The standard treatment for patients with primary
malignant glioma includes surgical resection,
radiotherapy, and nitrosourea. Despite this multimodality approach, adults with newly diagnosed
glioblastoma multiforme (GBM) and high-grade
astrocytoma have a median survival duration of 50 weeks and 150 weeks respectively.
Chemotherapy has had a limited impact on the survival of these patients.
Merbarone (5-phenylcarboxamide-2-thiobarbituric acid) is a nonsedating derivative of
barbituric acid that crosses the blood brain barrier. Antitumor activity of
merbarone has been described against L1210,
B16 melanoma cell line and the M5076
sarcoma cells in phase I studies.
Merbarone inhibits
DNA synthesis and
tumor growth by inducing single strand breaks in
DNA. It also inhibits
RNA and
protein synthesis. We evaluated
merbarone in a phase II trial in patients (pts) with recurrent or refractory GBM (7 pts) and high grade
anaplastic astrocytoma (7 pts). Fourteen patients (nine males, five females) were treated with
merbarone at a dose of 1000 mg per m2 per day by continuous
intravenous infusion for 5 days every 3 weeks. Every patient received at least two cycles of treatment. No complete or partial responses were observed, although one patient had stable disease lasting 20 weeks. Our conclusion is that
merbarone is ineffective against GBM and high-grade
anaplastic astrocytoma at the dose and schedule in which it was administered in this trial.