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)

A multidisciplinary approach including surgery, radiotherapy, chemotherapy, and, recently, biotherapy and immunotherapy has significantly increased the prognosis for a large variety of pediatric solid tumors over the past two decades. Ifosfamide, carboplatin, and etoposide, used singly and in combination, have demonstrated efficacy in a number of these malignancies. The combination of all three agents (ICE) has produced overall response rates (complete response + partial response) in excess of 50% in a wide variety of recurrent or persistent pediatric solid tumors. Until recently, ICE administration was limited by significant hematopoietic toxicities. However, the use of hematopoietic growth factors alone and in combination appears to enhance hematopoietic recovery and may allow further dose intensification of ICE in children with recurrent solid tumors.
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PMID:The use of ifosfamide, carboplatin, and etoposide in children with solid tumors. 761 Mar 95

As part of a Phase II clinical trial of topotecan, DNA breakage in vivo was measured by detecting covalent topoisomerase/DNA intermediates in peripheral blood. The ICE (in vivo complex of enzyme) bioassay was used to assess topotecan activity in the peripheral blood of patients before, during, and after infusion therapy. The results can be summarized as: (a) ICE bioassay is a specific, antibody-based assay for topoisomerase I-mediated DNA damage. Topoisomerase I/DNA complex formation can be monitored unambiguously in the absence of topotecan to establish a basal level of endogenous enzyme action on DNA; (b) infusion of topotecan significantly stimulated formation of covalent enzyme/DNA complexes. Complexes were detected within 5 min postinfusion and increased over the course of a 30-min treatment; (c) after termination of infusion, complex formation decreased by 3-4-fold within 30 min, showing that cleavage complexes quickly reseal after drug withdrawal; and (d) formation of complexes varied widely between patients. The ICE bioassay can evaluate the effects of topoisomerase I inhibitors on target tissues; thus, it may valuable in predicting response to these drugs.
Cancer Res 1995 May 15
PMID:Analysis of topoisomerase I/DNA complexes in patients administered topotecan. 774 9

Apoptosis is a regulated process of cell death by which cells actively participate in their own destruction. In multicellular organisms, the balance between cell proliferation and apoptosis provides homeostatic control, and a regulatory failure of either event can contribute to oncogenesis. The extracellular matrix (ECM) is known to play a regulatory role in cellular growth and differentiation, but only more recently has it been recognized as a regulator of apoptosis. In these processes the major transmitters of ECM-derived signals to the cell are members of the integrin family, although the mechanical process of cell spreading also plays a role. Both in vivo and in vitro the loss of adhesion to specific components of the ECM can lead to cell death, and such apoptosis can be induced experimentally by blocking integrin binding. Heterotypic and homotypic cell-cell adhesion can also protect from adhesion-dependent apoptosis and there is evidence to suggest that this too in integrin mediated. In addition, some integrin mediated signaling appears to promote apoptosis. The downstream mechanisms of integrin signaling causing cell death have not been greatly explored, but there is evidence from two different systems that the induction of ICE transcription and nuclear translocation of p53 are candidate processes. Alterations in integrin expression or signaling therefore are likely to contribute to tumor development by enabling escape from apoptosis. Also, the recognition of the importance of cell-cell adhesion in tumor cell survival offers the potential of developing improved drug regimes for the treatment of malignancy.
Cancer Metastasis Rev 1995 Sep
PMID:Involvement of integrins in cell survival. 854 68

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

Apoptosis is an important cellular process by which superfluous or unwanted cells are deleted from an organism during tissue remodeling and differentiation. Recent studies have demonstrated the role of this programmed cell death or "controlled cell suicide" in the physiological function of an organism. Suppression of apoptosis increases the susceptibility of an individual to malignancy whereas uncontrolled cell death is associated with degenerative diseases. Normal development of both female and male gonads is characterized by massive cell death. More than 99% of ovarian follicles endowed at early life are destined to undergo apoptosis and the exhaustion of these follicles serves as a "clock" for female reproductive senescence. In the testis, up to 75% of male germ cells also undergo apoptosis, perhaps as a mechanism to delete superfluous or defective germ cells. Gonadal cell apoptosis provides valuable models to study hormonal regulation of apoptosis. In the ovary, gonadotropins, estrogens, growth hormone, growth factors (IGFI, EGF/TGF-alpha, basic FGF), cytokine (interleukin-1 beta) and nitric oxide act in concert to ensure the survival of preovulatory follicles. In contrast, androgens, interleukin-6 and gonadal GnRH-like peptide are apoptotic factors. Developmental studies further indicate that fractions of endowed follicles are recruited throughout the reproductive life whereas most of the primordial follicles are "arrested" at the initial stage of development for a prolonged time. Because a transcriptional factor WT1 is expressed in high levels in follicles at early stages of development and because WT1 over-expression represses the promoter activity of inhibin-alpha gene, this nuclear protein may be important in the maintenance of follicles at early stages of development. Once a cohort of follicles is recruited to grow, it is destined to undergo apoptosis unless rescued by survival factors. After puberty onset and under gonadotropin stimulation, some of the growing antral follicles are "selected" to continue their final maturation and secrete high levels of estrogens to trigger ovulation. Following repeated cycles of recruitment, atresia or ovulation, the follicle reserve is exhausted, thus signaling the onset of reproductive senescence. Although the somatic granulosa cell is the major cell type undergoing apoptosis in the ovary, the germ cells in the testis also exhibit signs of apoptotic cell demise. In the testis, gonadotropins and androgens act as survival factors whereas exposure to elevated temperature in cryptorchid testes increases apoptosis. In the seasonally breeding hamster model, photoperiod-entrained regression and recrudescence of testis tissue serves as a unique natural model of apoptosis. With recent advances in our understanding of the cellular mechanism of apoptosis, including the elucidation of the Ced9/bc12 and Ced3/ICE family of proteins, further investigation of gonadal apoptosis may lead to a better understanding of gonadal degenerative disorders (such as premature ovarian failure and oligospermia), reproductive senescence and tumorigenesis. The gonadal model should also be valuable in studying the regulation of intracellular apoptosis genes by external hormonal signals.
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PMID:Gonadal cell apoptosis. 870 Oct 90

