Phase I study of bryostatin 1: Assessment of interleukin 6 and tumor necrosis factor α induction in vivo

Philip A. Philip, Daniel Rea, Prames Thavasu, James Carmichael, Nicholas S A Stuart, Helen Rockett, Denis C. Talbot, Trivadi Ganesan, George Pettit, Frances Balkwill, Adrian L. Harris

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

Background: Many oncogenes have been shown to code for growth factor receptors that are involved in regulation of cell growth and proliferation and can activate transcription via protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, has demonstrated potent antitumor activity in vitro and in vivo in human tumor xenografts. Purpose: The aim of this phase I study was to determine the optimal dosage and toxicity profile of bryostatin 1 and its influence on cytokine release in vivo. Methods: Three successive cohorts consisting of 35 patients with various malignant tumors were treated with bryostatin 1 by intravenous infusion over 1 hour as follows: cohort A-35 μg/m2(three patients) or 50 μg/m2 (eight patients) once every 2 weeks; cohort B-25 μg/m2 once a week (eight patients); and cohort C-25 μg/m2 once a week for 3 weeks, with no treatment during the 4th week (16 patients). Plasma levels of tumor necrosis factor a (TNF-α) and interleukin 6 (IL-6) were measured by immunoradiometric assay and by radioimmunoassay, respectively. Results: The dose-limiting toxicity was grade 3 or 4 myalgia in four of 11 patients in cohort A, in two of wight in cohort B, and in none of 16 in cohort C. Occurrence of myalgia was dose related. There was no significant myelosuppression, apart from a small and transient fall in platelet count. Six patients experienced acute but transient skin flushing, dyspnea, hypotension, and bradycardia, probably related to the bryostatin 1 vehicle. TNF-α and IL-6 were detected in plasma at 2 and 24 hours after treatment, respectively, and the levels were dose related (P =.02). Two patients with metastatic malignant melanoma had partial remission after three or four cycles of therapy; remission lasted 6 weeks and 10+ months, respectively. Conclusions: The dose-limiting toxicity of bryostatin 1 was myalgia. Plasma IL-6 and TNF-α concentrations were increased within 24 hours of therapy. Antitumor activity against malignant melanoma was observed early in the course of treatment. Implications: The recommended dosage of bryostatin 1 for phase II studies is 25 μg/m2 by intravenous infusion for 1 hour once a week for 3 weeks, with no treatment in the 4th week. IL-6 and TNF-α plasma concentrations may be useful in monitoring biological activity of bryostatin 1. Future studies should explore use of this drug with other conventional immune modulators and conventional cytotoxic drugs. [J Natl Cancer Inst 85: 1812-1818, 1993]

Original languageEnglish (US)
Pages (from-to)1812-1818
Number of pages7
JournalJournal of the National Cancer Institute
Volume85
Issue number22
DOIs
StatePublished - Nov 17 1993

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Phase I study of bryostatin 1: Assessment of interleukin 6 and tumor necrosis factor α induction in vivo'. Together they form a unique fingerprint.

  • Cite this

    Philip, P. A., Rea, D., Thavasu, P., Carmichael, J., Stuart, N. S. A., Rockett, H., Talbot, D. C., Ganesan, T., Pettit, G., Balkwill, F., & Harris, A. L. (1993). Phase I study of bryostatin 1: Assessment of interleukin 6 and tumor necrosis factor α induction in vivo. Journal of the National Cancer Institute, 85(22), 1812-1818. https://doi.org/10.1093/jnci/85.22.1812