Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The flux activities of de novo and salvage purine synthesis were compared in rat hepatoma 3924A cells in various growth phases. The initial rate assays of [14C]adenine, [14C]hypoxanthine, and [14C]guanine incorporation yielded Michaelis-Menten kinetics with Kms of 5, 7, and 7 microM, respectively. After replating plateau phase cells in lag and log phases the activity of purine de novo pathway increased 4.5- to 8-fold with a preferential rise in guanylate synthesis, whereas purine salvage activities increased only 1.6- to 2.1-fold. However, for the syntheses of IMP, AMP, and GMP, the activities of purine salvage pathways were 2- to 7-fold, 5- to 28-fold, and 2- to 32-fold higher than those of the de novo purine pathway. Treatment of cells with acivicin, an inhibitor of the activity of amidophosphoribosyltransferase, phosphoribosylformylglycinamidine synthase, and GMP synthase, inhibited the flux activities of de novo purine, adenylate, and guanylate syntheses to 37, 73, and 3% of the controls and decreased the concentration of GTP to 42%; the concentration of ATP did not change and that of 5-phosphoribosyl 1-pyrophosphate increased 3.1-fold. Under these conditions the activities of salvage synthesis from hypoxanthine and guanine were enhanced 2.5-fold. Treatment of hepatoma cells with IMP dehydrogenase inhibitors, tiazofurin, ribavirin, and 4-carbamoylimidazolium 5-olate, to block de novo guanylate synthesis accelerated the flux activity of guanine salvage pathway. The higher capacity of purine salvage pathway than that of the de novo one and the further rise of the activity in response to the drugs targeted against the de novo pathway highlight the important role salvage synthesis might play in circumventing the impact of antimetabolites of de novo purine synthesis in cancer chemotherapy.
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PMID:Significance of purine salvage in circumventing the action of antimetabolites in rat hepatoma cells. 246

The antitumor drug acivicin, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, irreversibly inactivated in vivo formylglycinamidine ribonucleotide synthetase (FGAM synthetase, EC 6.3.5.3) in transplantable rat hepatoma 3924A while the activity in host liver remained unchanged. At acivicin doses of 1.0 and 5.0 mg/kg body weight, enzyme activity in the hepatoma decreased to 26 and 5%, respectively, after 2 hr. The activity of the in vivo inactivated hepatoma 3924A enzyme could not be restored by gel filtration or 40 hr of dialysis. In the absence of L-glutamine, acivicin in vitro inactivated both liver and hepatoma FGAM synthetase in a time-dependent fashion, with an inactivation constant Kinact = 66 microM and a minimum inactivation half-time T = 1.0 min. In the presence of L-glutamine, competitive inhibition was observed with a Ki = 5 microM. Protection against in vitro inactivation was observed in the presence of 1 mM L-glutamine, suggesting that L-glutamine concentrations are important in the selective toxicity of acivicin on hepatoma cells in vivo. Irreversible inhibition of FGAM synthetase by acivicin is consistent with the view that this antibiotic is an active site-directed affinity analog of L-glutamine and indicates that this enzyme is a sensitive target of acivicin action.
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PMID:In vivo inactivation of formylglycinamidine ribonucleotide synthetase in rat hepatoma. 396 25

The behavior of phosphoribosylformylglycinamidine ( FGAM ) synthetase (EC 6.3.5.3) activity was elucidated in normal and proliferating tissues and in murine and human neoplasms. Enzymic activity was measured in the 100,000 X g crude supernatant fluid prepared from tissue homogenates. The assay was based on coupling FGAM produced to diazotizable aminoimidazole ribonucleotide. In the crude extracts of normal rat liver and hepatoma 3924A, the apparent KmS of FGAM synthetase for formylglycinamide ribonucleotide, adenosine triphosphate and L-glutamine were 0.06, 1.5, and 0.03 mM, respectively. The liver and hepatoma 3924A FGAM synthetases were saturated at formylglycinamide ribonucleotide, adenosine triphosphate, and L-glutamine concentrations of 0.1, 7.0, and 0.5 mM, respectively; both enzymes had a pH optimum of 7.4. In the liver of normal adult rats, the FGAM synthetase activity was 7.2 to 10.7 nmol/hr/mg protein. The synthetase specific activity in hepatomas of slow and medium growth rates increased 1.2- to 2.2-fold, and in rapidly growing hepatomas it was elevated 3.2- to 5-fold over the values of the respective control normal livers. There was a positive correlation between the increase in synthetase activity and hepatoma proliferation rate. In rat tissues of high cell renewal activity, thymus, spleen, and testis, synthetase specific activity was 7.0-, 3.9-, and 3.3-fold higher than that of normal liver. In the 24- and 48-hr regenerating liver, FGAM synthetase specific activity was increased by 1.2- and 1.5-fold, respectively. In 5-day-old differentiating liver, specific activity was 202% of the adult value; when data were expressed per average cell, the activity was 55% of that of the adult liver. The markedly increased activity in the rapidly proliferating hepatomas appears to be more characteristic of neoplastic growth than of normal liver proliferation. FGAM synthetase activity was also increased in human renal cell carcinoma and hepatocellular and colon carcinomas to 1.4-, 2.7-, and 3.8-fold of the activity of the respective homologous normal and host tissues. The synthetase activity in the rapidly proliferating murine Lewis lung carcinoma was 9.6-fold that of the normal lung. The increased activity of FGAM synthetase should confer selective advantages to the cancer cells and marks this glutamine-utilizing enzyme as a potentially important target in the design of chemotherapy.
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PMID:Proliferation-linked increase in phosphoribosylformylglycinamidine synthetase activity (EC 6.3.5.3). 672 84