Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From June 1991 to August 1994, 61 patients with stage III unresectable non-small-cell lung cancer (NSCLC; 16 cases of stage IIIA with N2 bulky disease and 45 cases of stage IIIB) were treated with ifosfamide given i.v. at 3 g/m2 on day 1, carboplatin given i.v. at 200 mg/m2 on days 1 and 2, etoposide given i.v. at 120 mg/m2 on days 1-3 (ICE) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) given s.c. at 5 micrograms/kg on days 4-13. Chemotherapy was given every 3 weeks for up to three cycles and, unless the disease progressed, was followed by thoracic radiotherapy on the tumor volume (total dose 60 Gy) and mediastinum (40 Gy). All patients had measurable or evaluable unresectable disease and a performance status (Eastern Cooperative Oncology Group) of 0-1. Only 61% of the enrolled patients received the full program of chemoradiotherapy according to the study design. At the end of sequential chemo-radiotherapeutic treatment, 41% of the patients had an objective response (24 partial responses and 1 complete response), 31% showed no change and 28% had progressive disease. The response rate noted for patients in stage IIIA with N2 bulky disease and that recorded for patients in stage IIIB did not differ significantly. The median time to progression was 5.4 months and the median survival was 8.2 months, with the 1-year survival rate being 31%. Sites of progression were mostly intrathoracic. Haematological toxicity was the main side effect, with grade III-IV thrombocytopenia being reported in 24% of the 165 courses of intensive ICE chemotherapy given. Febrile neutropenia was described in six courses (three patients). Non-haematological toxicities and radiotherapy-related side effects were generally mild and easily manageable. In conclusion, in unresectable stage III NSCLC a short program of moderately intensified ICE chemotherapy with rhG-CSF protection followed by sequential radiotherapy failed to increase the percentage of objective responses and reached a median survival comparable with that previously achieved with standard doses.
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PMID:Phase II study of intensive chemotherapy with carboplatin, ifosfamide and etoposide plus recombinant human granulocyte colony-stimulating factor and sequential radiotherapy in locally advanced, unresectable non-small-cell lung cancer. 882 99

Coexistence of Philadelphia chromosome (Ph)-negative, primitive hematopoietic progenitor cells with their malignant counterparts in chronic myelogenous leukemia (CML) has been reported. As most of the Ph-negative progenitor cells do not express the HLA-DR antigen, selection of them might be possible. Peripheral blood progenitor cells (PBPC) from eight early chronic phase (CML) patients were mobilized by ICE chemotherapy followed by simultaneous administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human interleukin 3 (rhIL-3). PBPCs were collected by leukapheresis in the early phase of hematopoietic recovery after chemotherapy, CD34 selected and cultured in vitro. The content of Ph chromosome-positive cells in leukapheresis products as well as after CD34 enrichment and after in vitro culture was analyzed by interphase fluorescence in situ hybridization (FISH) and RT-PCR. The percentage of Ph chromosome-positive PBPC was reduced after each purification step in almost all samples. A substantial number of PBPC samples were negative for the bcr/abl mRNA rearrangement as analyzed by RT-PCR. The present study demonstrates the feasibility of mobilizing Ph-negative PBPC during the early phase of hematopoietic recovery after ICE chemotherapy and simultaneous administration of rhIL-3 and rhG-CSF.
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PMID:Quality of IL-3 and G-CSF-mobilized peripheral blood stem cells in patients with early chronic phase CML. 952 27

IL-1 beta-converting enzyme (ICE), also known as caspase-1, subserves two dichotomous biologic roles. It processes newly synthesized pro-IL-1 beta to yield the active cytokine and, as the human homologue of the Caenorhabditis elegans gene product, ced-3, it also induces cellular apoptosis through the cleavage of key intracellular structural and regulatory proteins and through the catalytic activation of other caspase family members. We show here that two different proinflammatory stimuli, LPS and granulocyte-macrophage-CSF, up-regulate the expression of both ICE and IL-1 beta in human polymorphonuclear neutrophils, and that the ICE-dependent cleavage of pro-IL-1 beta results in delayed expression of the constitutive cell death program. The apoptotic delay can be blocked by inhibiting tyrosine kinases or NF-kappa B activation and by inhibiting protein synthesis. Since an antisense oligonucleotide for IL-1 beta, a blocking Ab to IL-1 beta, and preincubation with the IL-1R antagonist all prevent the delay in apoptosis, we conclude that IL-1 beta acts in an autocrine manner to inhibit granulocyte programmed cell death. We conclude that caspase-1 (ICE) subserves both pro- and antiapoptotic roles; the latter role is evident during inflammation as an inhibition of spontaneous neutrophil apoptosis through the processing of IL-1 beta. The ICE-dependent activation of IL-1 beta may represent a common autocrine pathway for the divergent stimuli that inhibit the constitutive expression of neutrophil programmed cell death during inflammation.
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PMID:The IL-1 beta-converting enzyme (caspase-1) inhibits apoptosis of inflammatory neutrophils through activation of IL-1 beta. 967 Sep 75

