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Advances in Enzyme Regulation 1983The regulation and integration of purine nucleotide biosynthesis is considered from the viewpoint of the main groups of reaction sequences involved and with respect to... (Review)
Review
The regulation and integration of purine nucleotide biosynthesis is considered from the viewpoint of the main groups of reaction sequences involved and with respect to some specific organs and tissues. Inhibiting either IMP dehydrogenase or adenylosuccinate synthetase in rat liver in vitro reduced the rate of purine do novo synthesis with respect to the purine remaining in the tissue and did not materially affect the rate with respect to the purines extruded into the incubation medium. These results are considered in contrast to the results of previous studies in cultured lymphoblasts. The relative activities of purine de novo synthesis and of purine salvage have been assessed in different tissues by the activities of amidophosphoribosyltransferase and hypoxanthine phosphoribosyltransferase (HPRT), respectively. Changes in purine de novo synthesis as measured by [14C]formate incorporation into cellular purines were reflected in the amidophosphoribosyltransferase activities. The capacity of different tissues to synthesize purines de novo is widespread and the role of the liver as the main site of purine de novo synthesis in vivo and exporting purines to other tissues appears questionable. Regulatory mechanisms may well be tissue specific. The age-related changes in the activity of the purine de novo synthesis and purine salvage pathways, respectively, in the brain suggest that it is physiological or neuropharmacological functions of the developed brain rather than cell division and organogenesis which require a high level of purine salvage relative to purine de novo synthesis. This is compatible with the observation that purine de novo synthesis alone can meet the needs for additional purine nucleotides which lectin induced lymphocyte transformation involves. The mechanism whereby purine de novo synthesis is initiated during lectin induced lymphoblast transformation remains obscure.
Topics: Adenylosuccinate Synthase; Alanine; Animals; Brain; Formates; Humans; IMP Dehydrogenase; Inosine Monophosphate; Liver; Lymphocyte Activation; Purine Nucleotides; Rats; Ribavirin; Ribonucleotides; S-Adenosylhomocysteine
PubMed: 6152730
DOI: 10.1016/0065-2571(83)90007-9 -
Biochemical Pharmacology Dec 1979
Topics: Alanine; Amines; Animals; Antibiotics, Antineoplastic; Blood Proteins; Decarboxylation; Hemoglobins; Malate Dehydrogenase; Male; Mice; Mitochondria; Neoplasms, Experimental; Nitrosamines; Oxidation-Reduction; RNA, Transfer
PubMed: 533558
DOI: 10.1016/0006-2952(79)90400-3 -
Biochemistry Jan 2006An X-ray diffraction study to 2.0 A resolution shows that this enzyme, ATCase, is in the T-state (the c3 to c3 distance is 45.2 A) when ATCase is bound to carbamyl...
An X-ray diffraction study to 2.0 A resolution shows that this enzyme, ATCase, is in the T-state (the c3 to c3 distance is 45.2 A) when ATCase is bound to carbamyl phosphate (CP) and to L-alanosine (an analogue of aspartate). This result strongly supports the kinetic results that alanosine did not inhibit the carbamylation of aspartate in the normal reaction of native ATCase plus CP and aspartate [Baillon, J., Tauc, P., and Hervé, G. (1985) Biochemistry 24, 7182-7187]. The structure further reveals that the phosphate of CP is 4 A away from its known position in the R-state and is in the T-state position of P(i) in a recent study of ATCase complexed with products, phosphate (P(i)) and N-carbamyl-L-aspartate [Huang, J., and Lipscomb, W. N. (2004) Biochemistry 43, 6422-6426]. Moreover, the alanosine position in this T-state is somewhat displaced from that expected for its analogue, aspartate, from the R-state position. The relations of these structural aspects to the kinetics are presented.
Topics: Alanine; Aspartate Carbamoyltransferase; Binding Sites; Carbamyl Phosphate; Crystallization; Crystallography, X-Ray; Escherichia coli; Ligands; Protein Structure, Tertiary
PubMed: 16401065
DOI: 10.1021/bi051543u -
American Journal of Clinical Oncology Apr 1983Thirty patients with advanced metastatic colorectal adenocarcinoma were treated with alanosine at a dose of 160 mg/m2 daily for 5 days every 4 weeks. Sixteen patients...
Thirty patients with advanced metastatic colorectal adenocarcinoma were treated with alanosine at a dose of 160 mg/m2 daily for 5 days every 4 weeks. Sixteen patients had received no prior chemotherapy and 14 had been previously treated with one or more cytotoxic agents. No patient met the criteria for a complete or partial response. The major toxicity was stomatitis.
Topics: Adenocarcinoma; Adult; Aged; Alanine; Antibiotics, Antineoplastic; Colonic Neoplasms; Drug Evaluation; Female; Humans; Male; Middle Aged; Nausea; Rectal Neoplasms; Stomatitis
PubMed: 6829493
DOI: 10.1097/00000421-198304000-00009 -
Biochemical Pharmacology May 1984
Synthesis of adenosine nucleotides from hypoxanthine by human malaria parasites (Plasmodium falciparum) in continuous erythrocyte culture: inhibition by hadacidin but not alanosine.
Topics: Adenosine Triphosphate; Adenylosuccinate Synthase; Alanine; Animals; Erythrocytes; Glycine; Humans; Hypoxanthines; Plasmodium falciparum; Purine Nucleotides
PubMed: 6375681
DOI: 10.1016/0006-2952(84)90427-1 -
Cancer Treatment Reports Dec 1983
Clinical Trial
Topics: Adult; Aged; Alanine; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Clinical Trials as Topic; Colonic Neoplasms; Female; Humans; Male; Middle Aged; Nausea; Phosphonoacetic Acid; Rectal Neoplasms; Stomatitis
PubMed: 6360350
DOI: No ID Found -
Journal of Immunopharmacology 1984L-alanosine is an antitumor compound which has recently entered clinical trials. Single i.p. doses of this drug inhibit antibody production to thymus-dependent and...
