Showing papers in "Nucleosides, Nucleotides & Nucleic Acids in 2004"
TL;DR: Febuxostat is a safe and potent hypouricemic agent in healthy humans and inhibition of xanthine oxidase activity by febuxostats is confirmed.
Abstract: In order to evaluate the safety, pharmacological properties, and urate-lowering efficacy of febuxostat, a non-purine, selective inhibitor of xanthine oxidase, a Phase 1, 2-week, multiple-dose, placebo-controlled, dose-escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self-limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.
93 citations
TL;DR: Five nucleoside analogs have been screened for antiviral property against HIV‐1, HSV‐1 and 2, parainfluenza‐3, reovirus‐ 1 and many others and it was observed that arabinosides had greater inhibitory action than ribosides.
Abstract: Different arabinosides and ribosides, viz. Ara‐DDA or 9(1‐β‐d‐arabinofuranosyl) 1,3‐dideazaadenine (6), Ara‐NDDP or 9(1‐β‐d‐arabinofuranosyl) 4‐nitro‐1,3‐dideazapurine (7), Ara‐DKP or 1(1‐β‐d‐arabinofuranosyl) diketopiperazine (8), Ribo‐DDA or 9(1‐β‐d‐ribofuranosyl) 1,3‐dideazaadenine (9) and Ribo‐NDDP or 9(1‐β‐d‐ribofuranosyl) 4‐nitro‐1,3‐dideazapurine (10) have been synthesized as probable antiviral agents. The arabinosides have been synthesized using the catalyst TDA‐1 that causes stereospecific formation of β‐nucleosides while a one‐pot synthesis procedure was adopted for the synthesis of the ribonucleosides where β‐anomers were obtained in higher yields. All the five nucleoside analogs have been screened for antiviral property against HIV‐1 (IIIB), HSV‐1 and 2, parainfluenza‐3, reovirus‐1 and many others. It was observed that arabinosides had greater inhibitory action than ribosides. The compound 7 or Ara‐NDDP has shown maximum inhibition of HIV‐1 replication than the rest of the molecules with an IC...
84 citations
TL;DR: Alternative immunosuppressive drugs, particularly 6‐thioguanine, should be considered for AZA‐intolerant patients with ITPase deficiency, and Polymorphism in the ITPA gene thus predicts AZA intolerance.
Abstract: Inosine triphosphate pyrophosphatase (ITPase) deficiency occurs with polymorphic frequencies in Caucasians and results in the benign accumulation of the inosine nucleotide ITP. In 62 patients treated with azathioprine for inflammatory bowel disease, the ITPA 94C>A deficiency-associated allele was significantly associated with adverse drug reactions (OR 4.2, 95% CI 1.6-11.5, p = 0.0034). Significant associations were found for flu-like symptoms (OR 4.7, 95% CI 1.2-18.1, p = 0.0308), rash (OR 10.3, 95% CI 4.7-62.9, p = 0.0213) and pancreatitis (OR 6.2,CI 1.1-32.6, p = 0.0485). Polymorphism in the ITPA gene thus predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.
61 citations
TL;DR: The consequences of a mitochondrial DNA mutation that causes a specific complex I defect is examined, and the effect was much less pronounced than with Rotenone, suggesting that complex I inhibiton cannot fully explain the marked effect ofRotenone on pyrimidine nucleotide synthesis.
Abstract: Since de-novo synthesis of pyrimidine nucleotides is coupled to the mitochondrial respiratory chain (RC) via dehydroorotic acid dehydrogenase (DHODH), respiratory chain dysfunction should impair pyrimidine synthesis. To investigate this, we used specific RC inhibitors, Antimycin A and Rotenone, to treat primary human keratinocytes and 143B cells, a human osteosarcoma cell line, in culture. This resulted in severe impairment of de novo pyrimidine nucleotide synthesis. The effects of RC inhibition were not restricted to pyrimidine synthesis, but concerned purine nucleotides, too. While the total amount of purine nucleotides was not diminished, they were significantly broken down from triphosphates to monophosphates, reflecting impaired mitochondrial ATP regeneration. The effect of Rotenone was similar to that of Antimycin A. This was surprising since Rotenone inhibits complex I of the respiratory chain, which is upstream of ubiquinone where DHODH interacts with the RC. In order to avoid unspecific effects of Rotenone, we examined the consequences of a mitochondrial DNA mutation that causes a specific complex I defect. The effect was much less pronounced than with Rotenone, suggesting that complex I inhibiton cannot fully explain the marked effect of Rotenone on pyrimidine nucleotide synthesis.
