Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria.
Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.
Samid
D
D
Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Ram
Z
Z
Hudgins
W R
WR
Shack
S
S
Liu
L
L
Walbridge
S
S
Oldfield
E H
EH
Myers
C E
CE
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010648:Phenylacetates / Q000494:pharmacology* / Q000627:therapeutic use; D010661:Phenylketonurias / Q000473:pathology*; D017368:Protein Prenylation; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D010648:Phenylacetates; C025136:phenylacetic acid; D008798:Mevalonic Acid