Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48-72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P < 0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P < or = 0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P < or = 0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.
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PMID:Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study. 754 56

Bryostatin 1 is a macrocyclic lactone derived from the marine invertebrate Bugula neritina. In vitro, bryostatin 1 activates protein kinase C (PKC), induces the differentiation of a number of cancer cell lineages, exhibits anti-tumour activity and augments the response of haemopoietic cells to certain growth factors. In vivo, bryostatin 1 is also immunomodulatory, but the range of tumours which respond to bryostatin 1 in xenograft tumour models is mostly the same as the in vitro tumour types, suggesting a direct mode of action. Nineteen patients with advanced malignancy were entered into a phase I study in which bryostatin 1 was given as a 24 h intravenous infusion, weekly, for 8 weeks. Myalgia was the dose-limiting toxicity and the maximum tolerated dose was 25 micrograms m-2 per week. The myalgia was cumulative and dose related, and chiefly affected the thighs, calves and muscles of extraocular movement. The mechanism of the myalgia is unknown. CTC grade 1 phlebitis affected every patient for at least one cycle and was caused by the diluent, PET, which contains polyethylene glycol, ethanol and Tween 80. Most patients experienced a 1 g dl-1 decrease in haemoglobin within 1 h of commencing the infusion which was associated with a decrease in haematocrit. Radiolabelled red cell studies were performed in one patient to investigate the anaemia. The survival of radiolabelled red cells during the week following treatment was the same as that seen in the week before treatment. However, there was a temporary accumulation of radiolabelled red cells in the liver during the first hour of treatment, suggesting that pooling of erythrocytes in the liver might account for the decrease in haematocrit. Total or activated PKC concentrations were measured in the peripheral blood mononuclear cells (PBMCs) of three patients for the first 4 h of treatment and during the last hour of the infusion. This showed that PKC activity was significantly modulated during the infusion. Bryostatin 1 is immunomodulatory in vitro, and we have confirmed this activity in vivo. An investigation of the first three cycles of treatment in seven patients showed an increased IL-2-induced proliferative response in peripheral blood lymphocytes and enhanced lymphokine-activated killer (LAK) activity. A previously reported rise in serum levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF 1) was not confirmed in our study; of nine patients in this study, including patients at all dose levels, none showed an increase in these cytokines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion. 764 Feb 33

Bryostatin 1, a macrocyclic natural lactone isolated from a marine Bryozoan, has undergone phase I testing in humans. Side effects of treatment have included muscle pain and joint aches, a transient decrease in platelets, and the release of tumor necrosis factor alpha (TNF alpha) and IL-6 into the blood stream. In animals, anticancer activity has been demonstrated against murine leukemias, lymphomas, melanomas, and sarcomas. The mechanism of action of this compound depends in part on its ability to activate protein kinase C. To determine the biologic activity and toxicity of other members of the family of bryostatin compounds, we studied the ability of bryostatins 5 and 8 to inhibit the growth of murine melanoma K1735-M2. Bryostatins 1, 5, and 8 induced equivalent inhibition of melanoma growth, but bryostatins 5 and 8 induced less weight loss than bryostatin 1 (P < 0.001). Neither the injection of an antimurine TNF alpha antibody nor an adenovirus, which produces a mutated TNF receptor inhibiting TNF alpha activity, into mice had any effect on either bryostatin-induced weight loss or melanoma tumor growth inhibition. Using a novel competition assay, the levels of bryostatin in the plasma were measured. The approximate half-life (t1/2) of bryostatin was 8.62 min, the clearance (Cl) 3.53 ml/min and the AUC 322.20 nmol/l min. A similar result was obtained with each bryostatin analog. These results suggest that human testing of additional bryostatin analogs may yield compounds with similar antitumor activity but decreased side effects. A novel assay to measure the level of all bryostatins in the plasma of patients undergoing treatment is described.
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PMID:Comparison of the antitumor activity of bryostatins 1, 5, and 8. 852 89