57 citations
TL;DR: The results demonstrate a very heterogeneous collection of mutations for both LND and its partial syndromes, and suggest the partial phenotypes are more likely to have mutations predicted to allow some residual enzyme function.
Abstract: Mutations in the gene encoding hypoxanthine‐guanine phosphoribosyltransferase (HPRT) cause Lesch–Nyhan disease, which is characterized by hyperuricemia, severe motor disability, and self‐injurious behavior. Mutations in the same gene also cause less severe clinical phenotypes with only some portions of the full syndrome. A large database of 271 mutations associated with both full and partial clinical phenotypes was recently compiled. Since the original database was assembled, 31 additional mutations have been identified, bringing the new total to 302. The results demonstrate a very heterogeneous collection of mutations for both LND and its partial syndromes. The differences between LND and the partial phenotypes cannot be explained by differences in the locations of mutations, but the partial phenotypes are more likely to have mutations predicted to allow some residual enzyme function. The reasons for some apparent exceptions to this proposal are addressed.
57 citations
TL;DR: The concentration of DNA and RNA in plasma of trauma patients correlates with the extent of posttraumatic organ failure and extracellular RNA was not found in the plasma of breast cancer patients and patients with nonmalignant breast tumors, whereas a very high concentration was found in patients with malignant and non malignant diseases of lung.
Abstract: The concentration of extracellular DNA and RNA in blood plasma of healthy donors, trauma patients, patients with breast and lung cancer, nonmalignant breast tumors and nonmalignant lung diseases were estimated. Significant amounts of extracellular RNA were found in plasma of trauma patients. The concentration of DNA and RNA in plasma of trauma patients correlates with the extent of posttraumatic organ failure. Extracellular RNA was not found in the plasma of breast cancer patients and patients with nonmalignant breast tumors, whereas a very high concentration of extracellular RNA was found in patients with malignant and nonmalignant diseases of lung.
56 citations
TL;DR: The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.
Abstract: A single oral dose of 20 mg febuxostat was administered to subjects with normal, mild or moderate impairment in renal function. There was less than a 2-fold difference in AUC of plasma unchanged febuxostat among the renal function groups, and changes in plasma urate levels from pre-dose levels were not significant. A total of five adverse events were reported with all mild in severity. The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.
55 citations
TL;DR: The sugar moiety of nucleosides has been shown to play a major role in permeant‐transporter interaction with human equilibrative nucleoside transporters 1 and 2 and a series of uridine analogs with sugar modifications were subjected to an assay that tested their abilities to inhibit [3H]uridine transport mediated by recombinant hENT1 and hENT2 produced in Saccharomyces cerevisiae.
Abstract: The sugar moiety of nucleosides has been shown to play a major role in permeant-transporter interaction with human equilibrative nucleoside transporters 1 and 2 (hENT1 and hENT2). To better understand the structural requirements for interactions with hENT1 and hENT2, a series of uridine analogs with sugar modifications were subjected to an assay that tested their abilities to inhibit [3H]uridine transport mediated by recombinant hENT1 and hENT2 produced in Saccharomyces cerevisiae. hENT1 displayed higher affinity for uridine than hENT2. Both transporters barely tolerated modifications or inversion of configuration at C(3'). The C(2')-OH at uridine was a structural determinant for uridine-hENT1, but not for uridine-hENT2, interactions. Both transporters were sensitive to modifications at C(5') and hENT2 displayed more tolerance to removal of C(5')-OH than hENT1; addition of an O-methyl group at C(5') greatly reduced interaction with either hENT1 or hENT2. The changes in binding energies between transporter proteins and the different uridine analogs suggested that hENT1 formed strong interactions with C(3')-OH and moderate interactions with C(2')-OH and C(5')-OH of uridine, whereas hENT2 formed strong interactions with C(3')-OH, weak interactions with C(5')-OH, and no interaction with C(2')-OH.
