interacts_with DB00762?
ABT-737 is highly effective against molecular subgroups of multiple myeloma . Multiple myeloma is a plasma cell malignancy that is heterogeneous with respect to its causative molecular abnormalities and the treatment response of patients . The Bcl-2 protein family is critical for myeloma cell survival . ABT-737 is a cell-permeant compound that binds to Bcl-2 and Bcl-x(L) but not to Mcl-1 . Using a myeloma cell line collection ( n = 25 ) representative of different molecular translocations , we showed that ABT-737 effectively kills a subset of cell lines ( n = 6 ) , with a median lethal dose ranging from 7 ± 0.4 nM to 150 ± 7.5 nM . Of interest , all sensitive cell lines harbored a t(11;14) . We demonstrated that ABT-737-sensitive and ABT-737-resistant cell lines could be differentiated by the P10415 / Q07820 expression ratio . A screen of a public expression database of myeloma patients indicates that the P10415 / Q07820 ratio of t(11;14) and hyperdiploid patients was significantly higher than in all other groups ( P < .001 ) . ABT-737 first induced the disruption of Bcl-2/Bax , Bcl-2/Bik , or Bcl-2/Puma complexes , followed by the disruption of Bcl-2 heterodimers with Bak and Bim . Altogether , the identification of a subset of cell lines and primary cells effectively killed by ABT-737 alone supported the evaluation of DB05764 , an orally active counterpart to ABT-737 , for the treatment of t(11;14) and hyperdiploid groups of myeloma harboring a Bcl-2(high)/Mcl-1(low) profile . Inhibition of the invasion capacity of carcinoma cells by DB05476 , a novel synthetic inhibitor of the urokinase-type plasminogen activator system . The overall survival rate of patients suffering from carcinomas has remained poor and nearly unchanged over the last decades . This is mainly due to the so-called minimal residual disease , i.e. , remaining tumor cells that overcome surgery and/or radiotherapy and are the cause of locoregional and distant metastases . To metastasize , tumor cells take advantage of proteases to invade and remodel surrounding tissues . Here , we analyzed the efficiency of DB05476 , a novel 3-amidinophenylalanine-based inhibitor of the uPA system , at inhibiting the invasive capacity of carcinoma cells . First , Q03405 expression was characterized in different carcinoma cell lines , including SCCHN , breast and cervical carcinoma . Thereafter , the invasive potential of these cell lines was determined using Matrigel invasion chambers and a spheroid cocultivation model with human fibroblasts . Q03405 expression levels correlated positively with invasion capacity , which could be significantly inhibited by DB05476 . A decrease of tumor cell invasion by up to 50 % was achieved in both models with the SCCHN line FaDu and the cervical carcinoma line HeLa after treatment with DB05476 . Thus , our results demonstrate the potential of DB05476 in vitro as a promising adjuvant antimetastatic therapy of carcinomas . An overview of phenserine tartrate , a novel acetylcholinesterase inhibitor for the treatment of Alzheimer 's disease . Existing cholinesterase ( ChE ) inhibitor therapies for Alzheimer 's disease ( AD ) , while effective in improving cognitive , behavioral and functional impairments , do not alter disease progression . Novel drug design studies have focused on the classical ChE inhibitor , (-)-physostigmine , producing alterations in chemical composition and three-dimensional structure , which may offer an improved therapeutic index . The phenylcarbamate derivative , DB04892 , is a selective , non-competitive inhibitor of acetylcholinesterase ( P22303 ) . In vivo , DB04892 produces rapid , potent , and long-lasting P22303 inhibition . As a possible result of its preferential brain selectivity , DB04892 is significantly less toxic than (-)-physostigmine . In studies using the Stone maze paradigm , DB04892 has been shown to improve cognitive performance in both young learning-impaired and elderly rats . In addition to reducing inactivation of acetylcholine in the brain , DB04892 appears to have a second mode of action . Reduced secretion of beta-amyloid ( Abeta ) has been observed in cell lines exposed to DB04892 , occurring through translational regulation of beta-amyloid precursor protein ( beta- P05067 ) mRNA via a non-cholinergic mechanism . These in vitro findings appear to translate in vivo into animal models and humans . In a small study of patients with AD , DB04892 treatment tended to reduce beta- P05067 and Abeta levels in plasma samples . Clinical studies also reveal that DB04892 ( 5-10 mg b.i.d. ) had a favorable safety and pharmacological profile , produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks . Further randomized , double-blind , placebo-controlled Phase III studies assessing the efficacy , safety/tolerability and potential disease-modifying effects of DB04892 in patients with AD are currently ongoing . Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein . DB08820 is approved in the USA for the treatment of cystic fibrosis ( CF ) in patients with a G551D- P13569 mutation or one of eight other P13569 mutations . A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 ( CYP ) 2C8 , P11712 , CYP3A , and P10635 , as well as P-glycoprotein ( P-gp ) . Based on these results , a series of clinical drug-drug interaction ( DB00900 ) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of P10632 ( rosiglitazone ) , CYP3A ( midazolam ) , P10635 ( desipramine ) , and P-gp ( digoxin ) . In addition , a DB00900 study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive , as this is considered an important comedication in CF patients . The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp , but has no effect on P10632 or P10635 . DB08820 caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure . Based on these results , caution and appropriate monitoring are recommended when concomitant substrates of P11712 , CYP3A and/or P-gp are used during treatment with ivacaftor , particularly drugs with a narrow therapeutic index , such as warfarin . Assessment of partially deoxygenated deoxynojirimycin derivatives as glucosylceramide synthase inhibitors . Q16739 ( Q16739 ) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies , including type 2 diabetes . The clinical drug N-butyldeoxynojirimycin ( DB00419 ) is thought to inhibit through mimicry of its substrate , ceramide . In this work we demonstrate that , in contrast to what is proposed in this model , the P06681 -hydroxyl of the deoxynojirimycin core is important for Q16739 inhibition . Here we show that P13671 -OH appears of less important , which may set guidelines for the development of Q16739 inhibitors that have less affinity ( in comparison with DB00419 ) for other glycoprocessing enzymes , in particular those hydrolases that act on glucosylceramide . Characterization of gonadotropin-releasing hormone analogs based on a sensitive cellular luciferase reporter gene assay . A novel cellular assay for the functional characterization of agonistic and antagonistic analogs of gonadotropin-releasing hormone ( DB00644 ) was developed . This assay is based on a fusion of the c-fos immediate-early gene promoter to Photinus pyralis luciferase ( Luc ) as a reporter gene , stably transfected in a recombinant cell line expressing the human P30968 . Transcription of endogenous c-fos and fos-Luc fusion gene are transiently induced quite similar by fetal calf serum or the superagonistic analog [ D-Trp6 ] DB00644 in a selected cell line . The reporter gene was therefore used to monitor agonist-induced signaling via the human P30968 . Whereas Luc activity was induced in a dose-dependent manner by DB00644 or [ D-Trp6 ] DB00644 , different antagonistic peptides completely inhibited this stimulation . The antagonistic potency ( IC50 ) of various peptides with DB00050 and Antarelix as lead compounds in general correlated well with the binding affinity ( KD ) as determined from ligand binding experiments . The specificity of an inhibitory effect was confirmed by P30968 -independent stimulation with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate or basic fibroblast growth factor . Since this new reporter gene assay is sensitive and simple and can be performed in a microtiter plate , it will significantly facilitate screening and functional characterization of DB00644 analogs . Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects . OBJECTIVE : The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug-metabolizing enzymes , transporters , or receptors . The aim of this study was to identify genetic markers predictive of pharmacokinetics , pharmacodynamics , and adverse effects of olanzapine . METHODS : Sixty-three healthy volunteers receiving a single 5-mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine . All genetic variants were analyzed by PharmaChip , but P14416 Taq1A polymorphism was determined by real-time polymerase chain reaction . Olanzapine was measured using high-performance liquid chromatography combined with tandem mass spectrometry . The relationship of gender and polymorphisms with olanzapine pharmacokinetics , the change in prolactin levels , and the incidence of adverse effects were evaluated by multiple regression analysis . RESULTS : The pharmacokinetics of olanzapine was influenced by polymorphisms in P20815 , P21266 , and Q13224 . P01236 levels were affected by gender and polymorphisms in P14416 and 5- P28223 . Polymorphisms in P11712 , P51580 , P22309 , P08183 , and 5- P28223 were related to some adverse effects of olanzapine . CONCLUSIONS : Several polymorphisms can explain differences in the pharmacokinetics , pharmacodynamics , and safety of olanzapine in healthy subjects . Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established . Genotoxicity and induction of DNA damage responsive genes by food-borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well-done meats and fish . The most abundant are 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP ) , 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline ( MeIQx ) , 2-Amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline ( 4,8-DiMeIQx ) and 2-Amino-3-methyl-3H-imidazo[4,5-f]quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4,8-DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up-regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up-regulation of P38936 and GADD45α the cell-cycle analysis showed arrest in S-phase by PhIP and IQ , and in P55008 -phase by 4,8-DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell-cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down-regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate . A meta-analysis of antipseudomonal penicillins and cephalosporins in pediatric patients with fever and neutropenia . BACKGROUND : Antipseudomonal penicillins ( P05067 ) and antipseudomonal cephalosporins ( P25054 ) play important roles in the management of pediatric patients with fever and neutropenia ( FN ) . Our primary objective was to describe the risk of treatment failure in children treated with an P05067 or P25054 as initial empiric therapy for FN . Our secondary objectives were to compare P05067 with P25054 and third- with fourth-generation P25054 as initial empiric therapy in this population . METHODS : We performed electronic searches of Ovid Medline , EMBASE , and the Cochrane Central Register of Controlled Trials , limiting studies to prospective pediatric trials in FN in which at least 1 treatment arm consisted of an P05067 or P25054 antibiotic with or without an aminoglycoside . Data abstraction was conducted by 2 independent reviewers . RESULTS : From 7281 reviewed articles , 41 studies comprising 51 treatment regimens were included in the meta-analysis . Treatment failure , including antibiotic modification , occurred in 34 % and 41 % of patients treated with P05067 and P25054 monotherapy , respectively , and 41 % and 33 % of patients treated with P05067 - and P25054 -aminoglycoside combination therapy , respectively . There were no statistically significant differences in treatment failure including modification , mortality , or adverse events when comparing P05067 with P25054 monotherapy , P05067 with P25054 combination therapy , or third- with fourth-generation P25054 therapy . CONCLUSIONS : Our meta-analysis suggests that P05067 and P25054 monotherapy , as well as combination therapy with an aminoglycoside , are efficacious and safe therapeutic options for the empiric management of pediatric patients with FN . Specific antibiotic selection should be based on other important factors , such as cost , availability , and local epidemiologic and resistance patterns . Inhibition of innate co-receptor Q9NP99 signaling reduces P01730 (+) T cell activation and prolongs cardiac allograft survival . The innate receptor " triggering-receptor-expressed-on-myeloid-cells-1 " ( Q9NP99 ) enhances downstream signaling of " pattern recognition receptor " ( PRR ) molecules implicated in inflammatory responses . However the mechanistic role of Q9NP99 in chronic heart rejection has yet to be elucidated . We examined the effect of Q9NP99 (+) antigen-presenting cells ( P25054 ) on alloreactive P01730 (+) lymphocytes . Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice . Progressive allograft rejection of bm12-donor hearts with decreased organ function , severe vasculopathy and allograft fibrosis was evident within 4 weeks . Q9NP99 (+) CD11b(+) MHC-II(+) F4/80(+) P41597 (+) P25054 and IFNγ-producing P01730 (+) cells were detected during chronic rejection . Peptide inhibition of Q9NP99 attenuated graft vasculopathy , reduced graft-infiltrating leukocytes and prolonged allograft survival , while being accompanied by sustained low levels of P01730 (+) and CD8(+) cell infiltration . Remarkably , temporary inhibition of Q9NP99 during early immune activation was sufficient for long-term allograft survival . Mechanistically , Q9NP99 inhibition leads to reduced differentiation and proliferation of IFNγ-producing Th1 cells . In conclusion , Q9NP99 influences chronic heart rejection by regulating the infiltration and differentiation of P01730 (+) lymphocytes . [ Toxicogenetics of antiretroviral treatment ( II ) : neurotoxicity , hepatotoxicity , lactic acidosis , kidney damage , and other adverse effects of antiretroviral drugs ] . Several pharmacogenetics studies have analyzed the influence of specific genetic polymorphisms on the toxicity of antiretroviral treatment . The present review describes some of the adverse effects of antiretroviral drugs in which a genetic predisposition may be involved : efavirenz-induced neurological toxicity , generally associated with the 516G > T polymorphism of liver enzyme cytochrome P450 2B6 ( P20813 ) ; hypersensitivity reactions to nevirapine , associated with specific alleles of major histocompatibility complex , mainly the HLA- Q8IUH3 *0101 allele , which , in combination with a high P01730 lymphocyte count , has been associated with systemic reactions and hepatitis in Caucasians , and the HLA-Cw8 allele , which is associated with hypersensitivity reactions in persons from the Italian island of Sardinia and from Japan ; nevirapine-induced hepatotoxicity associated with the C > T polymorphism in position 3435T of the P08183 ( MDR-1 ) gene codifying for glycoprotein P ( lower risk ) ; hyperbilirubinemia in patients exposed to atazanavir or indinavir carrying the P22309 *28 polymorphism ; peripheral neuropathy with nucleoside analogues associated with haplogroup T of the mitochondrial