[Antineoplastic effect of 5-fluorocytosine and cytosine deaminase on brain tumor (author's transl)].

The antifungal drug, 5-Fluorocytosine (5-FC) which is a derivative of 5-Fluorouracil (5-FU), lacks antineoplastic activity in human subjects because of the absence of cytosine deaminase (CDase) in mammalian cells. Therefore, intratumoral conversion of 5-FC to 5-FU by extrinsic CDase could be expected to induce antineoplastic effects at a local site with minimal systemic toxicity. The effects of combined administration of 5-FC and CDase in in vitro and in vivo were investigated. CDase was extracted from the E-Coli K-12 strain and purified. In vitro studies resulted in a significant inhibition of cell proliferation on cultured glioma cells (EA-285 cells) with 5-FC concentration over 10 μg/ml. Fluorocytographic studies of the tumor cell cycle progression showed synchronization in the early S phase at lower concentrations and complete blocking at the G1 and the early S phase with over 25 μg/ml. In in vivo studies, tissue concentrations of 5-FC and converted 5-FU were serially measured by a bioassay method after simultaneous intratumoral injection of CDase and systemic administration of 150 mg/kg of 5-FC to brain tumor bearing rats. The maximum concentrations of the drugs in the tumor tissue were 85 μg/g 5-FC at 1 hour and 9.6 μg/g 5-FU at 2 hours, which were sufficient to kill tumor cells. They were kept at higher levels in the tumor tissue than in the normal brain. In comparison, the maximum 5-FU concentration in the serum was only 0.4 μg/ml. The survival times and histological examinations of the experimental brain tumor models by this combined therapy were evaluated. The median survival time of the treated group was significantly prolonged (38.3 days) when compared with that of the control group (28.2 days). No side effects were recognized. Histological studies of the animal brains 2 weeks after the therapy revealed necrosis in the treated tumor. This combined treatment of 5-FC and CDase could be an ideal therapy for brain tumor in the future.