interacts_with DB01037?
P04035 inhibitor cerivastatin inhibits interleukin-6 expression and secretion in human adipocytes . Human adipose tissue is a main contributor to plasma levels of pro-inflammatory cytokine P05231 . How P05231 expression is regulated in adipocytes remains unclear . In the current study , we investigated the effect of the P04035 inhibitor , cerivastatin , on the production of P05231 from cultured human adipocytes . DB00439 reduced both P05231 mRNA and secretion in a dose- and time-dependent manner . The inhibitory effect on P05231 mRNA was prevented by the intermediates of the cholesterol synthesis pathway , mevalonate and geranyl-geranyl-phyrophosphate ( GGPP ) but not by farnesyl-pyrophosphate . This suggests the involvement of geranylgeranyl-modified intermediates in the effect of cerivastatin on P05231 . Moreover , cerivastatin induced an inactivation of the phosphorylation of the p65 subunit of NFkappaB which was prevented by GGPP . Our data suggest that cerivastatin exerts an anti-inflammatory effect by down-regulating P05231 levels in adipocytes , which seems to be mediated by reduced production of GGPP and interference with the NFkappaB pathway . Management of ocular inflammation and pain following cataract surgery : focus on bromfenac ophthalmic solution . Recently , several new ophthalmic NSAID products have been introduced for commercial use in the United States . The purpose of this review is to briefly overview the ophthalmic NSAIDs currently in use and to discuss the management of postoperative ocular inflammation and pain following cataract surgery with a particular focus on bromfenac ophthalmic solution 0.09 % . DB00963 ophthalmic solution 0.09 % is indicated for the reduction of ocular pain and inflammation following cataract surgery . Studies have shown that bromfenac ophthalmic solution 0.09 % has equivalent efficacy to the other topical NSAIDs in reducing postsurgical inflammation and controlling pain . The unique chemical structure of bromfenac makes it both a potent inhibitor of the P35354 enzyme and a highly lipophilic molecule that rapidly penetrates to produce early and sustained drug levels in all ocular tissues . Clinically , these pharmacokinetic features are manifested in a rapid reduction of postsurgical inflammation and pain with bid dosing . DB00963 ophthalmic solution 0.09 % is a versatile agent and is effective when used as either monotherapy or as an adjunct therapy to steroids . Interaction of early environment , gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort . Objectives Depression is a worldwide leading cause of morbidity and disability . Genetic studies have recently begun to elucidate its molecular aetiology . The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 ( 12 058 live births ) . Design The authors ascertained and subdivided the study sample ( n=5225 ) based on measures of early development and of social environment , and examined candidate genes of monoamine neurotransmission , many of which have shown prior evidence of a gene-environment interaction for affective disorders , namely P31645 , Q8IWU9 , P21964 , P21397 and the dopamine receptor genes P21728 - P21918 . Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness . However , when measures of early development and of social environment were considered , some evidence of interaction was observed . Allelic variants of P21964 interacted with high early developmental risk ( p=0.005 for rs2239393 and p=0.02 for rs4680 ) so that the association with depression was detected only in individuals at high developmental risk group ( p=0.0046 and β=0.056 for rs5993883-rs2239393-rs4680 risk haplotype CGG including Val158 ) , particularly in males ( p=0.0053 and β=0.083 for the haplotype CGG ) . Rs4274224 from P14416 interacted with gender ( p=0.017 ) showing a significant association with depressiveness in males ( p=0.0006 and β=0.0023 ; p=0.00005 and β=0.069 for rs4648318-rs4274224 haplotype GG ) . The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex , but not direct major effects of monoaminergic genes in this unselected population . DB00158 and thiamine transporters mediated by facilitative carriers ( P41440 -3 and Q96NT5 ) and folate receptors . The reduced folate carrier ( P41440 , P41440 ) , thiamine transporter-1 ( O60779 , O60779 ) and thiamine transporter-2 ( Q9BZV2 , Q9BZV2 ) evolved from the same family of solute carriers . P41440 transports folates but not thiamine . O60779 and Q9BZV2 transport thiamine but not folates . P41440 and O60779 deliver their substrates to systemic tissues ; Q9BZV2 mediates intestinal thiamine absorption . The proton-coupled folate transporter ( Q96NT5 , Q96NT5 ) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine . Two folate receptors ( P15328 and P14207 ) mediate folate transport across epithelia by an endocytic process . DB00158 transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases . There are autosomal recessive disorders associated with mutations in genes encoded for Q96NT5 ( hereditary folate malabsorption ) , P15328 ( cerebral folate deficiency ) , O60779 ( thiamine-responsive megaloblastic anemia ) , and Q9BZV2 ( biotin-responsive basal ganglia disease ) . P12004 -dependent kinase 5 is associated with risk for Alzheimer 's disease in a Dutch population-based study . Although the role of the Cdk5 protein in Alzheimer 's disease ( AD ) is well recognized , there have been relatively few studies investigating genetic variants in the Q00535 gene in AD . In this study , we assessed the association between five previously described single nucleotide polymorphisms ( SNPs ) in the Q00535 gene and late onset AD by means of logistic regression and haplotype association analyses . Including all prevalent and incident AD cases , we found a significantly increased risk of AD for carriers of the GG genotype of SNP rs2069442 ( OR = 1.79 , 95 % CI 1.16-2.79 , p = 0.001 ) in those without P02649 *4 . When limiting the analysis to incident cases without P02649 *4 , carriers of the GG genotype showed a 1.9-fold increased risk of AD ( 95 % CI 1.16-3.10 , p = 0.003 ) . Variations in the Q00535 gene can be described in 5 haplotype blocks . In our analysis , the haplotype tagged by the G allele of SNP rs2069442 was significantly associated with AD ( p = 0.05 ) . In conclusion , our study suggests that Q00535 may be associated with AD . Biological characterization of DB05037 , a small-molecule inhibitor of cyclin-dependent kinases , in human tumor cell lines . P12004 -dependent kinases ( CDK ) , and their regulatory cyclin partners , play a central role in eukaryotic cell growth , division , and death . This key role in cell cycle progression , as well as their deregulation in several human cancers , makes them attractive therapeutic targets in oncology . A series of CDK inhibitors was developed using Astex 's fragment-based medicinal chemistry approach , linked to high-throughput X-ray crystallography . A compound from this series , designated DB05037 , is currently in early-phase clinical development . We describe here the biological characterization of DB05037 , a potent inhibitor of several CDK family members . DB05037 showed potent antiproliferative activity ( 40-940 nmol/L ) in a panel of human tumor cell lines , and the mechanism of action was shown here to be consistent with the inhibition of P06493 and P24941 in solid tumor cell lines . DB05037 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models . Tumor regression was observed following twice daily dosing of DB05037 in the HCT116 and HT29 colon cancer xenograft models . We show that these biological effects are linked to inhibition of CDKs in vivo and that DB05037 induces tumor cell apoptosis in these xenograft models . DB05037 has an attractive biological profile for development as a clinical candidate , and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development . Studies described here formed the biological rationale for investigating the potential therapeutic benefit of DB05037 in cancer patients . P05231 ( P05231 ) and/or soluble P05231 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the P02458 promoter . Type II collagen is composed of alpha1(II) chains encoded by the P02458 gene . Alteration of this cartilage marker is a common feature of osteoarthritis . P05231 ( P05231 ) is a pro-inflammatory cytokine that needs a soluble form of receptor called sIL-6R to exert its effects in some cellular models . In that case , sIL-6R exerts agonistic action . This mechanism can make up for the partial or total absence of membrane-anchored P05231 receptors in some cell types , such as chondrocytes . Our study shows that P05231 , sIL-6R , or both inhibit type II collagen production by rabbit articular chondrocytes through a transcriptional control . The cytokine and/or sIL-6R repress P02458 transcription by a -63/-35 sequence that binds Sp1.Sp3 . Indeed , P05231 and/or sIL-6R inhibit Sp1 and Sp3 expression and their binding activity to the 63-bp promoter . In chromatin immunoprecipitation experiments , P05231 .sIL-6R induced an increase in Sp3 recruitment to the detriment of Sp1 . Knockdown of Sp1.Sp3 by small interference RNA and decoy strategies were found to prevent the P05231 - and/or sIL-6R-induced inhibition of P02458 transcription , indicating that each of these Sp proteins is required for down-regulation of the target gene and that a heterotypic Sp1.Sp3 complex is involved . Additionally , Sp1 was shown to interact with Sp3 and Q13547 . Indeed , overexpression of a full-length Sp3 cDNA blocked the Sp1 up-regulation of the 63-bp P02458 promoter activity , and by itself , inhibits P02458 transcription . We can conclude that P05231 , sIL-6R , or both in combination decrease both the Sp1.Sp3 ratio and DNA-binding activities , thus inhibiting P02458 transcription . Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual 's response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome . Aberrant accentuation of neurofibrillary degeneration in the hippocampus of Alzheimer 's disease with amyloid precursor protein 717 and presenilin-1 gene mutations . This study reports correlation of the hippocampal neurofibrillary tangles ( NFT ) density with beta-amyloid ( Abeta ) precursor protein ( P05067 ) 717 mutation , presenilin ( PS ) -1 mutation and apolipoprotein E ( P02649 ) e4 alleles ( E4 ) , being graded as 3 forms ( no-E4 , one-E4 and two-E4 ) in autopsied brains from patients with familial and non-familial Alzheimer 's disease ( AD ) . We studied the density of NFT-free neurons , intracellular NFT ( I-NFT ) , extracellular NFT ( E-NFT ) and total NFT ( I-NFT plus E-NFT ) in the six hippocampal subdivisions : cornu ammonis ( CA ) 1- P22748 , subiculum and entorhinal cortex . The P05067 mutation cases showed significantly higher total NFT density in the P00915 - P00918 region , and the P49768 mutation cases also showed higher density of total NFT in the P00915 - P07451 than non-familial cases . Moreover , high densities of the E-NFT contributed to these high total NFT densities . Non-familial AD cases showed a stereotypical NFT distribution with entorhinal accentuation in the hippocampus irrespective of E4 frequency . Thus , P05067 and P49768 mutations predominantly affect the CA regions with profound neurodegeneration , which contributes early and severe clinical features of familial AD . Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection . Alphaviruses , including Venezuelan Equine Encephalitis Virus ( VEEV ) , cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases . Features of the host immune response and tissue-specific responses may contribute to fatal outcomes as well as the development of encephalitis . It has previously been shown that VEEV infection of mice induces transcription of pro-inflammatory cytokines genes ( e.g. , IFN-γ , P05231 , IL-12 , P35228 and P01375 -α ) within 6 h . GSK-3β is a host protein that is known to modulate pro-inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer 's . Hence inhibition of GSK-3β in the context of encephalitic viral infections has been useful in a neuroprotective capacity . Small molecule GSK-3β inhibitors and GSK-3β siRNA experiments indicated that GSK-3β was important for VEEV replication . Thirty-eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor , with an IC(50) of ∼0.5 µM and a CC(50) of > 100 µM . BIOder was a more potent inhibitor of GSK-3β than BIO , as demonstrated through in vitro kinase assays from uninfected and infected cells . Size exclusion chromatography experiments demonstrated that GSK-3β is found in three distinct complexes in VEEV infected cells , whereas GSK-3β is only present in one complex in uninfected cells . Cells treated with BIOder demonstrated an increase in the anti-apoptotic gene , survivin , and a decrease in the pro-apoptotic gene , P55957 , suggesting that modulation of pro- and anti-apoptotic genes contributes to the protective effect of BIOder treatment . Finally , BIOder partially protected mice from VEEV induced mortality . Our studies demonstrate the utility of GSK-3β inhibitors for modulating VEEV infection . DB01037 transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson 's disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine-restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg/24 hours , tyramine dietary restrictions are not needed . Short-term treatment with fixed ( 6 mg/24 hours ) or flexible ( 6 , 9 or 12 mg/24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6- or 8-week , randomised , double-blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long-term treatment with a fixed dose of selegiline transdermal system 6 mg/24 hours was superior to placebo as maintenance therapy in a 52-week , randomised , double-blind , multicentre , relapse-prevention trial in patients with MDD . DB01037 transdermal system therapy was