Bryostatin 1, an anti-neoplastic agent and protein kinase C activator, has dose-limiting toxicity manifesting as myalgia. Studies in vivo have suggested that this myalgia may be caused by impairment of oxidative metabolism as mitochondrial capacity, muscle reoxygenation and proton washout from muscle are reduced by bryostatin, possibly as a result of vasoconstriction. To investigate these mechanisms further, and to enable use of bryostatin for prolonged periods, the effect of a vasodilator on the established effects of bryostatin on calf metabolism was studied using 31P magnetic resonance spectroscopy and near infrared spectroscopy. Six patients with disseminated melanoma were examined on four occasions: before and 1 week after initiation of long-term nifedipine (10 mg twice daily) treatment and then 4 and 48 h after bryostatin infusion (25 micrograms m(-2)). Nifedipine impaired muscle oxidative metabolism but had no effect on proton efflux or muscle reoxygenation rate. In the presence of nifedipine, two of the effects of bryostatin, impaired reoxygenation rate and reduced proton efflux, were abolished, but the impaired mitochondrial activity remained. These results show that nifedipine counteracted the vasoconstrictive effect of bryostatin 1. However, because nifedipine itself had an unexpected effect on mitochondrial metabolism, it was not possible to assess whether nifedipine modified bryostatin's effect on this variable. There was no additive detrimental effect of bryostatin on mitochondrial metabolism and nifedipine did not reduce the clinical toxicity of bryostatin 1, which cannot therefore be due to vasoconstriction.
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PMID:Modulation of bryostatin 1 muscle toxicity by nifedipine: effects on muscle metabolism and oxygen supply. 863 Feb 72

Bryostatin 1 is a protein kinase C partial agonist which has both antineoplastic and immune-stimulatory properties, including the induction of cytokine release and expansion of tumour-specific lymphocyte populations. In phase I studies, tumour responses have been observed in patients with malignant melanoma, lymphoma and ovarian carcinoma. The dose-limiting toxicity is myalgia. Sixteen patients (age 35-76 years, median 57 years) with malignant melanoma were treated. All had received prior chemotherapy. In each cycle of treatment, patients received bryostatin 25 degrees g m(-2) weekly for three courses followed by a rest week. The drug was given in PET diluent (10 microg bryostatin ml(-1) of 60% polyethylene glycol, 30% ethanol, 10% Tween 80) and infused in normal saline over 1 h. The principal toxicities were myalgia (grade 2, eight patients and grade 3, six patients) and grade 2 phlebitis (four patients), fatigue (three patients) and vomiting (one patient). Of 15 patients evaluable for tumour response, 14 developed progressive disease. One patient developed stable disease for 9 months after bryostatin treatment. In conclusion, single-agent bryostatin appears ineffective in the treatment of metastatic melanoma in patients previously treated with chemotherapy. It should, however, be investigated further in previously untreated patients.
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PMID:A phase II study of bryostatin 1 in metastatic malignant melanoma. 982 75

Bryostatin-1, a macrocyclic lactone, appears to elicit a wide range of biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of bryostatin-1 was performed in children with solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); (b) establish the pharmacokinetic profile in children; and (c) document any evidence of antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2-21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 microg/m2/ dose. Pharmacokinetics were performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At the 57 microg/m2/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache. Symptoms occurred in all patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were observed. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 microg/m2/dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.
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PMID:A Phase I trial of bryostatin-1 in children with refractory solid tumors: a Pediatric Oncology Group study. 1049 3

Bryostatin-1 is a protein kinase C regulator which has shown antitumour activity against B16 melanoma in animal models. Safety trials revealed this agent to be minimally toxic, thus a phase II trial of bryostatin-1 was conducted to determine its efficacy In patients with melanoma. Eighteen patients with metastatic melanoma, seven of whom had been previously treated, were enrolled in the study. Patients received bryostatin-1 25 microg/m2 intravenously weekly over 1 h for 3 out of 4 weeks. No objective responses were observed. One patient who had not previously received chemotherapy had stable disease for 4 months, and two patients (one previously treated) had a marked decrease in the skin component of their disease. The major toxicity was myalgia (one patient with grade III, two patients with grade II and five patients with grade I), with no grade IV toxicities reported. To Indirectly evaluate the stimulation of protein kinase C, a sensitive assay that measures the upregulation of the activated form of CD62 (glycoprotein IIb/IIIa) on platelets was performed. There was a statistically significant upregulation of this antigen 1 h after bryostatin-1 therapy. A bioassay based on the ability of bryostatin-1 to bind protein kinase C was used to measure bryostatin-1 levels in serum. This assay showed that bryostatin-1 has a volume of distribution of 2.1 l/m2, an elimination clearance of 32.9 ml/min per m2 and a half-life of 43.9 min. In conclusion, this phase II trial demonstrates that, although it is relatively non-toxic, bryostatin-1 therapy had minimal activity in metastatic melanoma.
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PMID:Treatment of patients with metastatic melanoma with bryostatin-1--a phase II study. 1066 72