genome ( higher risk ) and with the Q30201 C282Y genotype of the hemochromatosis gene ( lower risk ) ; the mutation in codon 964 ( R964C ) of the P54098 gene that codifies the mitochondrial polymerase DNA gamma described in a Thai patient with lactic acidosis ; the Q92887 gene haplotypes associated with tenofovir-induced proximal tubulopathy , and the risk of pancreatitis in persons with mutations in the P13569 and SPINK-1 genes . Discovery of DB05130 , a Potent , Selective , and Orally Bioavailable hCCR2 Antagonist . We report the identification of 13 ( DB05130 ) as a potent human P41597 ( hCCR2 ) antagonist . DB05130 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2 , an IC50 of 4.7 nM in antagonism of chemotaxis activity , an IC50 of 84 μM in inhibition of the hERG potassium current , a free fraction of 58 % in protein binding , high selectivity over other chemokine receptors and G-protein-coupled receptors , and acceptable oral bioavailability in rodents and primates . In human clinical trials , DB05130 exhibited a pharmacokinetic profile suitable for once-a-day dosing ( T 1/2 = 15 h ) . Lessons learned from the irinotecan metabolic pathway . DB00762 , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN-38 . SN-38 acts as a P11387 poison . DB00762 has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter-patient variability in irinotecan and SN-38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . DB00762 is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by P22309 to form SN-38G . The pharmacology of this compound is further complicated by the existence of genetic inter-individual differences in activation and deactivation enzymes of irinotecan ( e.g. , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John 's Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e.g. , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A-mediated drug-drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent . DB00996 prevents oxaliplatin-induced central sensitization in the dorsal horn neurons in rats . OBJECTIVES : The present study aims to study the alteration of glutamatergic transmission in the dorsal horn neurons and the effect of gabapentin on oxaliplatin-induced neuropathic pain in rats . MATERIALS AND METHODS : DB00526 ( 5 mg/kg ) or saline was administered to adult male Sprague-Dawley rats . DB00996 ( 60 mg/kg , IP ) or vehicle was injected daily . Mechanical allodynia was assessed using a series of von Frey filaments . The expression of glutamate receptor subunits ( Q13224 and GluR1 ) and brain-derived neurotrophic factor ( P23560 ) was measured in the dorsal horn . The glutamatergic strength was recorded in the spinal cord slices . RESULTS : Administration of oxaliplatin induced significant hyperreactivity to mechanical stimuli in rats , which was attenuated by gabapentin . Significant increase in the expression of P23560 was found in the dorsal horn in rats receiving oxaliplatin , which was prevented by gabapentin . Further studies also observed a significant increase in the expression of GluR1 and Q13224 , as well as enhanced glutamatergic transmission in the dorsal horn neurons in rats treated with oxaliplatin . The upregulation of glutamatergic transmission was significantly reversed by gabapentin . CONCLUSION : These results illustrated an increased expression of P23560 and enhanced glutamatergic transmission in rats with oxaliplatin-induced neuropathic pain , which was markedly attenuated by gabapentin . Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS-specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5-fluorouracil ( DB00544 ) , 5-fluorouridine ( DB01629 ) , 5-fluoro-2'-deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS-inhibitors AG-331 , nolatrexed ( AG337 ) , and raltitrexed ( DB00293 ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5-azacytidine , 8-thioguanosine ) . Except for 5-azacytidine and 8-thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS-affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630- P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , DB00293 , and methotrexate up-regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription-polymerase chain reaction . Our studies demonstrate a novel application of a TBE-dependent reporter plasmid that could be used for the high-throughput identification of potential chemotherapeutic agents that modulate TS RNA-binding activity , either directly or indirectly . [ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin-11 ] . DB00762 ( CPT-11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT-11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT-11 and topo I activity of glioma cells . Furthermore , we established CPT-11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT-11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT-11 sensitive group ( IC50 values for CPT-11 ; < 50 micrograms/ml ) tended to be higher than those in CPT-11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT-11 resistance cell lines ( T98G/CPT-11 and P13671 ) respectively exhibit a 5.4- and 7.3-fold increase in resistance to CPT-11 . No differences in topo I activity and intracellular accumulation of CPT-11 