Purine metabolism of human glioblastoma in vivo.

摘要: The aim of this study was to identify targets for rational chemotherapy glioblastoma. In order elucidate differences in the biochemistry tumor and normal human brain, vivo pool sizes purine nucleotides, nucleosides, nucleobases metabolizing enzymes biopsy material from 14 grade IV astrocytomas 4 temporal lobe samples were analyzed. Specimens collected during surgery using freeze-clamp sampling technique analyzed by high pressure liquid chromatography. Total adenylates, guanylates tumors 2186, 1865, 310 nmol/g (wet weight), respectively, which corresponds 61, 60, 71% brain tissue concentrations. Relative had significantly lower ATP GTP levels, essentially nucleosides bases, unchanged activities salvage hypoxanthine-guanine phosphoribosyltransferase, adenine adenosine kinase (659, 456, 98 nmol/h/mg protein, respectively) 4-fold higher IMP dehydrogenase (11.6 protein); latter is rate limiting enzyme guanylate de novo synthesis. pools 64% values brain. Modulation pathway glioblastoma inhibition with specific agents such as tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) appears be a therapeutic approach. Preliminary vitro experiments malignant specimens 2 additional patients revealed that significant amounts active metabolite thiazole-4-carboxamide dinucleotide are formed tiazofurin. At concentration 200 microM drug able deplete median 54% phosphate buffered saline treated controls. Flux studies [14C]formate showed strongly inhibited synthesis an average 10% This effect more pronounced compared No [14C]guanine could observed tissues. Supportive measures have considered inhibit highly phosphoribosyltransferase can partly antagonize induced decrease guanine nucleotides.