generally well tolerated in placebo-controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo . Attenuation of fever at near term : is interleukin-6- P40763 signalling altered ? Pregnant rats in late gestation show a reduced fever response after stimulation with lipopolysaccharide ( LPS ) . This can result from either an increased action of endogenous antipyretics or a reduction in the production or action of endogenous pyrogens . Nonpregnant rats given LPS release interleukin ( IL ) -6 , which causes nuclear translocation of the signal transducer and activator of transcription 3 ( P40763 ) in the vascular organ of the lamina terminalis ( OVLT ) , followed by a significant increase in core body temperature . The present study investigated whether the reduced fever response in near-term pregnant rats is associated with a reduced nuclear P40763 response . Rats at gestation day 15 ( Q99943 ) , gestation day 21 ( Q96NT5 , near term ) and at lactation day 5 ( Q15004 ) were injected with LPS ( 50 microg/kg , i.p. ) or vehicle . Only near-term pregnant rats responded with an attenuated body temperature during the fever response . Immunohistological analysis indicated no significant difference in nuclear P40763 in the OVLT of the different animal groups 2 h after LPS . Measurement of total and phosphorylated P40763 protein in the OVLT with semiquantitative western blot revealed no significant differences of this protein among these immune challenged animal groups . P05231 concentrations were also similar at Q99943 , Q96NT5 and Q15004 2 h after injection of LPS . These results lead to the conclusion that the attenuation of the fever response at near-term pregnancy is not associated with a reduced amount of nuclear P40763 in the OVLT , indicating a maintained P05231 - P40763 signalling pathway in the OVLT . Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone . The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system . The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission , mainly by blockade of D(2) dopamine receptors . N-methyl-D-aspartate ( DB01221 ) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 ( P48067 ) inhibitors , which regulate glycine concentrations at the vicinity of DB01221 receptors . Combined drug administration with P14416 blockade and activation of hypofunctional DB01221 receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia . To investigate this type of combined drug administration , rats were treated with the atypical antipsychotic risperidone together with the P48067 inhibitor Org-24461 . Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine , DOPAC , HVA , glycine , glutamate , and serine concentrations were carried out using HPLC/electrochemistry . DB00734 increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples . Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed . When risperidone and Org-24461 were added in combination , a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels . Interestingly , the extracellular concentrations of glutamate were also enhanced . Our data indicate that coadministration of an antipsychotic with a P48067 inhibitor may normalize hypofunctional DB01221 receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication . Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL-1A , IL-1B , IL-1RN , IL-1R1 , P05231 , P10145 , P22301 , P41159 , Le , L-myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF-B , P01375 -A , P01375 -B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C/T at intron 2 and G2502T , IL-1A 46-bp VNTR , IL-1R1 C-116T , P05231 Ins/Del 17C , P10145 A-278T and C74T , IL- 10 T-819C , P41159 A-2548G , P31213 2-bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL-1B C-31T and IL-1A C-889T , IL-1B C-31T and IL-1RN 86-bp VNTR , IL-1B C-31T and IL-1R1 C-116T , P01375 -A G-308A and P01375 -B A252G , P31213 Val89Leu and 2-bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose . Discovery of ( 2E ) -3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide ( DB05223 ) , an orally active histone deacetylase inhibitor with a superior preclinical profile . A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides ( 1 ) were designed and synthesized as HDAC inhibitors . Extensive SARs have been established for in vitro potency ( Q13547 enzyme and COLO 205 cellular IC(50) ) , liver microsomal stability ( t(1/2) ) , cytochrome P450 inhibitory ( 3A4 IC(50) ) , and clogP , among others . These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring . After comprehensive in vitro and in vivo profiling of the selected compounds , DB05223 ( 3 ) was identified as a preclinical development candidate . 