were observed between parent and CPT-11 resistant lines . On the other hand , topo I from T98G/CPT-11 and P13671 /CPT-11 cells were at least 4- and 2-fold resistant to the inhibitory effect of the CPT-11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT-11 . The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane . The mammalian type I gonadotropin releasing hormone receptor ( P30968 ) is a structurally unique G protein-coupled receptor ( GPCR ) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression ( PME ) . Compared to its murine counterparts , the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum ( ER ) leading to a further reduction in PME . The decrease in PME and concomitant increase in intracellular localization of the mammalian DB00644 -RI led us to characterize the spatial distribution of the human and mouse DB00644 receptors in two human cell lines , P29320 293 and HTR-8/SVneo . In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane . A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence ( NLS ) in the first intracellular loop of DB00644 -RI . Surprisingly , however , neither the deletion of the NLS nor the addition of the Xenopus P30968 cytoplasmic tail sequences to the human receptor altered its spatial distribution . Finally , we demonstrate that DB00644 treatment of nuclei isolated from P29320 293 cells expressing exogenous DB00644 -RI triggers a significant increase in the acetylation and phosphorylation of histone H3 , thereby revealing that the nuclear-localized receptor is functional . Based on our findings , we conclude that the mammalian DB00644 -RI is an intracellular GPCR that is expressed on the nuclear membrane . This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor . High expression levels of P48061 and P61073 predict recurrence of adamanti-nomatous craniopharyngiomas in children . BACKGROUND : Adamantinomatous craniopharyngioma ( O14561 ) is a benign but maldevelopmental tumor with a high recurrence rate . OBJECTIVE : Theaim of this study was to investigate the dysregulated biological molecules that play important roles in the recurrence of O14561 . METHODS : We first performed microarray analysis on tumor samples from two pediatric patients with recurrent O14561 and from two pediatric O14561 patients without recurrence after a one-year follow-up . The expression of P48061 and P61073 in 45 specimens of pediatric O14561 was further evaluated by immunohistochemistry . These results were correlated with the clinicopathological parameters and survival of the patients . RESULTS : Four downregulated genes ( P25054 , ITGA , P43121 , and Q99727 ) and 16 upregulated genes ( O76096 , P43235 , P07711 , P48061 , P61073 , P02751 , Q96DB9 , P05106 , P08253 , P08254 , P09237 , P14780 , Q92570 , Q03405 , P16035 , and P15692 ) were found in the recurrent patients . P48061 and P61073 were highly expressed in 13 patients ( 28.9 % ) and 14 patients ( 31.1 % ) , respectively . High levels of P48061 and P61073 expression were significantly associated with a poor recurrence-free survival and were the prognostic factors for O14561 recurrence in pediatric patients . CONCLUSIONS : High levels of P48061 and P61073 expression were associated with O14561 recurrence . The role of P48061 and P61073 in the development of brain tumors requires further research . Novel camptothecin analogues that circumvent Q9UNQ0 -associated drug resistance in human tumor cells . DB00762 ( 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin ; CPT-11 ) is a widely used potent antitumor drug that inhibits mammalian P11387 ( Topo I ) ; however , overexpression of Q9UNQ0 ( Q9UNQ0 / Q9UNQ0 / Q9UNQ0 ) can confer cancer cell resistance to SN-38 , the active form of CPT-11 . We have recently demonstrated that plasma membrane vesicles prepared from Q9UNQ0 -overexpressing PC-6/ Q8WUX1 -5H cells transported SN-38 and its glucuronide conjugate in an DB00171 -dependent manner ( Nakatomi et al. , Biochem Biophys Res Commun 2001;288:827-32 ) . In the present study , we have characterized a total of 14 new camptothecin ( CPT ) analogues with respect to both the inhibition of Topo I and the substrate specificity of Q9UNQ0 . All of the tested CPT analogues , which have different substitutions at positions 10 and 11 , strongly inhibited the Topo I activity in a cell-free system , as did SN-38 . Their antitumor activities in the SN-38-resistant PC-6/ Q8WUX1 -5H2 cell line greatly varied , however , being correlated with intracellular accumulation levels . We have examined DB00171 -dependent transport of those CPT analogues by using plasma membrane vesicles prepared from both PC-6/ Q8WUX1 -5H2 cells and Q9UNQ0 -transfected P29320 -293 cells . Based on the substrate specificity of Q9UNQ0 thus evaluated , it is strongly suggested that CPT analogues with high polarity are good substrates for Q9UNQ0 and are therefore effectively extruded from cancer cells . In this context , to circumvent Q9UNQ0 -associated drug resistance , low-polarity CPT analogues are considered to be potent lead compounds . The present study provides a practical approach to discover new CPT-based drugs for the chemotherapy of drug-resistant human cancer .