A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion.

2.50
Hdl Handle:
http://hdl.handle.net/10541/99448
Title:
A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion.
Authors:
Jayson, Gordon C ( 0000-0002-8515-8944 ) ; Crowther, Derek; Prendiville, Joseph A; McGown, Alan T; Scheid, Christof; Stern, Peter L; Young, R; Brenchley, P; Chang, James; Owens, S
Abstract:
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)
Affiliation:
CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK.
Citation:
A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion. 1995, 72 (2):461-8 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
Aug-1995
URI:
http://hdl.handle.net/10541/99448
PubMed ID:
7640233
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorJayson, Gordon Cen
dc.contributor.authorCrowther, Dereken
dc.contributor.authorPrendiville, Joseph Aen
dc.contributor.authorMcGown, Alan Ten
dc.contributor.authorScheid, Christofen
dc.contributor.authorStern, Peter Len
dc.contributor.authorYoung, Ren
dc.contributor.authorBrenchley, Pen
dc.contributor.authorChang, Jamesen
dc.contributor.authorOwens, Sen
dc.date.accessioned2010-05-20T15:38:24Z-
dc.date.available2010-05-20T15:38:24Z-
dc.date.issued1995-08-
dc.identifier.citationA phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion. 1995, 72 (2):461-8 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid7640233-
dc.identifier.urihttp://hdl.handle.net/10541/99448-
dc.description.abstractBryostatin 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)en
dc.language.isoenen
dc.subjectAnaemiaen
dc.subjectCanceren
dc.subjectTumour Necrosis Factor-alphaen
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAnemia-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBryostatins-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDrug Administration Schedule-
dc.subject.meshFemale-
dc.subject.meshHematocrit-
dc.subject.meshHumans-
dc.subject.meshInfusions, Intravenous-
dc.subject.meshInterleukin-6-
dc.subject.meshKiller Cells, Lymphokine-Activated-
dc.subject.meshLactones-
dc.subject.meshLeukocytes, Mononuclear-
dc.subject.meshMacrolides-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshNeoplasms-
dc.subject.meshPhlebitis-
dc.subject.meshProtein Kinase C-
dc.subject.meshTumor Necrosis Factor-alpha-
dc.titleA phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion.en
dc.typeArticleen
dc.contributor.departmentCRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK.en
dc.identifier.journalBritish Journal of Canceren

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