49 citations
TL;DR: The hypothesis is that the smaller the substituent at the C‐4′ position they have, the more acceptable biological activity they show, and 4′‐C‐cyano‐2′‐deoxy purine nucleosides, whose substituents are smaller than the ethynyl group, will have more potent antiviral activity.
Abstract: Some 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides showed the most potent anti‐HIV activity among the series of 4′‐C‐substituted 2′‐deoxynucleosides whose 4′‐C‐substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C‐4′ position they have, the more acceptable biological activity they show. Thus, 4′‐C‐cyano‐2′‐deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4′‐C‐cyano‐2′‐deoxy purine nucleosides (4′‐CNdNs) and 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides (4′‐EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2′‐deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C‐4′ position of the sugar moiety from 2′‐deoxyadenosine and 2,6‐diaminopurine 2′‐deoxyriboside. Unfortunately, 4′‐C‐cyano derivatives showed lower activity against HIV‐1, and two 4′‐C‐ethynyl derivatives sugge...
43 citations
TL;DR: The electrophilic fluorination of 4‐chloro‐5‐fluoro‐7‐(2,3,5,‐tri‐O‐benzoyl‐β‐d‐ribofuranosyl)pyrrolo[ 2,3‐d]pyrimidine was studied and increased activity of 7 over tubercidin was observed against L‐1210 cells and toxicity in fibroblast cells was reduced.
Abstract: The electrophilic fluorination of 4‐chloropyrrolo[2,3‐d]pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4‐chloro‐5‐fluoropyrrolo[2,3‐d]pyrimidine (2) using Selectfluor. This transformation proceeded via the 4‐chloro‐5,6‐dihydro‐5‐fluoro‐6‐hydroxypyrrolo[2,3‐d]pyrimidine (3) in a 9:1 trans:cis ratio. The trans isomer of compound 3 was studied by 1H NMR and 19F NMR, and the 5‐H tautomer (4) was observed as another intermediate. A modified Vorbruggen procedure of compound 2 and tetra‐O‐acetylribose gave 4‐chloro‐5‐fluoro‐7‐(2,3,5,‐tri‐O‐benzoyl‐β‐d‐ribofuranosyl)pyrrolo[2,3‐d]pyrimidine (6) in a 65% yield. Treatment of compound 6 with ammonia (l) in dioxane gave 5‐fluorotubercidin (7). No antibacterial activity was observed. An MTT assay (Promega) against Huh‐7 liver cells, normal mouse spleen cells stimulated with Con A (a T‐cell mitogen), and normal mouse spleen stimulated with LPS (a B‐cell mitogen) showed no significant toxicity. Increased activity of 7 over tubercidin was observ...
36 citations
TL;DR: In this paper, the fatty acid derivative CP•4125 was synthesized to facilitate accumulation of gemcitabine, which can be inactivated by deamination catalyzed by deoxycytidine deaminase (dCDA).
Abstract: Gemcitabine is a deoxycytidine analog, which can be inactivated by deamination catalyzed by deoxycytidine deaminase (dCDA). Altered transport over the cell membrane is a mechanism of resistance to gemcitabine. To facilitate accumulation, the fatty acid derivative CP‐4125 was synthesized. Since, the fatty acid is acylated at the site of action of dCDA, a decreased deamination was expected. CP‐4125 was equally active as gemcitabine in a panel of rodent and human cell lines and in human melanoma xenografts bearing mice. In contrast to gemcitabine, CP‐4125 was not deaminated but inhibited deamination of deoxycytidine and gemcitabine. Pools of the active triphosphate of gemcitabine increased for over 20 hr after CP‐4125 exposure, while these pools decreased directly after removal of gemcitabine. In conclusion: CP‐4125 is an interesting new gemcitabine derivative.
