Disease relevance of tubercidin

• For CFU-GEMM, BFU-E, and CFU-GM cells, reductions in tubercidin toxicity of 50-100% were achieved at these concentrations: > or = 0.1 microM (nitrobenzylthioinosine); > or = 0.1 microM (dilazep); and > or = 3.0 microM (dipyridamole) [1].
• Treatment of mice bearing i.p. implants of the Ehrlich ascites carcinoma, leukemia L1210/TG8, and colon carcinoma 26 with potentially lethal dosages of tubercidin administered together with host-protecting dosages of NBMPR-P resulted in substantial kill of neoplastic cells and long-term survivors [2].
• Overexpression/selection using the toxic nucleoside tubercidin similarly yielded the TOR (toxic nucleoside resistance) locus, as well as a new locus (TUB2) conferring collateral hypersensitivity to allopurinol [3].
• We describe the selective irreversible inhibition of mengovirus growth in cultured cells by a combination of two pyrrolopyrimidine nucleoside analogues, 5-bromotubercidin (BrTu) and tubercidin (Tu) [4].
• In vitro evaluation of a series of previously prepared tubercidin analogues revealed that certain 5-halogen-substituted analogues were active against human cytomegalovirus (HCMV) at concentrations lower than those that produced comparable cytotoxicity in uninfected cells [5].

Psychiatry related information on tubercidin

• In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model [6].

High impact information on tubercidin

• 2. A selection procedure against Fc receptor-mediated phagocytosis was devised using IgG-coated SRBC containing a toxic drug, tubercidin, as the lethal agent [7].
• Tubercidin has no effect on either capping of Con A receptors or phagocytosis in Dictyostelium [8].
• Tubercidin, an inhibitor of SAHH, inhibits both chemotaxis and chemotaxis-dependent cell streaming of Dictyostelium, and chemotaxis of neutrophils at concentrations that have little effect on cell viability [8].
• Tubercidin does not inhibit starvation-induced expression of the cAMP receptor, cAR1, or G protein-mediated stimulation of adenylyl cyclase activity and actin polymerization in Dictyostelium [8].
• Mice receiving the combination of tubercidin plus NBMPR-P appeared healthy and had normal-sized livers and spleens [9].

Chemical compound and disease context of tubercidin

• We have compared the relative abilities of these inhibitors to reduce the toxicity of in vitro exposures to tubercidin against clonogenic progenitor cells of normal human bone marrow (CFU-GEMM, BFU-E, CFU-GM) and of two leukemic human cell lines (HL-60/C1, CCRF-CEM) that differ in their expression of transporter subtypes [1].
• Adenosine and tubercidin binding and transport in Chinese hamster ovary and Novikoff rat hepatoma cells [10].
• Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis [11].
• Several tubercidin based AKIs, including the ribo- and lyxo-furanosyltubercidin analogues as well as the newly discovered erythro-furanosyltubercidin analogues, designed to prevent 5'-O-phosphorylation and associated toxicities, were tested for their analgesic activity in the rat formalin paw model [12].
• 5-(1-Hydroxyethyl)-, 5-(1-methoxyethyl)-, and 5-(2-buten-1-yl)tubercidin were more selective against reovirus type 1, parainfluenza virus type 3 and Coxsackie virus B4 than tubercidin and the 5-halotubercidins [13].

Biological context of tubercidin

• A tubercidin-resistant clonal derivative of FBD5, FBD5-TUB, has acquired the combined biochemical phenotype of each single mutant [14].
• Initial rate kinetics of the transport of adenosine and 4-amino-7-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (tubercidin) in cultured cells [15].
• These observations suggested that glycolysis could be a target of tubercidin action and that RNAi silencing of glycolytic enzymes was gradual enough to allow the parasites to adapt to alternative sources of energy [16].
• The binding of tubercidin 5' -PO4 is not affected by either Mg2+ or MgATP2-; however, in initial velocity experiments MgATP2- caused from greater than100- to 4,000-fold activation of substrate hydrolysis depending on the concentration of AMP [17].
• Binding studies with tritiated tubercidin 5' -PO4 (4-amino-7-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine-5' -monophosphate), a competitive inhibitor with respect to the substrate, AMP, indicate the presence of three independent, identical binding sites for the substrate analog [17].