We studied the effects of an intensified induction/consolidation treatment containing fludarabine (ICE/FLAN/FLAN) on the mobilization and collection of peripheral blood stem cells (PBSC) in 31 consecutive untreated acute myeloid leukaemia (AML) patients. The complete remission (CR) rate was comparable to classic inductions (68% after ICE; 84% after ICE-FLAN I). To mobilize PBSC, 19 patients received 10 microg/kg/d of granulocyte-colony stimulating factor (G-CSF) starting at day 13 after FLAN, 13 (69%) of whom were found to be nonmobilizers. When a second G-CSF administration was performed in 10/13 patients mobilization was either not achieved (8/10) or was considered insufficient (<1 x 106 CD34+ cells/kg) (2/10) and all 13 were subsequently submitted to bone marrow harvest. The harvest was considered adequate in 12/13 (92%) patients and autologous BMT (ABMT) has so far been performed in 10/12 cases with a mean of 8.6 x 108/kg nucleated reinfused cells. The median times to neutrophil and platelet recovery after ABMT did not significantly differ from those of two previous series of patients treated with ABMT without fludarabine-containing regimens. Adequate amounts of PBSC were obtained in 6/19 (31%) patients, who were then reinfused. Median times for platelet recovery were significantly longer than in a previous series of 26 AML cases reinfused with PBSC after treatment with the ICE-NOVIA induction/consolidation regimen (125 v 20 d to 20 x 109 plt/l, P < 0.02; 218 v 37 d to 50 x 109 plt/l, P < 0.02). In addition, times for platelet recovery after ICE/FLAN/FLAN were not significantly different from those in a previous group treated with ABMT performed after ICE/NOVIA,without fludarabine. We conclude that fludarabine-containing regimens severely impair mobilization and collection of PBSC in AML patients and seem unsuitable when PBSC autotransplantation is programmed.
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PMID:Fludarabine-containing regimens severely impair peripheral blood stem cells mobilization and collection in acute myeloid leukaemia patients. 1035 46

In the presence of granulocyte colony-stimulating factor (G-CSF), the release of IL-1beta and TNF-alpha by LPS-stimulated human whole blood was suppressed. Via measurement of cytokine mRNA, inactive precursor and mature protein, we investigated whether this inhibition occurs at the transcriptional, translational or post-translational level of cytokine production. G-CSF inhibited IL-1beta release, but the formation of proIL-1beta was not attenuated, indicating that G-CSF interferes with the proteolytic processing of proIL-1beta. Since the release of IL-1beta in LPS-stimulated whole blood was blocked by the caspase-1 inhibitor YVAD-cmk, processing of proIL-1beta appears to depend on caspase-1 activity. The conclusion that G-CSF inhibits caspase-1 activity was supported bythe finding that the release of IL-18 was also inhibited by G-CSF, similar to IL-1beta release. Intracellular caspase-1 activity in monocytes was measured by flow cytometry with the cell-permeablecaspase substrate Asp(2)-rhodamine. In the presence of G-CSF the cleavage of this substrate was inhibited by more than 50%. G-CSF had no effect on LPS-induced doubling of caspase-1 mRNA, indicating that G-CSF affects caspase-1 activation and not its formation. For TNF-alpha another mechanism of G-CSF action was identified: TNF-alpha as well as proTNF-alpha formation were inhibited by G-CSF, butG-CSF had no influence on LPS-induced TNF-alpha mRNA level. We therefore suggest that G-CSF causes translational silencing of LPS-induced TNF-alpha mRNA.
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PMID:Granulocyte colony-stimulating factor attenuates LPS-stimulated IL-1beta release via suppressed processing of proIL-1beta, whereas TNF-alpha release is inhibited on the level of proTNF-alpha formation. 1211 55

We have compared the efficacy of two PBSC mobilisation regimens, mini-ICE+filgrastim (second consolidation) and HiDAC+AMSA+filgrastim (third consolidation), in two consecutive cohorts of patients with AML CR1 receiving treatment according to a joint protocol. Group A: 18 patients, aged 41 (21-65) years, were mobilised with mini-ICE (idarubicin 8 mg/m(2)+cytarabine 800 mg/m(2)+etoposide 150 mg/m(2) days 1-3) followed by filgrastim 300-480 microg once daily s.c. from day 11 after start of chemotherapy. Only four patients reached >5 CD34+ cells/microl blood (B-CD34+) and were able to undergo leukaphereses. Two out of 18 (11%) reached the defined target of >/=2.0 x 10(6) CD34+ cells/kg after 1-3 leukaphereses. Group B: 20 patients, aged 50 (29-67) years, received HiDAC+AMSA (cytarabine 3 g/m(2) b.i.d. days 1, 3, 5+amsacrine 150 mg/m(2) q.d. days 2, 4) followed by filgrastim at a similar dose starting on day 7. A total of 18 patients reached B-CD34+ >5/microl and underwent PBSC harvesting, starting on day 23 (14-29) and yielding 4.0 (0.9-21) x 10(6) CD34+ cells/kg. Of 20 patients, 17 (85%) reached the defined target of >/=2.0 x 10(6) CD34+ cells/kg after 1-3 leukaphereses. We conclude that HiDAC+AMSA+G-CSF - in contrast to mini-ICE+G-CSF - is an efficient regimen for mobilising PBSC in patients with AML CR1.
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PMID:More efficient mobilisation of peripheral blood stem cells with HiDAC+AMSA+G-CSF than with mini-ICE+G-CSF in patients with AML. 1464 65

