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

Ifosfamide, carboplatin, cisplatin, etoposide, and paclitaxel are chemotherapeutic agents active in treating many malignant diseases. The ICE combination (ifosfamide/carboplatin [or cisplatin]/etoposide) has been studied in breast cancer, small cell and non-small cell lung cancer, testicular cancer, lymphoma, and other malignancies with promising results. We conducted a dose-escalation study of paclitaxel in combination with ICE (ICE-T) to evaluate the toxicity and define the maximum tolerated dose of paclitaxel. To date, 24 patients have been treated with ICE-T. Patients had to have no or minimal prior chemotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate bone marrow, liver, and kidney function. The doses of ICE were as follows: ifosfamide 1.25 g/m2/d days 1 to 3, carboplatin 300 mg/m2 day 1, and etoposide 80 mg/m2/d days 1 to 3. Paclitaxel was given at a dose of 120 mg/m2 to five patients, 135 mg/m2 to five patients, 150 mg/m2 to three patients, and 175 mg/m2 to 11 patients. All patients received granulocyte colony-stimulating factor support. The most common side effect was neutropenia. Grade 4 neutropenia and thrombocytopenia occurred during 34% and 20% of 94 cycles, respectively, with leukopenic fever occurring during 14% of cycles. No treatment-related death or sepsis occurred due to brief nadir durations of 3.5 days for neutropenia and thrombocytopenia. Other toxicities were mostly mild to moderate and did not require dose modification, although alopecia was universal. Nine patients (100%) with metastatic breast cancer and four (67%) with soft tissue sarcoma have attained documented objective responses with four complete remissions (one breast cancer and three sarcoma patients). The maximum tolerated dose of paclitaxel has not yet been defined, and the study is ongoing. In conclusion, this pilot study showed that ICE-T is safe and tolerable. The response to ICE-T is encouraging and warrants further study with this regimen.
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PMID:Ifosfamide, carboplatin, etoposide, and paclitaxel chemotherapy: a dose-escalation study. 867 54

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

In 1988, a 27-year-old male patient received an allogeneic BMT for leukemic relapse 8 months after ABMT for AML (M2) in first complete remission. Because of chronic GVHD of the liver CsA was administered until 1994. Nine months after discontinuation of CsA, locally advanced gastric granulocytic sarcoma (GS) was diagnosed without evidence of systemic relapse. The patient was treated with two courses of polychemotherapy (ICE, NOVIA). Granulocyte colony-stimulating factor (G-CSF)-mobilized donor buffy coat cells were reinfused after each chemotherapy cycle in an attempt to accelerate hematopoietic regeneration and to induce a graft-versus-leukemia (GVL) effect. Local irradiation and surgical resection of residual leukemic cells resulted in complete remission. Seventeen months from diagnosis of GS the patient relapsed again with multiple lesions and died of generalized bleeding during aplasia after a third course of polychemotherapy (ICE). In our patient donor peripheral blood stem cell support did not accelerate hematopoietic regeneration (time to neutrophil recovery > 0.5 x 10(9) g/l from the start of chemotherapy was 27 days after ICE and 36 days after NOVIA) and did not result in long-term disease-free survival.
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PMID:Polychemotherapy combined with G-CSF-mobilized donor buffy coat transfusion for granulocytic sarcoma after allogeneic BMT for AML. 915 72