TL;DR: The results show that a 6‐week treatment with febuxostat is safe and well‐tolerated in the target patient population for this drug.
Abstract: The diurnal change of sUA and the effect of febuxostat on this change were investigated in 10 patients with gout and/or hyperuricemia. The diurnal sUA change after the last dose during the 4-week treatment phase (20 mg, QD) was almost the same as the pre-treatment value. Considering the dose, the AUC(obs) and Cmax of unchanged drug in patients with gout and/or hyperuricemia were estimated to be similar to those of healthy male adults. The results show that a 6-week treatment with febuxostat is safe and well-tolerated in the target patient population for this drug.
TL;DR: TFT can be taken up and activated very rapidly by FM3A cancer cells, probably due to favourable TK enzyme properties, and TPI did not influence this.
Abstract: Trifluorothymidine (TFT) can be phosphorylated by thymidine kinase (TK) to TFTMP which can inhibit thymidylate synthase (TS), resulting in depletion of thymidine nucleotides. TFT can be degraded by thymidine phosphorylase (TP) which can be inhibited by thymidine phosphorylase inhibitor (TPI). Using the TS in situ Inhibition Assay (TSIA) FM3A breast cancer cells were exposed 4 h or 24 h to TFT and 5‐Fluorouracil (5FU). TS activity reduced to 9% (0.1 µM TFT) and 58% (1 µM 5FU) after 4 h exposure and to 6% (TFT) and 21% (5FU) after 24 h exposure. TPI did not affect TS inhibition by TFT. FM3A cells lacking TK or TS activity (FM3A/TK−) were far less sensitive to TFT compared to FM3A cells. Conclusion: TFT can be taken up and activated very rapidly by FM3A cancer cells, probably due to favourable TK enzyme properties, and TPI did not influence this.
TL;DR: A partial dihydropyrimidinase deficiency proved to be a novel pharmacogenetic disorder associated with severe 5FU toxicity and patients with a (partial) diHydropyrimidine dehydrogenase deficiency proving to be at risk of developing severe toxicity after the administration of 5FU.
Abstract: 5‐Fluorouracil (5FU) remains one of the most frequently prescribed chemotherapeutic drugs for the treatment of cancer. Recently, the pivotal role of the catabolic pathway of 5FU in the determination of toxicity towards 5FU has been highlighted. Patients with a (partial) dihydropyrimidine dehydrogenase deficiency proved to be at risk of developing severe toxicity after the administration of 5FU. A partial dihydropyrimidinase deficiency proved to be a novel pharmacogenetic disorder associated with severe 5FU toxicity.
TL;DR: Analysis of the gene encoding PNP in patients with PNP deficiency reveals several recurring mutations, and identification of these hot‐spots for mutation may allow faster confirmation of the diagnosis in suspected cases.
Abstract: Purine nucleoside phosphorylase (PNP) deficiency results in severe immune dysfunction and early death from infections. Lymphopenia, reduced serum uric acid, and abnormal PNP enzymatic activity assist in the diagnosis of PNP‐deficient patients. Analysis of the gene encoding PNP in these patients reveals several recurring mutations. Identification of these hot‐spots for mutation may allow faster confirmation of the diagnosis in suspected cases. Other polymorphisms have recently been described (Yu, L., Kalla, K., Guthrie, E., Vidrine, A., Klimecki, W.T.; Genetic variation in genes associated with arsenic metabolism: glutathione S‐transferase omega 1‐1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans. Environ. Health. Perspect. 2003, 111, 1421–1427).
TL;DR: Six new examples of intercalating nucleic acids were synthesized in order to evaluate the dependence of the length of the linker between oligo and intercalator on the thermal stability of their corresponding duplexes and triplexes.