We reported two cases with germ cell tumor in which new preliminary treatment trials were performed by chemotherapy using anti-cancer drug selected on the basis of multidrug resistance gene mRNA expression, such as MDR1, MRP1, MRP2, MXR1, MGMT, GST pi and TopoII alpha, from RT-PCR assay. A 28-year-old male had gradually developed DI. MR imaging revealed enhanced tumors in the medulla oblongata, the pineal region and the suprasella region. Biopsy of tumor in the medulla oblongata demonstrated germinoma histologically. RT-PCR assay of this tissue revealed overexpression of MRP1, MGMT and GST pi mRNA, but neither MDR1, MRP2 nor MXR1 was observed. The patient was successfully given carboplatin, mitoxanthrone and ifosphamide after irradiation. A 15-year-old male was admitted to our hospital with high intracranial pressure syndrome. MR imaging revealed enhanced tumor in the pineal region. The tumor was diagnosed as a malignant germ cell tumor, histopathologically. RT-PCR assay of this tissue revealed overexpression of MRP1, MRP2, MXR1, MGMT and GST pi mRNA. Only MDR1 was not expressed. The patient was treated by irradiation including radiosurgery combined with chemotherapy, given cisplatin, etoposide and ifosphamide (ICE regimen), but he died because of progressive disease such as CSF dissemination. It seems that preliminary individual adjuvant chemotherapy based on mRNA expression of drug-resistance gene is available for the treatment of germ cell tumors.
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PMID:[Report of two cases with germinoma treated by individual adjuvant chemotherapy based on the mRNA expression of drug-resistance gene]. 1497 20

In the present study, we have determined levels of soluble interleukin-1 (IL-1) receptor type II (sIL-1RII), interleukin-18 (IL-18) and caspase-1 in cerebrospinal fluid and serum from mild cognitive impairment patients that later progressed to Alzheimer's disease (AD) and severe AD patients. Previous studies have shown that a chronic local inflammatory process is a part of AD neuropathology. In this process, activated microglial production of IL-1 seems to play an important role. In a previous study, we have shown increased levels of sIL-1RII in CSF from AD patients in a mild-moderate disease stage. In the present study, we found no significant differences in CSF or serum levels of sIL-1RII in either mild cognitive impairment or advanced AD patients as compared to control subjects. Likewise, there was no significant difference between mild cognitive impairment and severe AD patients. The same was true for caspase-1 and IL-18 serum levels, whereas CSF levels of caspase-1 and IL-18 were below detection limits. Our data indicate that the IL-1 system is relatively intact in the early and late stages of AD.
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PMID:Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer's disease. 1584 49

The inflammatory cytokines can initiate nerve cell degeneration and enhance the plaque production typically found in Alzheimer's disease (AD). Interleukin-18 (IL-18) is an inflammatory cytokine, which can induce the expression of interferon-gamma. This interleukin shares similarities with the IL-1 family of proteins. Like IL-1 beta, IL-18 is cleaved by caspase-1 (ICE) to an active secreted form. We examined the expressions of IL-18, -1 beta and ICE in different brain regions from AD patients that were categorized with respect to the Braak stage, and age-matched with non-demented controls. The levels of total-RNA and protein of IL-18 and ICE were increased, especially in the frontal lobe of AD patients and this change was not modified by ApoE genotype. Immunohistochemistry of AD brain samples detected IL-18 in microglia, astrocytes, and surprisingly in neurons, and it is also co-localized not only with amyloid-beta plaques but also with tau. In CSF, elevated IL-18 level was detected only in men and it also correlated with CSF tau in MCI. IL-18 may thus be a potential biomarker for men. Plasma levels of IL-18 showed no correlation with the disease. In conclusion, amyloid-beta may induce the synthesis of IL-18, and IL-18 kinases involved in tau phosphorylation as a part of the amyloid-associated inflammatory reaction.
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PMID:Expression of interleukin-18 is increased in the brains of Alzheimer's disease patients. 1765 66

The natural history of external hydrocephalus (EH) in adults is often marked by conversion into internal hydrocephalus. We describe a complication of this conversion, the ICE (intracerebral CSF entrapment) phenomenon, and demonstrate that both EH and ICE represent a challenge to current theories on the pathophysiology of communicating hydrocephalus (CHC). We propose a new model for CHC where the pattern of CSF distribution is largely determined by the intrinsic compliance of each of the intracranial structures. In this model, failure of distal CSF absorption resulting in an excessive intracranial CSF volume is the common denominator and CSF diversion the common solution to all forms of CHC.
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PMID:Internal hydrocephalus, external hydrocephalus, and the syndrome of intracerebral cerebrospinal fluid entrapment: a challenge to current theories on the pathophysiology of communicating hydrocephalus. 1971 62


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