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Clinical Therapy Trials—Drugs |
delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas
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.)
3 Address correspondence to Stuart A. Grossman, The New Approaches to Brain Tumor Therapy CNS Consortium, 1650 Orleans Street, Room G93, Baltimore, MD 21231 (grossman{at}jhmi.edu).
Abstract
Protein kinase C alpha (PKC-
) is a cytoplasmic serine threonine
kinase involved in regulating cell differentiation and proliferation.
Aprinocarsen is an antisense oligonucleotide against PKC- that reduces
PKC- in 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 bleed-ing 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- 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 blood-brain barrier
integrity.
References
Basu, A. (1993) The potential of protein kinase C as a target for anticancer treatment. Pharmacol. Therr. 59,257 -280.
Bignon, E., Ogita, K., Kishimoto, A., Gilbert, J., Abecassis, J., Miquel, J.F., and Nishizuka, Y. (1989) Modes of inhibition of protein kinase C by triphenylacrylonitrile antiestrogens. Biochem. Biophys. Res. Commun. 163,1377 -1383.[CrossRef][Web of Science][Medline]
Ciordia, R., Supko, J., Gatineau, M., and Batchelor, T. (2000) Cytotoxic chemotherapy: Advances in delivery, pharmacology, and testing. Curr. Oncol. Rep. 2, 445-453.[Medline]
Cox, D.R. (1972) Regression models and life-tables (with discussion). J. R. Stat. Soc. B 34,187 -220.
Cripps, M.C., Figueredo, A.T., Oza, A.M., Taylor, M.J., Fields,
A.L., Holmlund, J.T., McIntosh, L.W., Geary, R.S., and Eisenhauer, E.A.
(2002) Phase II randomized study of ISIS 3521 and ISIS 5132 in
patients with locally advanced or metastatic colorectal cancer: A National
Cancer Institute of Canada Clinical Trials Group study. Clin.
Cancer Res. 8,2188
-2192.
Davies, D.C. (2002) Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J. Anat. 200,639 -646.[CrossRef][Web of Science][Medline]
Dean, N.M., and McKay, R. (1994) Inhibition of protein
kinase C-alpha expression in mice after systemic administration of
phosphorothioate antisense oligodeoxynucleotides. Proc. Natl. Acad.
Sci. USA 91,11762
-11766.
Dean, N.M., McKay, R., Condon, T.P., and Bennett, C.F.
(1994) Inhibition of protein kinase C-alpha expression in human
A549 cells by antisense oligonucleotides inhibits induction of intracellular
adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. J. Biol.
Chem. 269,16416
-16424.
Fetell, M.R., Grossman, S.A., Fisher, J.D., Erlanger, B., Rowinsky, E., Stockel, J., and Piantadosi, S. (1997) Preirradiation paclitaxel in glioblastoma multiforme: Efficacy, pharmacology, and drug interactions. New Approaches to Brain Tumor Therapy Central Nervous System Consortium. J. Clin. Oncol. 15,3121 -3128.[Abstract]
Gescher, A. (1992) Towards selective pharmacological modulation of protein kinase C—opportunities for the development of novel antineoplastic agents. Br. J. Cancer 66, 10-19.[Web of Science][Medline]
Gilbert, M.R., Supkko, J.G., Batchelor, T., Lesser, G., Fisher,
J.D., Piantadosi, S., and Grossman, S.A. (2003) Phase I clinical
and pharmacokinetic study of irinotecan in adults with recurrent malignant
glioma. Clin. Cancer Res.
9,2940
-2949.
Goekjian, P.G., and Jirousek, M.R. (2001) Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Investig. Drugs 10,2117 -2140.[CrossRef][Web of Science][Medline]
Grossman, S.A., Hochberg, F., Fisher, J., Chen, T.L., Kim, L., Gregory, R., Grochow, L.B., and Piantadosi, S. (1998) Increased 9-aminocamptothecin requirements in patients on anticonvulsants. Cancer Chemother. Pharmacol. 42,118 -126.[CrossRef][Web of Science][Medline]
Han, Z., Wax, M.B., and Patil, R.V. (1998) Regulation
of aquaporin-4 water channels by phorbol ester-dependent protein
phosphorylation. J. Biol. Chem.
273,6001
-6004.
Kalbfleisch, J.D., and Prentice, R.L. (1980) Estimation of the survivor function. In: The Statistical Analysis of Failure Time Data. New York: John Wiley and Sons, pp.16 -19.
Kaplan, E.L., and Meier, P. (1958) Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53,457 -481.[CrossRef][Web of Science]
Kiening, K.L., van Landeghem, F.K., Schreiber, S., Thomale, U.W., von Deimling, A., Unterberg, A.W., and Stover, J.F. (2002) Decreased hemispheric Aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci. Lett. 324,105 -108.[CrossRef][Web of Science][Medline]
Kobayashi, H., Minami, S., Itoh, S., Shiraishi, S., Yokoo, H., Yanagita, T., Uezono, Y., Mohri, M., and Wada, A. (2001) Aquaporin subtypes in rat cerebral microvessels. Neurosci. Lett. 297,163 -166.[CrossRef][Web of Science][Medline]
Lacey, L.F., Keene, O.N., Pritchard, J.F., and Bye, A. (1997) Common noncompartmental pharmacokinetic variables: Are they normally or lognormally distributed? J. Biopharm. Stat. 7,171 -178.[Medline]
Lam, F.C., Hung, C.T., and Perrier, D.G. (1985) Estimation of variance for harmonic mean half-lives. J. Pharm. Sci. 74,229 -231.[Web of Science][Medline]
Leeds, J.M., Graham, M.J., Truong, L., and Cummins, L.L. (1996) Quantitation of phosphorothioate oligonucleotides in human plasma. Anal. Biochem. 235, 36-43.[CrossRef][Web of Science][Medline]
Mani, S., Rudin, C.M., Kunkel, K., Holmlund, J.T., Geary, R.S.,
Kindler, H.L., Dorr, F.A., and Ratain, M.J. (2002) Phase I
clinical and pharmacokinetic study of protein kinase C-alpha antisense
oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and
leucovorin in patients with advanced cancer. Clin. Cancer
Res. 8,1042
-1048.