Abstract: Six new examples of intercalating nucleic acids were synthesized in order to evaluate the dependence of the length of the linker between oligo and intercalator on the thermal stability of their corresponding duplexes and triplexes.
TL;DR: Lipophillic prodrugs were synthesized to facilitate uptake of the hydrophilic drug ara‐C, and the compounds with the shortest fatty‐acid group and highest number of double bonds were the more active.
Abstract: Resistance to, the hydrophilic drug ara‐C, might be meditated by decreased membrane transport. Lipophillic prodrugs were synthesized to facilitate uptake. These compounds were equally active as ara‐C, while the compounds with the shortest fatty‐acid group and highest number of double bonds were the more active. These compounds also show a better retention profile, their effect is retained longer than for ara‐C.
TL;DR: The HPMPO‐, PMEO‐ and PMPO‐DAPym derivatives represent a novel well‐defined subclass among the acyclic nucleoside phosphonates endowed with potent and selective antiviral activity.
Abstract: Acyclic nucleoside phosphonate derivatives containing a pyrimidine base preferably bearing amino groups at C‐2 and C‐4 (DAPym), and linked at the C‐6 position to (S)‐[3‐hydroxy‐2‐(phosphonomethoxy)propoxy] (HPMPO), 2‐(phosphonomethoxy) ethoxy (PMEO) or (R)‐[2‐(phosphonomethoxy)propoxy] (PMPO), display an antiviral sensitivity spectrum that closely mimic that of the parental (S)‐HPMP‐, PME‐ and (R)‐PMP‐purine derivatives. Several PMEO‐DAPym derivatives proved as potent as PMEA (adefovir) and (R)‐PMPA (tenofovir) in inhibiting Moloney murine sarcoma virus (MSV)‐induced tumor formation in newborn NMRI mice. The HPMPO‐, PMEO‐ and PMPO‐DAPym derivatives represent a novel well‐defined subclass among the acyclic nucleoside phosphonates endowed with potent and selective antiviral activity.
TL;DR: A series of azole nucleoside 5′‐MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises, demonstrating substantial IMPDH inhibition with Ki values in low micromolar range.
Abstract: IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5′‐MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient. In order to bypass cellular phosphorylation, a series of azole nucleoside 5′‐MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises. P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with Ki values in low micromolar range. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
TL;DR: Inhibition of p‐glycoprotein (PGP) expression and reverse of multidrug resistance (MDR) phenotype in KB‐8‐5 cells by synthetic 21‐bp double‐stranded oligoribonucleotides were investigated.
Abstract: Inhibition of p‐glycoprotein (PGP) expression and reverse of multidrug resistance (MDR) phenotype in KB‐8‐5 cells by synthetic 21‐bp double‐stranded oligoribonucleotides were investigated. siRNA constructs for the efficient down regulation of MDR1 that are active in nanomolar concentrations and cause reversal of MDR phenotype in cells were developed.
TL;DR: The new fluorinated pyrimidine derivative 16 that is phosphorylated by HSV‐1 TK could be developed as non‐toxic PET‐tracer molecule.
Abstract: Synthesis of pyrimidine derivatives with a side‐chain attached to the C‐6 of pyrimidine ring (6–14) is reported. Target compounds 8 and 12 were subjected to in vitro phosphorylation tests, determination of their binding affinities to herpes simplex virus (HSV‐1) thymidine kinase (TK) and catalytic turnover constants. Fluorinated pyrimidine derivative 12 (40 µM) exhibited better binding affinity for HSV‐1 TK than acyclovir (ACV, 170 µM) and ganciclovir (GCV, 48 µM). Catalytic turnover constant (k cat) of 12 (0.08 s− 1) was close to the k cat values of ACV (0.10 s− 1) and GCV (0.10 s− 1). Furthermore, compounds 8 and 12 showed no cytotoxic effects in HSV‐1 TK‐transduced and non‐transduced cell lines. Besides, compounds 8 and 12 did not exhibit antiviral or cytostatic activities against several viruses and malignant tumor cell lines that were evaluated. The new fluorinated pyrimidine derivative 16 that is phosphorylated by HSV‐1 TK could be developed as non‐toxic PET‐tracer molecule. Thus, 18F labelling of t...