Tumor cells undergo apoptotic cell death when treated with several chemotherapeutic agents. Since these agents, acting on different cellular targets, induce a similar pattern of cell death (apoptosis), it is suggested that a common signaling pathway of apoptosis could exist and that apoptosis resistance could cause a new form of multi-drug resistance in tumor cells. Although the mechanisms of apoptosis are not fully understood, the involvement of ICE/ced-3 family proteases in chemotherapy-induced apoptosis is strongly suggested. Identification of factors directly acting on these apoptosis pathway will offer new strategies in cancer chemotherapy.
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PMID:[Cancer chemotherapy and apoptosis]. 874 91

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.
Cancer Chemother Pharmacol 1996
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

The induction of apoptosis by the Fas/APO-1 receptor is important for T-cell-mediated cytotoxicity and down-regulation of immune responses. Binding of Fas ligand to the Fas/APO-1 receptor transduces an apoptotic signal that requires activation of interleukin 1beta-converting enzyme (ICE) and CPP32beta, members of a family of cysteine proteases that are evolutionarily conserved determinants of cell death. We report here that Fas/APO-1-triggered apoptosis involves ICE-mediated activation of p34cdc2 kinase. Ligation of the Fas receptor resulted in the rapid stimulation of ICE proteolytic activity and activation of p34cdc2 kinase. Specific tetrapeptide inhibitors of ICE (Acetyl-Tyr-Val-Ala-Asp-chloromethylketone) or CPP32beta (Acetyl-Asp-Glu-Val-Asp-aldehyde) prevented the anti-Fas antibody-mediated activation of p34cdc2 and inhibited apoptosis. Inhibition of p34cdc2 activity by transient overexpression of a dominant-negative cdc2 construct or human WEE1 kinase inhibited Fas-mediated apoptosis. These results suggest that activation of p34cdc2 kinase is a critical determinant of cell death mediated by Fas and ICE family proteases.
Cancer Res 1996 Oct 15
PMID:Requirement of p34cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1beta-converting enzyme-related proteases. 884 Sep 58

We have previously reported that actin cleavage activity (ACA) by interleukin 1beta-converting enzyme (ICE) family protease was elevated during anticancer drug-induced apoptosis in human leukemia U937 cells. In this study, the involvement of ACA in the drug-induced apoptosis in solid tumor cells was investigated. Human ovarian carcinoma OVCAR-3 cells undergo apoptotic cell death when cells are treated with chemotherapeutic agents such as cisplatin and etoposide. The induction of the actin cleavage activity accompanied the development of apoptosis. ICE/ced-3 family protease inhibitors such as Z-VAD-CH2DCB and Z-EVD-CH2DCB at 100 microg/ml prevented both the emergence of ACA and the morphological change, characteristics of apoptosis, in cisplatin-treated OVCAR-3 cells. The ACA in apoptotic OVCAR-3 cell lysate was greatly adsorbed by antibody against CPP-32, an ICE family protease. Furthermore, the immunoprecipitated CPP-32 from OVCAR-3 lysate could cleave actin to generate a 15-kDa fragment, as did the apoptotic OVCAR-3 cell lysate, indicating that CPP-32 is a major protease responsible for the ACA. The activation of CPP-32 in the drug-treated cell lysate was verified with Western blot analysis. Our present results indicate that CPP-32, an actin cleavage ICE/ced-3 family protease, could be a common mediator involved in the process of chemotherapy-induced apoptosis of cancer cells.
Cancer Res 1996 Nov 15
PMID:Activation of actin-cleavable interleukin 1beta-converting enzyme (ICE) family protease CPP-32 during chemotherapeutic agent-induced apoptosis in ovarian carcinoma cells. 891 61

The aim of this study was to determine whether stable differences in apoptosis sensitivity were selected for in nonmetastatic and metastatic variants of the LNCaP human prostate carcinoma line that had been isolated from tumors grown orthotopically in the prostate glands and regional lymph nodes of nude mice. The nonmetastatic LNCaP-Pro5 cells were significantly more sensitive to thapsigargin-induced apoptosis than were the metastatic LNCaP-LN3 cells, as measured by viability, DNA fragmentation, and interleukin 1beta-converting enzyme family-mediated cleavage of the DNA repair enzyme, poly(ADP-ribose) polymerase. Apoptosis resistance in the metastatic cells was associated with higher levels of expression of the cell death suppressor BCL-2 and lower levels of the death promoters BAX and BAK than were detected in the nonmetastatic LNCaP-Pro5 cells, whereas levels of two other BCL-2 family members (BCL-X(L) and BAD) were indistinguishable. Our data support the hypothesis that apoptosis resistance contributes to prostate cancer metastasis and that elevated expression of BCL-2 is involved.
Cancer Res 1996 Dec 15
PMID:Apoptosis resistance increases with metastatic potential in cells of the human LNCaP prostate carcinoma line. 897 Nov 61


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