Anatomical context of tubercidin

• Natural killer (NK) cell activity is inhibited by the adenosine analogue tubercidin (Tub) and stimulated by the deoxyadenosine analogue 2-fluoro-1-beta-D-arabinofuranosyladenine 5'-monophosphate (F-ara-AMP) in the spleen lymphocytes from mice treated with the drugs in vivo (T. Priebe et al., Cancer Res., 48:4799, 1988) [18].
• Tubercidin, which did not affect glycogen synthase or phosphorylase in liver cells, was 300 times less potent as a protein kinase inhibitor [19].
• The results confirmed our previous findings for the unpurified human erythrocyte enzyme, and demonstrated that the most potent inhibitors of human liver SAH-hydrolase were neplanocin A, 7-deaza-adenosine (tubercidin), 2'-deoxyadenosine, and 9-beta-D-arabino-furanosyladenine [20].
• The ei-mediated process, although small, was of pharmacologic importance since K562 cells could not be protected by NBMPR (10 microM) from the cytotoxic effects of tubercidin (7-deazaadenosine) [21].
• The i.p. administration of tubercidin caused ascites and the appearance of amylase in the peritoneal fluid evidently because of peritonitis and pancreatic injury [22].

Associations of tubercidin with other chemical compounds

• These effects, which were consistent with the nucleoside transport phenotypes of CCRF-CEM cells (inhibitor-sensitive) and HL-60/C1 cells (inhibitor-sensitive and inhibitor-resistant), suggested that protection was due to the inhibition of tubercidin uptake via equilibrative nucleoside transport system(s) [1].
• Resistance to ara-A, and cross-resistance to tubercidin, methylmercaptopurine ribonucleoside, and cordycepin is attributed to loss of adenosine kinase activity [23].
• Cytostatic concentrations of 9-beta-D-arabinofuranosyladenine induced an S-phase block, while 3'-deoxyadenosine (cordycepin) and tubercidin (7-deazaadenosine) induced a cycle-nonspecific block [24].
• Furthermore, tubercidin triphosphate inhibited recombinant T. brucei phosphoglycerate kinase activity in vitro with an IC50 of 7.5 microm [16].
• Cytotoxicity evaluation against L1210 murine leukemic cells in vitro showed that although the parent compounds tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were very potent growth inhibitors, the acyclic derivatives 6, 7a-c, and 9a-c had only slight growth-inhibitory activity [25].

Gene context of tubercidin

• From a mutagenized population of wildtype Leishmania donovani promastigotes, a clonal cell line, TUBA2, was isolated by virtue of its ability to survive and grow in 20 microM tubercidin (7-deazaadenosine) [26].
• The influx of tubercidin into MOLT 4 cells was found to occur primarily by means of the NBMPR-sensitive nucleoside transport system [27].
• Short (1-h) exposures to 1 microM tubercidin alone inhibited colony formation (a) of normal human hematopoietic progenitors (CFU-GEMM, BFU-E, CFU-GM) by 100%, and (b) of HL-60/C1 and CCRF-CEM cells by > 90% [1].
• We conclude that 5 microm tubercidin kills trypanosomes by targeting glycolysis, especially by inhibition of phosphoglycerate kinase [16].
• We subsequently found that silencing of hexokinase, a glycolytic enzyme, also yielded tubercidin-resistant parasites [16].

Analytical, diagnostic and therapeutic context of tubercidin

• Administration of NBMPR-P with high doses of tubercidin (lethal doses if injected alone) by intraperitoneal injection into S. mansoni-infected mice was highly toxic to the parasite but not to the host [9].
• From physical data (thermal melting, NMR, and circular dichroism) it is concluded that tubercidin destabilizes the structure of the polynucleotide chain and that this may be due to an altered polarization of the nucleobases and their enhanced rotation around the N-glycosylic bond [28].
• It was found to be mutant in four other traits, being resistant to tubercidin, incapable of growth at 31.5 degrees C, abnormal in development, and slow growing at 25 degrees C. Genetic crosses using the macrocyst cycle showed that these five traits are controlled by five unlinked genes [29].
• Treatment of schistosomiasis mansoni and japonica in baboons with tubercidin given by direct intravenous injection [30].
• Baboons (Papio cyanocephalus and P. anubis), infected with Schistosoma mansoni or S. japonicum, were treated with single doses of tubercidin (7-deazaadenosine; Tu), 1, 3, and 5 mg per kg of body weight, administered by intravenous drip [30].

References