TREATMENT OF GLIOBLASTOMA U-87 BY SYSTEMIC ADMINISTRATION OF AN ANTISENSE PROTEIN-KINASE C-ALPHA PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE

Glioblastoma multiforme is the most common form of malignant brain can cer in adults and, unfortunately, is not amenable to treatment with cu rrent 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 al pha (PKC alpha), and infiltration via white matter tracts. We show tha t treatment of mice bearing U-87 xenografts with an antisense phosphor othioate 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 tum ors, and in the latter instance, treatment with the antisense PKC alph a S-oligodeoxynucleotide resulted in a doubling in median survival tim e (>80 days), with 40% long term survivors. The antisense S-oligodeoxy nucleotide did not produce systemic toxicity in mice with subcutaneous or intracranial tumors after daily intraperitoneal injection for 21 o r 80 days, respectively, and a scrambled S-oligodeoxynucleotide with t he 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 mu M after 21 daily doses of 20 mg/kg S-oligodeoxynucleotide. T he antisense S-oligodeoxynucleotide selectively reduced the levels of PKC alpha in subcutaneous tumors but not those of protein kinase C eps ilon or protein kinase C zeta. This is the first demonstration that th e 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.