Bryostatin 1 (bryo 1) is an example of a novel class of anticancer drug which modulates protein kinase C (PKC) activity. It has varied biological effects mediated largely by the initial activation of PKC, followed by its rapid downregulation. Bryo 1 stimulates in vitro and in vivo haematopoietic progenitor cell growth in a concentration-dependent and lineage-specific fashion. Granulocytes, lymphocytes, monocytes and platelets are all functionally stimulated by bryo 1. Stimulation of cytotoxic T-cell activity by bryo 1 has led to research utilising bryo 1 as an immunotherapeutic agent in mouse tumour xenograft models. The clinical development of bryo 1 followed the demonstration of direct in vitro activity against various tumour cell lines. Multiple Phase I trials have shown muscle pain and flu-like symptoms are the most common toxicities associated with administration of bryo 1. There is particular interest in the role of bryo 1 in haematologic malignancies because of its capacity to induce leukaemic cell differentiation. There is ample in vitro data demonstrating that bryo 1 can sensitise tumour cells to cytotoxic agents. Recent clinical work has focused on combining bryo 1 with traditional chemotherapeutic agents for both haematologic and non-haematologic cancers.
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PMID:Pharmacology and clinical experience with bryostatin 1: a novel anticancer drug. 1113 48

Current chemotherapy for patients with advanced colorectal cancer is relatively ineffective and may be associated with significant toxicity. Bryostatin 1 (bryo 1) influences cell proliferation, intracellular metabolism and signaling, differentiation, and apoptosis in human cancer cell lines via modulation of protein kinase C (PKC) activity. This trial investigates the efficacy and toxicity of bryo 1 as a novel therapeutic agent for patients with advanced colorectal cancer who have had previous 5-fluorouracil therapy. The primary end point was tumor response to bryo 1. Toxicity was also assessed. Twenty-eight patients with advanced colorectal cancer were enrolled. The mean age was 59 years (range, 38-76), with 16 men and 12 women, and good minority representation (11 African-Americans). The first 10 patients initially received 25 microg/m2 of bryo 1 weekly as a 24-h infusion for 3 weeks of every 4-week cycle, with dose escalation to 35 microg/m2 starting with the second cycle. The remaining patients were started at 35 microg/m2 and escalated to 40 microg/m2, if toxicity was minimal. Twenty-five patients were evaluable for objective tumor response, and complete data on toxicity were collected on 26 patients. No partial or complete tumor responses were observed. All 25 patients had disease progression within four cycles. Myalgia was the most common toxicity. Myelosuppression was not seen. bryo 1 as a weekly 24-h continuous infusion lacks single-agent antitumor activity in advanced colorectal cancer. Toxicity differs from that of traditional chemotherapeutic drugs.
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PMID:A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. 1120 15

The bryostatins are a group of novel macrocyclic lactones derived from the marine bryozoan, Bugula neritina. In vitro evidence indicates that their main mechanism of action is modulation of protein kinase C (PKC) activity. Phase I studies suggested significant antineoplastic activity against several tumor types and defined the main dose-limiting toxicity as myalgia. Bryostatin-1 has subsequently been investigated extensively in phase II clinical trials as a single agent, although trial design has been hampered by lack of human pharmacokinetic data. Results have been generally disappointing but in vitro and animal data suggests an important role for bryostatin-1 in combination with cytotoxic agents. Preliminary results of phase I studies support these observations but further work needs to be done to define the future role of the bryostatins in the clinic.
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PMID:The clinical development of the bryostatins. 1218 23


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