The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients

Parames Thavasu, David Propper, Alexander McDonald, Nicola Dobbs, Trivadi Ganesan, Dennis Talbot, Jeremy Braybrook, Francesco Caponigro, Cathy Hutchison, Christopher Twelves, Anthony Man, Doriano Fabbro, Adrian Harris, Frances Balkwill

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Abstract

Components of cell signaling pathways provide important targets for anticancer drugs. Protein kinase C (PKC) is a serine/threonine-specific kinase that regulates cell growth and differentiation. It is also implicated in tumor promotion. The staurosporine analogue CGP41251 is a PKC inhibitor, and it is currently in a Phase I clinical trial for treatment of advanced cancer. However, it is difficult to define its biological activity. We have used two approaches to measure the in vivo biological response to CGP41251: (a) sequential whole blood samples were taken from 27 patients before and during treatment and incubated with mitogen (PHA), and cytokine [tumor necrosis factor (TNF)-α and interleukin (IL)-6] release was measured ex vivo; and (b) peripheral blood lymphocytes were isolated from seven of these patients, and the levels of extracellular signal-regulated kinase 2 were measured by Western blotting. Response to PHA was significantly lowered during treatment (P <0.001 for TNF-α production; P <0.03 for IL-6). This was most evident at 7 and 28 days after the start of treatment in patients receiving higher doses (150-300 mg/day; P = 0.002 and P = 0.02, respectively, for TNF-α and P = 0.001 and P = 0.003, respectively, for IL-6 release). Whole blood cytokine production returned to pretreatment levels after drug administration ceased. The levels of extracellular signal-regulated kinase 2 were reduced by 50-97% during treatment in all seven patients tested. These results show for the first time that a PKC inhibitor can block in vivo signaling pathways in cancer patients. The assays we describe complement toxicity studies in selecting relevant doses for Phase II trial of novel agents, particularly when biological activity occurs at doses below those that cause obvious side effects.

Original languageEnglish
Pages (from-to)3980-3984
Number of pages5
JournalCancer Research
Volume59
Issue number16
Publication statusPublished - Aug 15 1999

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Protein C Inhibitor
Mitogen-Activated Protein Kinase 1
Protein Kinase Inhibitors
Protein Kinase C
Cytokines
Interleukin-6
Tumor Necrosis Factor-alpha
Neoplasms
Therapeutics
Clinical Trials, Phase I
Staurosporine
Protein-Serine-Threonine Kinases
Cellular Structures
Mitogens
Pharmaceutical Preparations
Cell Differentiation
Western Blotting
Lymphocytes
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Thavasu, P., Propper, D., McDonald, A., Dobbs, N., Ganesan, T., Talbot, D., ... Balkwill, F. (1999). The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. Cancer Research, 59(16), 3980-3984.

The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. / Thavasu, Parames; Propper, David; McDonald, Alexander; Dobbs, Nicola; Ganesan, Trivadi; Talbot, Dennis; Braybrook, Jeremy; Caponigro, Francesco; Hutchison, Cathy; Twelves, Christopher; Man, Anthony; Fabbro, Doriano; Harris, Adrian; Balkwill, Frances.

In: Cancer Research, Vol. 59, No. 16, 15.08.1999, p. 3980-3984.

Research output: Contribution to journalArticle

Thavasu, P, Propper, D, McDonald, A, Dobbs, N, Ganesan, T, Talbot, D, Braybrook, J, Caponigro, F, Hutchison, C, Twelves, C, Man, A, Fabbro, D, Harris, A & Balkwill, F 1999, 'The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients', Cancer Research, vol. 59, no. 16, pp. 3980-3984.
Thavasu, Parames ; Propper, David ; McDonald, Alexander ; Dobbs, Nicola ; Ganesan, Trivadi ; Talbot, Dennis ; Braybrook, Jeremy ; Caponigro, Francesco ; Hutchison, Cathy ; Twelves, Christopher ; Man, Anthony ; Fabbro, Doriano ; Harris, Adrian ; Balkwill, Frances. / The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. In: Cancer Research. 1999 ; Vol. 59, No. 16. pp. 3980-3984.
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