SELECTIVE ACTIVITY OF PHENYLACETATE AGAINST MALIGNANT GLIOMAS - RESEMBLANCE TO FETAL BRAIN-DAMAGE IN PHENYLKETONURIA

Phenylacetate, a deaminated metabolite of phenylalanine, has been impl icated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous s ystem, these neoplasms should be equally vulnerable. We shes here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmaco logical concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to thos e observed in phenylketonuria-like conditions, including selective dec line in de novo cholesterol synthesis from mevalonate. Because gliomas , but not mature normal brain cells, are highly dependent on mevalonat e for production of sterols and isoprenoids vital for cell growth, sod ium phenylacetate would be expected to affect tumor growth in vivo whi le sparing normal tissues. Systemic treatment of rats bearing intracra nial gliomas resulted in significant tumor suppression with no apparen t toxicity to the host. The data indicate that phenylacetate, acting t hrough inhibition of protein prenylation and other mechanisms, may off er a safe and effective novel approach to treatment of malignant gliom as and perhaps other neoplasms as well.