L-alanosine is an antitumor compound which has recently entered clinical trials. Single i.p. doses of this drug inhibit antibody production to thymus-dependent and thymus-independent antigens as well as delayed hypersensitivity to SRBC in mice. Moreover, the in vitro lymphoproliferative responses of splenocytes to Concanavalin A and bacterial Lipopolysaccharides are also affected when the drug is added upon setting up the cultures. On the other hand, in vivo treatment with L-alanosine does not impair spleen natural killer (NK) activity. The results are discussed in an effort to characterize the immuno-suppressive activity of L-alanosine.
Topics: Alanine; Animals; Antibiotics, Antineoplastic; Antibody Formation; Cells, Cultured; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Erythrocytes; Female; Hypersensitivity, Delayed; Killer Cells, Natural; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mitogens; Neoplasms, Experimental; Sheep; Spleen
PubMed: 6470495
DOI: 10.3109/08923978409026456 -
Planta Medica Aug 2010Personalized cancer medicine aims to develop individualized treatment options adapted to factors relevant for the prognosis of each patient. Molecular biomarkers are... (Review)
Review
Personalized cancer medicine aims to develop individualized treatment options adapted to factors relevant for the prognosis of each patient. Molecular biomarkers are required to predict the likelihood of an individual tumor's responsiveness or of toxicity in normal organs and to advise optimized treatments with improved efficacy at reduced side effects for each cancer patient. In the present review, we present a concept, which takes advantage of methods of molecular diagnostics to identify predictive markers at the DNA, mRNA, and protein levels. Markers with prognostic value concerning treatment response and patient survival can then be used as targets to develop optimized drugs. We focus on three examples to illustrate this strategy: (i) chemoselective treatment of tumors with 9p21 deletion by L-alanosine, (ii) treatment of multidrug-resistant P-glycoprotein-expressing tumor cells by non-cross-resistant natural products or by inhibitors of P-glycoprotein to overcome multidrug resistance, and (iii) natural products that inhibit the epidermal growth factor receptor (EGFR) in EGFR-overexpressing tumor cells.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Alanine; Antibiotics, Antineoplastic; Biological Products; Biomarkers, Tumor; Cytogenetics; Drug Resistance, Neoplasm; ErbB Receptors; Genetic Variation; Humans; Neoplasms; Phytotherapy; Precision Medicine; RNA, Messenger
PubMed: 20486071
DOI: 10.1055/s-0030-1249937 -
Methods and Findings in Experimental... Sep 2009Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AAV1/SERCA2a, Abacavir sulfate/lamivudine, Adalimumab, Aliskiren fumarate, Ambrisentan, Aripiprazole, AT-7519, Atazanavir sulfate, Atomoxetine hydrochloride, Azacitidine, Azelnidipine; Besifloxacin hydrochloride, Bevacizumab, Bioabsorbable everolimus-eluting coronary stent, Bortezomib, Bosentan, Budesonide/formoterol fumarate; CAIV-T, Carisbamate, Casopitant mesylate, Certolizumab pegol, Cetuximab, Ciclesonide, Ciprofloxacin/dexamethasone, CTCE-9908; Dalcetrapib, Darunavir, Deferasirox, Desloratadine, Disitertide, Drotrecogin alfa (activated), DTA-H19, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Efalizumab, Emtricitabine, Eribulin mesilate, Escitalopram oxalate, Eszopiclone, EUR-1008, Everolimus-eluting coronary stent, Exenatide; Fampridine, Fluticasone furoate, Formoterol fumarate/fluticasone propionate, Fosamprenavir calcium, Fulvestrant; Gabapentin enacarbil, GS-7904L; HPV-6/11/16/18, Human Secretin, Hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, Imexon, Inalimarev/Falimarev, Indacaterol, Indacaterol maleate, Inhalable human insulin, Insulin detemir, Insulin glargine, Ixabepilone; L-Alanosine, Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Loratadine/montelukast sodium, Lutropin alfa; MeNZB, Mepolizumab, Micafungin sodium, Morphine hydrochloride; Nabiximols, Nikkomycin Z; Olmesartan medoxomil, Omalizumab; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Perifosine, PF-489791, Plitidepsin, Posaconazole, Pregabalin; QAX-576; Raltegravir potassium, Ramelteon, Rasagiline mesilate, Recombinant human relaxin H2, rhGAD65, Rivaroxaban, Rosuvastatin calcium, Rotigotine; Saxagliptin, SCH-530348, Sirolimus-eluting stent, SLIT-amikacin, Sorafenib, Sotrastaurin, SR-16234, Sulforaphane; Tadalafil, Tanespimycin, Tapentadol hydrochloride, Teriparatide, Tesofensine, Tiotropium bromide, Tipifarnib, Tirapazamine, TMC-207, Tocilizumab, Tolvaptan, Tosedostat, Treprostinil sodium; Ustekinumab; Varespladib methyl, Vicriviroc, Vildagliptin, Vildagliptin/metformin hydrochloride, Volociximab, Voriconazole; Ziconotide, Ziprasidone hydrochloride.
Topics: Clinical Trials as Topic; Humans
PubMed: 19907722
DOI: No ID Found -
Methods and Findings in Experimental... Dec 2007Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide, Uracil, Ustekinumab; V-260, Vandetanib, Vatalanib succinate, Vernakalant hydrochloride, Vorinostat; YM-155; Zileuton, Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans; Meta-Analysis as Topic; Treatment Outcome
PubMed: 18200333
DOI: No ID Found