TL;DR: Treatment of sugar‐protected 2‐N‐trityl derivatives of guanosine and 2‐deoxyguanosine with imidazole/triphenylphosphine/iodine/ethyldiisopropylamine gives the corresponding 6‐(imidazol‐1‐yl)‐2‐(tritylamino)purine nucleosides and 2′‐deoxynucleosides.
Abstract: Treatment of sugar‐protected 2‐N‐trityl derivatives of guanosine and 2′‐deoxyguanosine with imidazole/triphenylphosphine/iodine/ethyldiisopropylamine gives the corresponding 6‐(imidazol‐1‐yl)‐2‐(tritylamino)purine nucleosides. SNAr displacement of the imidazole moiety with nucleophiles provides 2‐amino‐6‐substituted‐purine nucleosides and 2′‐deoxynucleosides. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend. #This paper is: Nucleic Acid Related Compounds, 122. Paper 121 is Ref. 1.
TL;DR: QSAR analysis has revealed that binding affinity of the adenine nucleosides upon interaction with ADA depends on the molecular volume, dipole moment of the molecule, electric charge around the N1 atom, and the highest of positive charge for the related molecules.
Abstract: The kinetic parameters of adenosine deaminase such as Km and Ki were determined in the absence and presence of adenine derivatives (R1–R24) in sodium phosphate buffer (50 mM; pH 7.5) solution at 27°C. These kinetic parameters were used for QSAR analysis. As such, we found some theoretical descriptors to which the binding affinity of adenosine deaminase (ADA) towards several adenine nucleosides as inhibitors is correlated. QSAR analysis has revealed that binding affinity of the adenine nucleosides upon interaction with ADA depends on the molecular volume, dipole moment of the molecule, electric charge around the N1 atom, and the highest of positive charge for the related molecules.
TL;DR: It is hypothesized that the increased levels of intracellular thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in turn, lead to the mtDNA abnormalities.
Abstract: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). The disease is characterized clinically by impaired eye movements, gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, and leukoencephalopathy. Molecular genetic studies of MNGIE patients' tissues have revealed multiple deletions, depletion, and site-specific point mutations of mitochondrial DNA. TP is a cytosolic enzyme required for nucleoside homeostasis. In MNGIE, TP activity is severely reduced and consequently levels of thymidine and deoxyuridine in plasma are dramatically elevated. We have hypothesized that the increased levels of intracellular thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in turn, lead to the mtDNA abnormalities. MNGIE was the first molecularly characterized genetic disorder caused by abnormal mitochondrial nucleoside/nucleotide metabolism. Future studies are likely to reveal further insight into this expanding group of diseases.
TL;DR: The results obtained indicate that promoter hypermethylation of a number of marker genes represents a promising serum marker for early breast and lung cancer detection.
Abstract: The frequency of APC, RASSF1A, RARbeta, CDH1 and CDH13 gene promoter methylation in samples of DNA isolated from breast and lung patient plasma was studied in order to develop the noninvasive tumor-specific DNA detection method. Methylation of at least one of genes was detected in extracellular DNA from most of the cancer blood specimens. The results obtained indicate that promoter hypermethylation of a number of marker genes represents a promising serum marker for early breast and lung cancer detection.
TL;DR: Variation in the level of thiopurine methyltransferase (TPMT) activity appears to be a major molecular determinant of the extent ofThiopurines metabolism, and single nucleotide polymorphisms within the TPMT gene have been identified.
Abstract: Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood. Although current treatment results in long term survival in over 70% of cases there is evidence that as many as 50% could have been cured using a less complex regimen with a lower incidence of long term side effects. In previous studies it has been found that thiopurines given as part of continuing therapy are key agents in preventing relapse. However, optimal administration during continuing therapy is often not achieved. Variation in the level of thiopurine methyltransferase (TPMT) activity appears to be a major molecular determinant of the extent of thiopurine metabolism. TPMT activity shows a trimodal distribution pattern. A lack of activity is found in approximately one in 300 Caucasians; approximately 11% have intermediate activity and the remaining 89% high activity. Congenital loss of activity is associated with grossly elevated levels of active drug and profound myelosuppression on exposure to thiopurines. This loss o...
