Elimination of the 4-hydroxyl group of the alkaloids related to morphine. VI. Synthesis of (-)-3-hydroxy-N-methyl-C-nor-morphinan derivatives.
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Alkaloids↗
Biomedical subjects
N Tsuji
Publications and source records attributed to N Tsuji.
Heat-induced apoptosis via caspase-3 activation in tumour cells carrying mutant p53.
Apoptosis plays an important role in heat-induced cell death. However, the mechanism of heat-induced apoptosis has not yet been elucidated. In the present study, the signal transduction pathway underlying heat-induced apoptosis was investigated in heat-resistant HeLa cells carrying mutant p53 gene and heat sensitive HeLa cells that had been transduced with an antisense TNF gene. Induction of mutant p53, but not p21/WAF-1, was observed after heat treatment of both the resistant and sensitive cells. Heat-induced cytotoxicity was not inhibited in either cells with interleukin-1beta-converting enzyme (ICE: caspase-1) like protease inhibitor Ac-YVAD-CHO. In contrast, there was 48% and 63% inhibition of cytotoxicity in HeLa and transfectants, respectively, with a caspase-3 inhibitor (Ac-DEVD-CHO). Heat-induced apoptosis was also prevented by administration of Ac-DEVD-CHO in both cells. In addition, an augmentation of heat-induced cytotoxicity in transfectants was almost completely inhibited by Ac-DEVD-CHO. Further, caspase-3 mRNA expression was increased remarkably in heat-treated HeLa cells and transfectants. Taken together, these results suggest that activation of caspase-3 is involved in the signal transduction pathway of heat-induced apoptosis of the tumour cells carrying mutant p53.
Base Sequence↗
The possible prognostic significance of p53 immunostaining status of the primary tumor in patients developing local recurrence after breast-conserving surgery.
Prognostic factors for distant metastases in patients with local recurrence after breast-conserving treatment (BCT) were studied. Fifty-six patients who developed local recurrence after BCT were recruited from 18 key hospitals/institutes in Japan. All 10 patients whose primary tumors were DCIS fared well without evidence of distant failure for a median follow-up period of 57 months (range 41-72) after the local recurrence. Inflammatory local recurrence was observed in 5 patients whose prognosis was grave: 3 with concomitant distant metastases and 1 developing them 7 months later. In the remaining 41 patients with noninflammatory local recurrence, various clinicopathological factors including age, disease-free interval, histology of the primary and recurrent tumors, axillary lymph node status, estrogen and progesterone receptor, immunohistochemical staining of erbB2 and p53 protein were evaluated as prognostic factors. Only the p53 immunostaining status of the primary tumor was found to be a significant prognostic indicator for distant metastases; distant disease-free survival at 5 years after the local recurrence was 92% for patients with p53-negative cancers and 51% for those with p53-positive cancers (p < 0.05).
Adult↗
Nucleolar organizer regions in intraductal lesions associated with invasive ductal carcinoma of the breast.
To estimate cell kinetics of intraductal carcinoma present outside the invasive ductal carcinoma of the breast, an argyrophil stain for proteins associated with nucleolar organizer regions (Ag-NOR) was applied on paraffin sections of 28 breast cancers with an extensive intraductal component. The patients chosen for study were comparable to those eligible for breast-conserving surgery in our institute. The mean numbers of Ag-NOR in the nucleus were: normal duct 1.2 +/- 0.2 (mean +/- SD), normal lobule 3.1 +/- 1.2, main tumor 10.7 +/- 4.1 and intraductal lesion 7.7 +/- 2.6. A significant difference of Ag-NOR numbers was observed not only between the normal epithelium and main tumor (p < 0.01) but also between the main tumor and intraductal lesion (p < 0.01). As for intersite variation in individual cases, the Ag-NOR number of the intraductal lesion was lower than that of the main tumor in 25 out of 28 cases (89%). These results demonstrate that an intraductal lesion is less aggressive than the main tumor.
Adult↗
Recombinant human tumor necrosis factor causes regression in patients with advanced malignancies.
Fifteen patients with advanced solid tumors of various types were treated by the intratumoral administration of recombinant human tumor necrosis factor (rH-TNF). The treatment appeared to benefit the 4 cases of superficial tumors: there were 1 complete response, 1 partial response and 2 minor responses. In all 11 patients with deep-seated tumors, including 6 cases of pancreatic cancer, 4 of liver cell cancer and 1 of metastatic liver tumor, no tumor regression was observed, but progression stopped in all these tumors. Seven of the 11 with deep-seated tumors showed a decrease in tumor markers and/or the development of tumor necrosis. Fever, hypotension and fatigue were the main clinical side effects. No significant changes were found in hematologic, renal or liver parameters. These results suggest that administration of rH-TNF to the tumor site has the potential for controlling local tumor growth.