The use of high-dose chemotherapy followed by hematopoietic rescue is increasing worldwide for solid tumors. Several studies have suggested that the period of absolute neutrophil count (ANC, < 500/ml) may be shortened in patients who receive peripheral blood progenitor cells (PBPC). To estimate the clinical value of granulocyte-colony-stimulating factor, we examined a cohort of 26 consecutive patients with advanced breast cancer who received one or two cycles of high-dose chemotherapy with PBPC rescue with or without filgrastim. Thirty-five courses of high-dose ICE (ifosfamide, carboplatin, etoposide) chemotherapy were administered and evaluated. All patients received PBPC rescue. Sixteen patients (21 courses) received subcutaneous filgrastim (5 mg/kg) following PBPC infusion. Recovery to > or = 500 ANC occurred at a median time of 7 days post PBPC infusion among patients who received filgrastim versus 10 days among patients who received standard support care only (P < 0.01). The administration of filgrastim was not associated with a reduction in the duration of hospitalization, in the total number of days on nonprophylactic antibiotics, number of red blood cell transfusions, time to platelet engraftment, or number of febrile days. This could be the consequence of the high hematopoietic cell dose administered in the study. Therefore, any effect of filgrastim was probably masked by the use of a large number of PBPC. Larger prospective randomized studies, specifically focused on the utility of the administration of growth factors following high-dose chemotherapy and PBPC rescue, may be warranted to know whether the administration of filgrastim after PBPC transplantation is really necessary.
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PMID:The use of granulocyte colony-stimulating factors following peripheral blood progenitor cell rescue after high-dose chemotherapy for advanced breast cancer: a prospective study. 952 80

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

Patients with high-risk breast cancer may benefit from dose-escalated chemotherapy. We studied toxicity and therapeutic efficacy of sequential high-dose therapy consisting of two cycles of ifosfamide 12,000 mg/m2, carboplatin 900 mg/m2, and epirubicin 180 mg/m2 (ICE) with peripheral blood stem cell support. Ninety-one patients with advanced breast cancer were included. Fifty-one patients with stage II/III disease and 10 or more tumor-positive axillary lymph nodes received high-dose therapy as adjuvant treatment; the remaining 40 patients were treated for metastatic disease. Peripheral blood stem cells were collected following granulocyte colony-stimulating factor-supported induction chemotherapy. In 68 patients, induction chemotherapy included two cycles of ifosfamide 7,500 mg/m2 and epirubicin 120 mg/m2, while 23 patients received one cycle of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 135 mg/m2, ifosfamide 6,000 mg/m2, and epirubicin 90 mg/m2. One hundred ninety-two cycles of ICE were supported with a median of 3.5 x 10(6) CD34+ cells/kg body weight (range, 1.7 to 38 x 10(6) CD34+ cells/kg body weight), which resulted in rapid hematologic reconstitution with recovery times, for a median neutrophil count of 0.5 x 10(9)/L of 13 days (range, 6 to 20 days) and for a median platelet count greater than 20 x 10(9)L of 9 days (range, 5 to 24 days). Seven patients received only one cycle of ICE because of progressive disease (in two patients with metastatic disease), central nervous system toxicity (one patient), cardiac toxicity (one patient), severe enterocolitis (one patient), development of human leukocyte antigen antibodies (one patient), and wish to withdraw from the study (one patient). Seventeen patients with metastatic disease received an additional high-dose cycle consisting of the non-cross-resistant agents thiotepa 600 mg/m2, etoposide 1,500 mg/m2, and paclitaxel 165 mg/m2. In patients treated adjuvantly, the probability of disease-free survival was 64% at 47 months, which compares favorably with results of conventional treatment protocols, with a 47% event-free probability at the same time period. The probability of progression-free survival in patients with metastatic disease was 18% at 44 months. In conclusion, sequential high-dose therapy with peripheral blood stem cell support in patients with high-risk breast cancer can be administered safely and offers a potential benefit in the adjuvant setting.
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PMID:Efficacy and toxicity of sequential high-dose therapy with peripheral blood stem cell support in patients with high-risk breast cancer. 957 56