Mizuta, E., and Tsubotani, A. (1985) Preparation of mean drug concentration-time curves in plasma: A study on the frequency distribution of pharmacokinetic parameters. Chem. Pharm. Bull. 33,1620 -1632.
Nakahama, K., Nagano, M., Fujioka, A., Shinoda, K., and Sasaki, H. (1999) Effect of TPA on aquaporin 4 mRNA expression in cultured rat astrocytes. Glia 25,240 -246.[CrossRef][Web of Science][Medline]
Nemunaitis, J., Holmlund, J.T., Kraynak, M., Richards, D., Bruce,
J., Ognoskie, N., Kwoh, T.J., Geary, R., Dorr, A., Von Hoff, D., and Eckhardt,
S.G. (1999) Phase I evaluation of ISIS 3521, an antisense
oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced
cancer. J. Clin. Oncol.
17,3586
-3595.
Nishizuka, Y. (1988) The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334,661 -665.[CrossRef][Medline]
O'Brian, C.A., Vogel, V.G., Singletary, S.E., and Ward, N.E.
(1989) Elevated protein kinase C expression in human breast tumor
biopsies relative to normal breast tissue. Cancer Res.
49,3215
-3217.
Palayoor, S.T., Stein, J.M., and Hait, W.N. (1987) Inhibition of protein kinase C by antineoplastic agents: Implications for drug resistance. Biochem. Biophys. Res. Commun. 148,718 -725.[CrossRef][Web of Science][Medline]
Portnow, J., Eller, S., Stecker, K., and Grossman, S.A.
(2000) The distribution of an antisense oligonucleotide directed
against protein kinase C- (ISIS 3521) in rats with brain tumors.
Proc. Am. Soc. Clin. Oncol.
19, 170a (Abstract
660).
Prados, M.D., Schold, S.C., Jr., Fine, H.A., Jaeckle, K., Hochberg, F., Mechtler, L., Fetell, M.R., Phuphanich, S., Feun, L., Janus, T.J., Ford, K., and Graney, W. (2003) A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro-Oncol. 5,96 -103.[Abstract]
Rotenberg, S.A., Smiley, S., Ueffing, M., Krauss, R.S., Chen, L.B.,
and Weinstein, I.B. (1990) Inhibition of rodent protein kinase C
by the anti-carcinoma agent dequalinium. Cancer Res.
50,677
-685.
Saadoun, S., Papadopoulos, M.C., Davies, D.C., Krishna, S., and
Bell, B.A. (2002) Aquaporin-4 expression is increased in
oedematous human brain tumours. J. Neurol. Neurosurg.
Psychiatry 72,262
-265.
Simon, R. (1989) Optimal two-stage designs for phase II clinical trials. Control. Clin. Trials 10, 1-10.[Web of Science][Medline]
Swannie, H.C., and Kaye, S.B. (2002) Protein kinase C inhibitors. Curr. Oncol. Rep. 4, 37-46.[Medline]
Vecht, C.J., Wagner, G.L., and Wilms, E.B. (2003) Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol. 2,404 -409.[CrossRef][Web of Science][Medline]
Venero, J.L., Vizuete, M.L., Machado, A., and Cano, J. (2001) Aquaporins in the central nervous system. Prog. Neurobiol. 63,321 -336.[CrossRef][Web of Science][Medline]
Verkman, A.S. (2002) Aquaporin water channels and endothelial cell function. J. Anat. 200,617 -627.[CrossRef][Web of Science][Medline]
Yamamoto, N., Sobue, K., Miyachi, T., Inagaki, M., Miura, Y., Katsuya, H., and Asai, K. (2001) Differential regulation of aquaporin expression in astrocytes by protein kinase C. Brain Res. Mol. Brain Res. 95,110 -116.[Medline]
Yazaki, T., Ahmad, S., Chahlavi, A., Zylber-Katz, E., Dean, N.M., Rabkin, S.D., Martuza, R.L., and Glazer, R.I. (1996) Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide. Mol. Pharmacol. 50,236 -242.[Abstract]
Yuen, A.R., Halsey, J., Fisher, G.A., Holmlund, J.T., Geary, R.S.,
Kwoh, T.J., Dorr, A., and Sikic, B.I. (1999) Phase I study of an
antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in
patients with cancer. Clin. Cancer Res.
5,3357
-3363.
Zelenina, M., Zelenin, S., Bondar, A.A., Brismar, H., and Aperia,
A. (2002) Water permeability of aquaporin-4 is decreased by
protein kinase C and dopamine. Am. J. Physiol. Renal
Physiol. 283,F309
-318.
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