TL;DR: FdUMP[N] molecules and conjugates are much more effective at inhibiting the proliferation of human tumor cells than is the widely used anticancer drug 5‐fluorouracil (5FU).
Abstract: FdUMP[N] molecules and conjugates are much more effective at inhibiting the proliferation of human tumor cells than is the widely used anticancer drug 5-fluorouracil (5FU). We have evaluated the inhibition of thymidylate synthase (TS), the extent of DNA damage, cell cycle arrest, and the induction of apoptosis by FdUMP[10] and 5FU in the human colorectal cancer cell line HT29. The magnitude and duration of TS inhibition following exposure of HT29 cells to FdUMP[10] at 1 x 10(-8) M was greater than that which occurred following exposure of these cells to 5FU at 1 x 10(-6) M. FdUMP[10] exposure also resulted in much more extensive DNA damage to HT29 cells than occurred following exposure to 100-fold higher concentrations of 5FU. Although exposure of HT29 cells to both drugs resulted in S-phase arrest, more complete accumulation of cells in S-phase was achieved following FdUMP[10] exposure at much lower drug concentrations. FdUMP[10] was also much more effective at inducing apoptosis in HT29 cells than was 5FU. The results are consistent with FdUMP[10] being much more efficient that 5FU at inducing DNA damage that results in apoptotic cell death in colon cancer cells.
TL;DR: An efficient total synthesis of triciribine, a tricyclic nucleoside with antineoplastic and antiviral properties, starting from 4‐amino‐6‐bromo‐5‐cyanopyrrolo[2,3‐d]pyrimidine is described.
Abstract: We describe an efficient total synthesis of triciribine, a tricyclic nucleoside with antineoplastic and antiviral properties, starting from 4‐amino‐6‐bromo‐5‐cyanopyrrolo[2,3‐d]pyrimidine. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
TL;DR: Powerful inhibitors of PNP have been designed from the experimental determination of the transition state structure of PNPs with K d values as low as 7 pM, and the Immucillins are orally available and of low toxicity to mice.
Abstract: The genetic deficiency of human PNP causes a specific immunodeficiency by inducing apoptosis in dividing T-cells. Powerful inhibitors of PNP have been designed from the experimental determination of the transition state structure of PNPs. The Immucillins are transition state analogue inhibitors with Kd values as low as 7 pM. In the presence of deoxyguanosine the Immucillins kill activated human T-cells but not other cell types. The Immucillins are orally available and of low toxicity to mice. Immucillins also inhibit PNP from Plasmodium falciparum. Parasites cultured in human erythrocytes are killed by purine starvation in the presence of Immucillins and can be rescued by hypoxanthine.
TL;DR: A novel improvement to SSOH is described that incorporates an additional mismatch into the oligonucleotide probe using the universal base analogue 3‐nitropyrrole, which greatly increases allelic differentiation compared to standard SSOH, which contains only SNP‐defining base changes.
Abstract: Sequence-specific oligonucleotide hybridization (SSOH, 'dot-blotting') is a widely employed method of typing single nucleotide polymorphisms (SNPs), but it is often compromised by lack of allelic differentiation. We describe a novel improvement to SSOH that incorporates an additional mismatch into the oligonucleotide probe using the universal base analogue 3-nitropyrrole. This method greatly increases allelic differentiation compared to standard SSOH where oligonucleotides contain only SNP-defining base changes. Moreover, stringency of the hybridisation is predictably maintained over a wide range of temperatures, which can be calculated empirically, thus facilitating the genotyping of multiple SNPs using similar conditions. This improved method increases the usefulness of hybridisation-based methods of rapid genotyping of SNPs and may have implications for array methodologies.