Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Alanosine [3-(hydroxynitrosoamino)-L-alanine] is an antitumor antibiotic that at the present is undergoing phase II clinical trials. Its mode of action as well as its metabolism has been extensively studied, and the metabolite N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosoamino)-L-alanine ribonucleotide (L-alanosine AICOR) proved to be an extremely potent inhibitor of de novo purine biosynthesis and is thus primarily responsible for the antitumor activity of the drug. The synthesis of the corresponding ribonucleoside, i.e., N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosamino)-L-alanine ribonucleoside (L-alanosine AICO ribonucleoside), was accomplished by condensation of a suitably protected derivative of L-alanosine with N-succinimidyl-5-amino-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1H-im idazole-4-carboxylate followed by the removal of the protective groups. The biological activity of L-alanosine AICO ribonucleoside was tested in vitro on whole tumor cells and on the isolated enzyme adenylosuccinate synthetase and in vivo on murine experimental leukemia. The compound was found to be inactive in these tests.
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PMID:Synthesis and in vitro biological evaluation of N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosamino)-L-alanine (L-alanosine AICO ribonucleoside). 659 59

This article reports a Phase I study of combined therapy with N-(phosphonacetyl)-L-aspartate (PALA) and L-alanosine in 26 patients with advanced cancer. Each agent exhibits antitumor effect by enzyme inhibition: PALA blocks pyrimidine biosynthesis by impeding aspartate transcarbamylase and L-alanosine depletes purine nucleotides by interfering with adenylosuccinate synthetase. These agents were selected for clinical investigation in light of synergistic cytotoxicity in vitro against human tumor cell lines and in vivo against P-388 murine leukemia resistant to cytosine arabinoside. Dose-limiting toxicities were stomatitis and diarrhea to a lesser extent. There was no substantial myelosuppression. The authors recommend either of two intravenous regimens for studies of therapeutic activity in selected patients with neoplastic diseases: a one-day treatment repeated of PALA, 5.0 g/m2 and L-alanosine, 3.0 g/m2, repeated every 3 weeks; or a monthly program of PALA, 500 mg/m2/d 1-5 and L-alanosine, 60 mg/m2/d 1-5.
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PMID:A Phase I study of the combination N-(phosphonacetyl)-L-aspartate (PALA, NSC-224131) and L-alanosine (NSC-153353) in patients with advanced cancer. 686 Oct 99

The conjugate of L-alanosine [L-2-amino-3-(N-hydroxyN-nitrosamino)propionic acid] and 5-amino-4-imidazolecarboxylic acid ribonucleotide has been synthesized in good yield by enzymatic means, using partially purified chicken liver 5-amino-4-imidazole-N-succinocarboxamide ribonucleotide synthetase (EC 6.3.2.6). The chromatographic behavior of this molecule was characterized, as was its ability to inhibit adenylosuccinate synthetase, an enzyme long considered to be the locus of action of the drug. The Ki of-L-alanosyl-5-amino-4-imidazolecarboxylic acid ribonucleotide versus a partially purified adenylosuccinate synthetase frm the L5178y/AR leukemia of C57BL X DBA/2 F1 (hereafter called BD2F1) mice was 0.228 microM, whereas the Ki of L-alanosine was 57.23 mM. Administration of 50 microCi of DL-[1-14C]alanosine along with unlabeled L-alanosine (500 mg/kg) to BD2F1 mice bearing s.c. nodules of Leukemia L5178Y/AR resulted in the accumulation in tumors of a material with properties compatible with those of L-alanosyl-5-amino-4-imidazolecarboxylic acid ribonucleotide. It coeluted with L-alanosyl-5-amino-r-imidazolecarboxylic acid ribonucleotide in the high-resolution chromatographic system used, was Bratton-Marshall positive, and inhibited adenylosuccinate synthetase strongly. In tumor nodules 2 hr after dosage, the concentration of this compound approximated 70 microM. Under the same circumstances, the intratumoral concentration of L-alanosine was found to be 440 microM. At this concentration, the antibiotic itself exerts only a marginal inhibition of leukemic adenylosuccinate synthetase. In ancillary studies, it was shown for the first time in vivo that the parenteral administration of L-alanosine reduces the specific activity of intratumoral adenylosuccinate synthetase by 70% and depresses the synthesis of DNA to an equivalent or greater extent; adenine but not hypoxanthine (both at 250 mg/kg) was able to reverse the latter inhibition. No effect on purine salvage enzymes was exerted by L-alanosine. Viewed in concert, these experiments establish that the adduct of L-alanosine with 5-amino-4-imidazolecarboxylic acid is formed by neoplastic cells in vivo and that this anabolite is most probably responsible for the inhibition of adneylosuccinate synthetase and, in turn, for the diminished synthesis of DNA seen after a therapeutic dose of L-alanosine.
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PMID:Identification of the antimetabolite of L-alanosine, L-alanosyl-5-amino-4-imidazolecarboxylic acid ribonucleotide, in tumors and assessment of its inhibition of adenylosuccinate synthetase. 743 71

Vertebrates have muscle and non-muscle isozymes of adenylosuccinate synthetase (AdSS, EC 6.3.4.4), which catalyzes the first committed step in AMP synthesis. A novel muscle isozyme of adenylosuccinate synthetase, human AdSSL1, is identified from human bone marrow stromal cells. AdSSL1 is 98% identical to mouse muscle type AdSS1 and contains conserved sequence and structural features of adenylosuccinate synthetase. Human AdSSL1 gene is mapped to chromosome 14p32.33. After stimulation, leukemia cells express AdSSL1 in a time-dependent manner different from that of non-muscle adenylosuccinate synthetase. The human AdSSL1 is predominantly expressed in skeletal muscle and cardiac tissue consistent with the potential role for the enzyme in muscle metabolism. Overexpressed AdSSL1 protein in COS-7 cells locates in cytoplasm. Recombinant AdSSL1 protein possesses typical enzymatic activity to catalyze adenylosuccinate formation. The identification of human AdSSL1 with predominant expression in muscle tissue will facilitate future genetic and biochemical analysis of the enzyme in muscle physiology.
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PMID:Molecular cloning and characterization of a novel muscle adenylosuccinate synthetase, AdSSL1, from human bone marrow stromal cells. 1578 19

Our previous studies have classified 3-Hydrogenkwadaphnin (3-HK), isolated from Dendrostellera lessertii (Thymelaeaceae), as a strong anti-proliferative agent that induces apoptosis among the treated leukemia cells mainly through IMP dehydrogenase inhibition. To disclose this point, we measured the intracellular ATP and GTP levels among K562 cells exposed to a single dose of 3-HK (7, 12 and 25nM). The HPLC analyses of the 3-HK-treated cell lysates indicated a dose-dependent reduction in both GTP and ATP levels. The reduction of purine nucleotide levels was also associated with decreased activity of adenylosuccinate synthetase (AdSS) and enhanced level of cell death through apoptosis. However, the inhibitory effect of 3-HK was reversed by exogenous addition of guanosine with respect to GTP and partially with respect to ATP level. These data suggest that 3-HK targets a delicate regulatory system which governs the life/death fate of the cells partially through modulation of the GTP/ATP pool sizes.
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PMID:Effects of 3-Hydrogenkwadaphnin on intracellular purine nucleotide contents and their link to K562 cell death. 2521 32