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dc.contributor.authorJayson, Gordon C
dc.contributor.authorCrowther, Derek
dc.contributor.authorPrendiville, Joseph A
dc.contributor.authorMcGown, Alan T
dc.contributor.authorScheid, Christof
dc.contributor.authorStern, Peter L
dc.contributor.authorYoung, R
dc.contributor.authorBrenchley, P
dc.contributor.authorChang, James
dc.contributor.authorOwens, S
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)
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
html.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)


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