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

Autografting with CD34+ cell-selected peripheral blood progenitor cells (PBPC) is often associated with a prolonged recovery time and a higher incidence of infections. The aim of our study was to evaluate whether underlying disease influences hemopoietic recovery and the infectious complications occurring after transplantation. We studied 19 breast cancer (BC) patients and 17 multiple myeloma (MM) patients entered in a high-dose chemotherapy (HDC) program of tandem autografting with CD34+ cell-selected PBPC. PBPC were collected after mobilizing chemotherapy plus granulocyte colony-stimulating factor and were processed for selection of CD34+ cells. After selection, a median of 53% CD34+ cells was recovered with a median final purity of 92% with no significant differences between the MM (52% and 92%, respectively) and BC (53% and 89%, respectively) patients. Medians of 4.5 x 10(6)/kg CD34+ cells (BC, 4.4 x 10(6)/kg; MM, 5.4 x 10(6)/kg) and 18 x 10(4)/kg colony-forming units-granulocyte-macrophage (BC, 21 x 10(4)/kg: MM, 16 x 10(4)/kg) were reinfused after each HDC. Twenty-six patients (10 MM and 16 BC) underwent tandem autografting, and 10 patients received only 1 autograft because of inadequate collection (5 patients), clinical condition (3 patients), and refusal (2 patients). In the BC patients, the HDC regimen included a high-dose melphalan course followed by an ICE (ifosfamide, carboplatin, and etoposide) course. In the MM patients, the regimen consisted of a course of high-dose melphalan therapy and a course of ICBV (idarubicin, cyclophosphamide [Cytoxan], BCNU, and etoposide) or total body irradiation, etoposide, and Cytoxan. We found a significantly prolonged time for neutrophil recovery to > 500/microL in the MM patients (13 days versus 10 days; P < .002), whereas the times for platelet recovery to > 20,000/microL in the two groups were not different (13 days versus 12 days; not significant). No late engraftment failures and no toxic deaths were observed. The incidences of extrahematologic toxicity were similar for the two patient groups. All patients received similar anti-infection prophylaxis for 3 months after transplantation. After 12 months of observation, we found a statistically significant higher incidence of bacterial infections in MM patients in both the early (77.8% versus 48.6%; P < .034) and the late (41.1% versus 0%; P < .014) posttransplantation periods, whereas the incidences of fungal infections were similar in the two groups. Viral infections consisted of herpes zoster virus infection in 2 patients of each group, and cytomegalovirus infection was observed in 3 MM patients and no BC patients. Our experience demonstrates a prolonged neutrophil recovery time and higher incidences of bacterial and viral infections in MM patients compared with BC patients. These observations, although limited by the small sample size, suggest that the underlying disease may influence the incidence of infections after CD34- cell-selected transplantation and should be considered in the planning of appropriate antimicrobial prophylaxis in the autologous transplantation setting.
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PMID:Hemopoietic recovery and infectious complications in breast cancer and multiple myeloma after autologous CD34+ cell-selected peripheral blood progenitor cell transplantation. 1497 84

Spontaneous apoptosis of normal purified bone marrow CD34+ cells induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) via the Fas pathway appears to be mediated by caspase-1 and caspase-8 activity. In seeking an alternative explanation for this observation, the present study examined CD34+ cell growth with different cytokines, cytokine concentrations, caspase inhibitors, cell crowding and different media. Exposure of the normal CD34+ cells to different concentrations of GM-CSF and granulocyte colony-stimulating factor (G-CSF) increased apoptosis at lower concentrations. However, these GM-CSF effects were suppressed by G-CSF. Investigation of the association between apoptosis and crowding and different media showed that: 1) G-CSF and GM-CSF are equally effective as survival factors, and 2) the percentage of apoptotic cells in liquid culture was markedly lower than that found in methylcellulose culture. Finally, immunofluorescence staining showed that Fas was expressed at 10 ng/mL GM-CSF, while Bcl-2 expression was detected at 100 ng/mL. These findings suggest that cytokine concentration, cell culture conditions, cell crowding and cell interactions all are important factors in GM-CSF-induced apoptosis.
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PMID:Induction of apoptosis in myeloid progenitors by granulocyte-macrophage colony-stimulating factor. 1564 13


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