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Efficacy and toxicity of the antisense
oligonucleotide aprinocarsen directed against protein kinase C-α
delivered as a 21-day continuous intravenous infusion in patients with
recurrent high-grade astrocytomas
Stuart A. Grossman, Jane B. Alavi,
Jeffrey G. Supko, Kathryn A. Carson, Regina Priet, F. Andrew Dorr,
John S. Grundy, and Jon T. Holmlund
The New Approaches to Brain Tumor
Therapy CNS Consortium, Baltimore, MD 21231 (S.A.G., J.B.A., J.G.S.,
K.A.C., R.P.); Isis Pharmaceuticals, Inc., Carlsbad, CA 92008 (F.A.D.,
J.S.G., J.T.H.). Address correspondence to Stuart A. Grossman, The New
Approaches to Brain Tumor Therapy CNS Consortium, 1650 Orleans Street,
Room G93, Baltimore, MD 21231 (grossman@jhmi.edu).
Protein kinase C alpha (PKC-α)
is a cytoplasmic serine threonine kinase involved in regulating cell
differentiation and proliferation.
Aprinocarsen is an antisense oligonucleotide against PKC-α
that reduces PKC-αin human cell lines and inhibits
a human glioblastoma tumor cell line in athymic mice.
In this phase 2 study, aprinocarsen was administered to patients with
recurrent high-grade gliomas by continuous intravenous infusion (2.0
mg/kg/day for 21 days per month).
Twenty-one patients entered this trial.
Their median age was 46 years (range, 28-68 years), median Karnofsky
performance status was 80 (range, 60-100), median tumor volume was 58
cm3 (range, 16-254 cm3 ), and histology included
glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n =
4), and anaplastic astrocytoma (n = 1).
The number of prior chemotherapy regimens included none (n = 3), one
(n = 10), and two (n = 8).
No tumor responses were observed.
Patients on this therapy rapidly developed symptoms of increased
intracranial pressure with increased edema, enhancement, and mass
effect on neuroimaging.
The median time to progression was 36 days, and median survival was
3.4 months.
The observed toxicities were mild, reversible, and uncommon (grade 3
thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy
or CNS bleeding resulted from this therapy.
Plasma concentrations of aprinocarsen during the infusion exhibited
significant interpatient variability (mean = 1.06 μg/ml;
range, 0.34-6.08 μg/ml).
This is the first study to use an antisense oligonucleotide or a
specific PKC-α inhibitor in patients with high-grade
gliomas.
No clinical benefit was seen.
The rapid deterioration seen in these patients could result from tumor
growth or an effect of aprinocarsen on bloodbrain barrier integrity.
© 2005 Duke University Press
Source: http://hermia.ingentaselect.com/vl=4330213/cl=26/nw=1/rpsv/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v7n1/s4/p32&user_id=undefined
DOI: http://dx.doi.org/10.1215/S1152851703000353
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