Glioblastoma multiforme is the most common form of malignant
brain cancer in adults and, unfortunately, is not amenable to treatment with current therapeutic modalities. Human
glioblastoma U-87 has many of the distinguishing phenotypic features of primary
glioblastoma, including an autocrine form of proliferation, high levels of
protein kinase C alpha (PKC alpha), and infiltration via white matter tracts. We show that treatment of mice bearing U-87 xenografts with an antisense phosphorothioate
oligodeoxynucleotide (S-
oligodeoxynucleotide) against the 3'-untranslated region of PKC alpha
mRNA results in suppression of
tumor growth. Growth was inhibited in both subcutaneous and intracranial
tumors, and in the latter instance, treatment with the antisense PKC alpha S-
oligodeoxynucleotide resulted in a doubling in median survival time ( > 80 days), with 40% long term survivors. The antisense S-
oligodeoxynucleotide did not produce systemic toxicity in mice with subcutaneous or intracranial
tumors after daily
intraperitoneal injection for 21 or 80 days, respectively, and a scrambled S-
oligodeoxynucleotide with the same
nucleotide composition as the antisense S-
oligodeoxynucleotide did not produce an antitumor effect. The intratumoral levels of both antisense and scrambled S-
oligodeoxynucleotide in subcutaneous
tumors were 2 microM after 21 daily doses of 20 mg/kg S-
oligodeoxynucleotide. The antisense S-
oligodeoxynucleotide selectively reduced the levels of PKC alpha in subcutaneous
tumors but not those of
protein kinase C epsilon or
protein kinase C zeta. This is the first demonstration that the growth of
glioblastoma multiforme can be suppressed by an antisense PKC alpha S-
oligodeoxynucleotide and suggests that this may represent an effective
therapy for this type of
malignancy.