abl, and that the antiapoptotic effect of Bcr-Abl in chronic myelogenous leukemia cells is mediated via the MEKK1-NF-kappaB pathway.     

Clinical significance of thrombospondin-1 expression in relation to vascular endothelial growth factor and interleukin-10 expression at the deepest invasive tumor site of advanced colorectal carcinoma

Various angiogenic and angiostatic factors regulate angiogenesis. Tumor angiogenesis is a complicated process for which the detailed mechanisms remain unclear. The aim of this study was to elucidate the clinical significance of TSP-1 expression in relation to expression of VEGF and IL-10 and angiogenesis at the deepest invasive tumor site as a predictor of invasive/metastatic potential and prognosis of advanced colorectal carcinoma (CRC). Patients (n=152) who had undergone surgical resection for advanced CRC were entered in this study. Expression of TSP-1, VEGF, and IL-10 was examined immunohistochemically with specific antibodies. Tumor microvessel density (MVD) was also determined immunohistochemically with anti-CD34 antibody (NU-4A1). Expression of TSP-1, VEGF, and IL-10 at the deepest invasive tumor site was detected in 46 (30.3%), 62 (40.8%), and 39 (25.7%) of 152 lesions, respectively. TSP-1, VEGF, and IL-10 expression at the superficial part was detected in 60 (39.5%), 35 (23.0%), and 46 (30.3%) of 152 lesions, respectively. Although there was no significant difference between the incidence of TSP-1 and IL-10 expression at the deepest invasive site or at the superficial part, there was a significant difference between the incidence of VEGF expression at the deepest invasive site and that at the superficial part. Expression of TSP-1 and IL-10 at the deepest invasive tumor site was inversely correlated with metastatic potential and prognosis in relation to MVD. Furthermore, lesions that were TSP-1-negative and VEGF-positive at the deepest invasive tumor site showed the strongest association with MVD. The 5-year survival rate for patients with TSP-1-negative or IL-10 negative lesions at the deepest invasive tumor site was significantly poorer than that for patients with TSP-1-positive or IL-10-positive lesions, respectively. The 5-year survival rate for patients with VEGF expression at the deepest invasive tumor site was significantly poorer than that for patients without VEGF expression. The 5-year survival rate for patients with TSP-1-negative, VEGF-positive lesions at the deepest invasive site were significantly poorer than that for patients with lesions without these characteristics. Multivariate analysis with logistic regression for 5-year survival in patients with curative surgery showed that lymph node metastasis and VEGF expression were significant prognostic factors. Although lack of TSP-1 or IL-10 expression was associated significantly with poorer prognosis, this may be less important in poorer prognosis than the presence of VEGF expression.     

Development of a new respirator for organic vapors with a breakthrough detector using a semiconductor gas sensor

A method for determining breakthrough of organic vapors in a respirator cartridge was developed. A thick film semiconductor gas sensor was used as a breakthrough detector. Air containing organic vapor was introduced into the cartridge, and an output signal from the sensor inserted in the downstream flow of the cartridge was recorded on an IC card. Simultaneously, the breakthrough curve was obtained by measuring the vapor concentration at downstream from the respirator cartridge with a gas chromatograph (GC) equipped with a flame ionization detector. When the breakthrough was almost completed, the data recorded in the card were transferred to a personal computer and the change in the output signal from the sensor was compared with the breakthrough curve obtained by the GC. Twelve organic solvents including aromatic hydrocarbons, chlorinated hydrocarbons, acetates, alcohols, ketones, and aliphatic hydrocarbons were tested under low (20%-25%) and high (70%-80%) relative humidity ranges. The sensitivity of the sensor for chlorinated hydrocarbons such as 1,1,1-trichloroethane was relatively low, especially when the relative humidity was high, but the rise time of the sensor output signal was almost the same as or earlier than the breakthrough time by the GC. Based on the experimental results, a new respirator for organic vapors that can detect the end of service life was developed.     

Uptake of cadmium in meals from the digestive tract of young non-smoking Japanese female volunteers

OBJECTIVES: To estimate rates of cadmium (Cd) uptake from the digestive tract and changes in Cd in biological specimens after intake of Cd mainly in rice. METHODS: Twenty-five young non-smoking Japanese female volunteers (20-23 in age) were recruited and a 20-d experimental study was conducted. With polished rice containing 0.004 ppm and 0.340 ppm of Cd, Meal L and Meal H were prepared. Approximately 12% of total Cd in Meal L and 92% of total Cd in Meal H originated in rice. The volunteers ate Meal L for 11 d to achieve a stable intake-output balance of Cd. Fifteen of the 25 volunteers ate Meal H on the 12(th) day (Group D1), and the remaining 10 ate Meal H on the 12(th), 13(th) and 14(th) day (Group D3). All 25 subjects then resumed the consumption of Meal L to the end of the study (20(th) day). All meals, feces and urine were collected during the study, and Cd intake from the daily meals (Cd-I), Cd in feces (Cd-F) and Cd in urine (Cd-U) were determined. For measurement of Cd in blood (Cd-B), venous blood was collected from all volunteers on the day before the study and again on the 12(th) and 20(th) day; venous blood was also collected from 4-8 volunteers at additional time points. RESULTS: Mean Cd-I was 4.51 microg/d (range: 1.85-6.93) or 48.48 microg/d (range: 27.98-56.27) when they ate Meal L or Meal H. Cd-F and Cd-B exhibited faster responses to the change in Cd-I than did Cd-U. The Cd(uptake) rate, defined as (1-Cd-F(excess) /Cd-I(excess)) (Fig. 1), was 47.2% (range: -9.4-83.3%) in Group D1 and 36.6% (range: -9.2-73.5%) in Group D3, and the Cd(balance) rate, defined as (1-Cd-F(output) /Cd-I(intake)), was 23.9% (range: -4.0-37.7%) in Group D1 and 23.7% (range: -8.2-56.9%) in Group D3. CONCLUSIONS: Cd-F and Cd-B are better biological monitoring parameters for assessing change in Cd-I than Cd-U. The Cd(uptake) and Cd(balance) rates appeared to be higher than those in previous papers when ingested Cd mainly originated in rice.