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All results were significant as described previously.No TNF was detectable in pretreatment samples.In one patient, there was a steep increase in immunoreactive TNF over the whole time course compared with all of the others.Wilcoxonmatched pairs Chlorophyllin signedranks test was performed comparing day level with all other time points for TNF and pretreatment level with all other time points for IL and CCL.SD SD SD SD SD SD. A statistically significant decrease in mean CCL was seen, respectively.Although in most patients CCL decreased, in some patients during the first month there was an initial transient increase.PHA stimulated whole blood cytokine release assay; bars, SEM.The percentage difference in CCL level was calculated, and B and C show the trend in individual patients.This was shown with a substantial increase in plasma TNF levels from day to day after start of treatment.In contrast to all of the others, one patient showed continued rising levels of TNF.weeks and was withdrawn because of gastric outlet obstruction.The marked elevation shows, however, that for most patients, there is spare capacity of the solubleTNF receptor and that the dose was reasonable for the first trial of this agent in breast cancer.Diminished cytokine production in joints has been shown in Imiquimod rheumatoid arthritis patients receiving antiTNF therapy, and a decrease in serum levels of several cytokines and chemokines has also been shown in rheumatoid arthritis. The decrease in TNF seen at day and maintenance of a lower steady state level subsequently may reflect equilibrium of tissue production versus depletion of TNF.We also evaluated whether the depletion of biologically active TNF could have a functional effect on target cells.The whole blood cytokine release assay showed reduction in CCL and IL levels in response to PHA.This reduction is consistent with those seen in rheumatoid arthritis patients who show reduction in serum levels of IL, chemokines, and acute phase proteins. For IL levels, with therapy, no statistical significance was reached and there was marked fluctuation of release, although in patients on most chronic treatment there was a decrease.For CCL, there was a clear decrease overall from the first month of therapy onwards.The reasons for fluctuations in these downstream markers compared with the steady trapping of TNF are not clear but could reflect adaptive responses or changes in successive generations of lymphocytes.Clearly, there is variability between patients, but considering variable amounts of chemotherapy and radiotherapy and bone involvement that could affect lymphocyte function, there was a pattern of response in the majority of patients, indicating a functional blockade of pathways known to be activated by TNF.Only patients thought not to have progressive disease in month would have stayed on therapy, so this may reflect biological differences between patients, with those having some effect of TNF depletion showing slower tumor growth and cellular effects of therapy.There was no relation of TNF plasma level to the effects on cytokine release.We have shown similar effects in peripheral blood mononuclear cells.Other potential roles of TNF blockade include its use in antiangiogenic combinations to block multiple pathways.Serum concentration of tumor necrosis factor in patients with breast cancer.Nat Rev Immunol. Expert Opin Pharmacother. The protein kinase C inhibitor CGP suppresses cytokine release and extracellular signalregulated kinase expression in cancer patients.A Phase II Study of Etanercept Srinivasan Madhusudan, Martin Foster, Sethupathi R.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from clincancerres.aacrjournals.org on April. American Association for Cancer Research.

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