Evidence for Protein Kinase C Pathway in the Response of Human Peripheral Blood Mononuclear Cells to Cholera Toxin

1996 ◽  
Vol 172 (2) ◽  
pp. 224-228 ◽  
Author(s):  
Teresa Krakauer
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cholera Toxin ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Kinase C ◽  
Blood Mononuclear Cells

Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors

2005 ◽  
Vol 23 (9) ◽  
pp. 1875-1884 ◽  
Author(s):  
Jeremy Kortmansky ◽  
Manish A. Shah ◽  
Andreas Kaubisch ◽  
Amanda Weyerbacher ◽  
Sandy Yi ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phase I ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Cyclin Dependent Kinase ◽  
Peripheral Blood Mononuclear ◽  
Kinase C ◽  
Blood Mononuclear Cells ◽  
Protein Kinase C Inhibitor

Purpose Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. Patients and Methods FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m2 over 72 hours in cycle 1 and 67.5 mg/m2 over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. Results We escalated the weekly FU dose to 2,600 mg/m2 in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 μmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. Conclusion The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m2.

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