Adult↗
A case-control study on risk factors for local recurrences or distant metastases in breast cancer patients treated with breast-conserving surgery.
A case-control study was conducted on 143 case-control sets recruited from the 18 key hospitals/ institutes in Japan to identify risk factors for local recurrences and distant metastases after breast-conserving surgery in breast cancer patients: (1) positive surgical margin was a risk factor for local recurrences (relative risk (RR) = 16.70, p < 0.001) but not for distant metastases, (2) positive p53 immunostaining was a risk factor for both local recurrences (RR = 5.62, p = 0.003) and distant metastases (RR = 3.11, p = 0.034), (3) lymph node metastasis was a risk factor for distant metastases (RR = 9.28, p = 0.001) but not for local recurrences, (4) radiation therapy reduced local recurrences (RR = 0.13, p = 0.004) and (5) adjuvant chemotherapy (RR = 0.27, p = 0.120), endocrine therapy (RR = 0.21, p = 0.037), and chemoendocrine therapy (RR = 0.05, p = 0.013) reduced local recurrences.
Adult↗
Endogenous tumor necrosis factor functions as a resistant factor against hyperthermic cytotoxicity in pancreatic carcinoma cells via enhancement of the heart shock element-binding activity of heart shock factor 1.
To elucidate the relationship between two distinct resistant factors, endogenous tumor necrosis factor (enTNF) and heat shock proteins (HSPs), against hyperthermia, we assessed whether enTNF enhances HSP72 expression. Although there was a variability in the sensitivity of pancreatic carcinoma cell lines to heat, enTNF and HSP72 expression as well as MnSOD activity correlated positively with heat resistance. When MIAPaCa-2 pancreatic carcinoma cells, which had the lowest enTNF expression and highest heat sensitivity, were transfected with a nonsecretory-human TNF gene (pTNF delta pro), intracellular manganous superoxide dismutase (MnSOD) activity, HSP72 expression, and heat resistance were significantly increased. Furthermore, in these cells, enTNF expression correlated with the binding activity of heat shock factor 1 (HSF 1) to an oligonucleotide containing the human heat shock element. These results indicate that enTNF participates in the intrinsic resistance against heat via induction of MnSOD, enhances HSF1-binding activity, and augments of HSP72 expression. Therefore, inhibition of enTNF expression in pancreatic carcinoma cells would improve the efficacy of hyperthermia for pancreatic carcinoma.
DNA-Binding Proteins↗
Protein kinase C inhibitors augment tumor-necrosis-factor-induced apoptosis in normal human diploid cells.
In this report we show augmentation of tumor necrosis factor (TNF)-induced apoptosis by protein kinase C (PKC) inhibitors in human embryonic lung fibroblast (HEL) cells. Staurosporine (STS) reportedly potentiates TNF-mediated cytotoxicity in cancer cell lines via inhibition of PKC. We investigated whether STS or another potent PKC inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), augmented TNF-induced apoptosis in normal human diploid cells and examined the effects of the PKC inhibitors on the expression of endogenous TNF (enTNF) and manganous superoxide dismutase (MnSOD) as possible cell resistance factors opposing TNF-induced apoptosis. Both PKC inhibitors augmented TNF-mediated DNA fragmentation in HEL cells, which are normally TNF resistant and constitutively express high amounts of enTNF and MnSOD activity. Neither the number nor the affinity of TNF receptors were altered by STS and H7. The expression of enTNF and MnSOD was suppressed by the presence of STS or H7 along with TNF. The results indicate that PKC inhibitors augment TNF-induced apoptosis not only in tumor cells but also in normal cells by inhibitory effects on cellular resistance factors such as enTNF and MnSOD.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Endogenous tumour necrosis factor regulates heat-inducible heat shock protein 72 synthesis.
Endogenous tumour necrosis factor (enTNF) acts as a resistant factor against cytotoxicity of heat by induction of manganous superoxide dismutase (MnSOD), thereby scavenging reactive oxygen free radicals. On the other hand, it is also well known that heat shock proteins (HSPs), which are induced by heat-stress, behave as cytoprotecting factor against this stress. However, the relationship of these two resistant factors is not yet elucidated. In the present study we would therefore propose the possibility that enTNF enhances HSP72 expression. Heat-sensitive L-M (mouse tomourigenic fibroblast) cells, which normally do not express enTNF, were transfected with a nonsecretory-type human TNF expression vector to produce enTNF. Stable transfectants showed resistance to heat treatment and an increase of HSP72 expression. Conversely, when HeLa (human uterine cervical cancer) cells, which normally produce an appreciable amount of enTNF, were transfected with an antisense TNF mRNA expression vector to inhibit enTNF synthesis, their heat sensitivity was enhanced and HSP72 expression was reduced by half. In conclusion, these findings indicate that enTNF regulates heat-inducible HSP72 synthesis.
Animals↗