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)

A study on the oncolytic activity of the L-cysteine derivative L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride (NSC 303861), revealed that the drug caused complete regression of the MX-1 human mammary tumor xenograft. The compound also exhibited moderate antitumor activity against murine leukemia P388 (T/C value of 169% at a daily dose of 400 mg/kg) and against M5076 sarcoma (T/C value of 135% at a daily dose of 600 mg/kg). The drug was inactive against B16 melanoma, Lewis lung, colon 38 and CD8F1 mammary carcinomas. The compound exhibited significant cytotoxicity against hepatoma 3924A cells in culture (LC50 = 6 microM). Studies on the mechanism of action revealed that the cytotoxicity of the drug could be partially abrogated by protecting hepatoma 3924A cells in culture with L-glutamine. At 6 h after injection of the compound (400 mg/kg) into rats bearing hepatoma 3924A, the pools of L-glutamine and L-glutamate in the tumor decreased to 33% and 71%, respectively, of control levels; the drug selectively inhibited the activities of L-glutamine-requiring enzymes of purine nucleotide biosynthesis, amidophosphoribosyltransferase, FGAM synthase, and GMP synthase, to 21%, 1%, and 69%, respectively, without significantly altering the activities of pyrimidine biosynthetic enzymes, carbamoylphosphate synthase II and CTP synthase. Measurement of the nucleotide concentrations further corroborated the actions of the drug on the purine nucleotide biosynthetic enzyme activities. Drug injection (400 mg/kg) in the hepatoma 3924A-bearing rats reduced the concentrations of IMP in the tumor to 52%, those of total adenylates to 52%, those of total guanylates to 57%, and those of NAD to 73%, without significantly perturbing the pyrimidine nucleotide pools. Studies on the mechanism of action of the L-cysteine derivative suggested that the compound behaved as an L-glutamine antagonist, selectively acting on the enzymes of purine nucleotide biosynthesis.
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PMID:Oncolytic activity and mechanism of action of a novel L-cysteine derivative, L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride. 234 42

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