3 is a potent pan-HDAC inhibitor with excellent druglike properties , is highly efficacious in in vivo tumor models ( HCT-116 , PC-3 , A2780 , MV4-11 , Ramos ) , and has high and dose-proportional oral exposures and very good ADME , safety , and pharmaceutical properties . When orally dosed to tumor-bearing mice , 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action . 3 is currently being tested in phase I and phase II clinical trials . Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide : molecular basis of isozyme-drug discrimination . P22748 ( CAIV ) is a membrane-associated enzyme anchored to plasma membrane surfaces by a phosphatidylinositol glycan linkage . We have determined the 2.8-angstroms resolution crystal structure of a truncated , soluble form of recombinant murine CAIV . We have also determined the structure of its complex with a drug used for glaucoma therapy , the sulfonamide inhibitor brinzolamide ( DB01194 ) . The overall structure of murine CAIV is generally similar to that of human CAIV ; however , some local structural differences are found in the active site resulting from amino acid sequence differences in the " 130 's segment " and the residue-63 loop ( these may affect the nearby catalytic proton shuttle , DB00117 -64 ) . Similar to human CAIV , the C-terminus of murine CAIV is surrounded by a substantial electropositive surface potential that may stabilize the interaction with the phospholipid membrane . Binding interactions observed for brinzolamide rationalize the generally weaker affinity of inhibitors used in glaucoma therapy toward CAIV compared with CAII . Effect of licofelone -- a dual P36551 /5- P28300 inhibitor in intracerebroventricular streptozotocin-induced behavioral and biochemical abnormalities in rats . The present study was designed to investigate the effect of licofelone-a dual cyclooxygenase/ P09917 ( P36551 /5- P28300 ) inhibitor in intracerebroventricular streptozotocin ( ICV- Q11206 ) -induced cognitive deficit and biochemical abnormalities in rats . ICV- Q11206 is a widely used model of sporadic Alzheimer 's disease . In this study , Q11206 was administered intracerebroventricular (i.c.v.)-bilaterally 3 mg/kg in rats . The Q11206 -injected rats were treated with different doses of licofelone ( 2.5 , 5 , and 10 mg/kg , p.o. ) for 21 days . Cognitive functions were assessed by using Morris water maze and passive avoidance task . Levels of malondialdehyde ( MDA ) , nitrite , reduced glutathione ( DB00143 ) , and acetylcholinesterase ( P22303 ) activity were determined to check oxidative stress and cholinergic function . Cytokine levels ( IL-1β and P01375 -α ) were also determined as markers of neuroinflammation . Administration of Q11206 caused a significant increase in P22303 activity and cognitive dysfunction . Increased oxidative stress and the proinflammatory cytokine levels were also observed following Q11206 administration in rats . DB04725 treatment attenuated Q11206 -induced cholinergic hypofunction and cognitive deficit in rats . In addition , licofelone attenuated Q11206 -induced oxidative stress and elevated cytokine levels . The cognitive enhancement following licofelone administration in Q11206 rats may be due to its ability to restore cholinergic functions or its antioxidant activity . These observed results suggest the therapeutic potential of dual P36551 /5- P28300 inhibitors in neurodegenerative disorders associated with oxidative stress and cognitive impairment . Clinical development of eniluracil : current status . DB03516 is a potent inactivator of dihydropyrimidine dehydrogenase ( Q12882 ) , which is the first enzyme in the degradative pathway of systemically administered 5-fluorouracil ( DB00544 ) . Two completely oral regimens of eniluracil plus DB00544 are being evaluated in clinical trials : ( 1 ) a chronic schedule with both agents administered P55957 in a 10:1 ratio for 28 days of a 5-week course , and ( 2 ) a 5-day schedule of eniluracil once daily on days 1 through 7 and DB00544 once daily on days 2 through 6 . The clinical development of eniluracil is being pursued in several tumor types , including colorectal cancer , breast cancer , and pancreatic cancer . Response rates achieved in a phase II study of the chronic schedule of oral eniluracil/ DB00544 in patients with colorectal cancer compare favorably with those obtained in trials of intravenous DB00544 and leucovorin , while results from other trials are awaited . Safety analysis for the 28-day schedule has revealed a low incidence of severe toxicities , particularly as compared with standard DB00544 regimens .