interacts_with DB01259?
Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines . Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia , and prostate cancer . Although testosterone is the main androgen secreted from the testes , dihydrotestosterone ( DB02901 ) , a more potent androgen converted from testosterone by 5alpha-reductase isozymes , type I and II , is the major androgen in the prostate cells . The aim of this study is to investigate the cellular and molecular effects of dutasteride , a potent inhibitor of 5alpha-reductase type I and type II , in androgen-responsive ( LNCaP ) and androgen-unresponsive ( DU145 ) human prostate cancer(PCa) cell lines . The expression pattern of 190 genes , selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling , were analysed using a low density home-made oligoarray ( AndroChip 2 ) . Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested . AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed ( FC > or= +/-1.5 ) . Eight of these genes , were overexpressed and three were underexpressed . Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen ( P14061 ; P37058 ; P19099 ) , androgen receptor and androgen receptor co-regulators ( AR; P24385 ) , and signal transduction ( P04626 ; V- P62158 ; Q07889 ) whereas , underexpressed genes ( KLK3 ; P20151 ; Q15392 ) were androgen-regulated genes ( ARGs ) . No differentially expressed genes were scored in DU145 . Microarray data were confirmed by quantitative real-time PCR assay ( QRT-PCR ) . These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology . Integrating bevacizumab , everolimus , and lapatinib into current neoadjuvant chemotherapy regimen for primary breast cancer . Safety results of the GeparQuinto trial . BACKGROUND : Safety data for combining bevacizumab , everolimus , or lapatinib with anthracycline- and taxane-based neoadjuvant chemotherapy for breast cancer are limited . PATIENTS AND METHODS : The neoadjuvant GeparQuinto trial investigates the addition of ( i ) bevacizumab to four cycles epirubicin/cyclophosphamide ( EC ) followed by four cycles docetaxel ( Taxotere ) in patients with human epithelial growth factor receptor (HER)2-negative tumors , ( ii ) everolimus to weekly paclitaxel in patients with P04626 -negative tumors not responding to EC ± bevacizumab , and ( iii ) lapatinib instead of trastuzumab to EC-docetaxel in patients with P04626 -positive tumors to improve the rate of pathological complete response . Tolerable dose , need for supportive treatments , and early signals for toxic effect were evaluated in a planned safety analysis of 270 patients . RESULTS : Treatment with chemotherapy plus bevacizumab , everolimus , or lapatinib was discontinued in 23.0 % , 25.8 % , and 34.5 % compared with chemotherapy alone or plus trastuzumab in 19.4 % , 24.1 % , 3.2 % , respectively . More leukopenia , infections , mucositis , and hypertension but less edema was observed by adding bevacizumab ; a trend toward more thrombocytopenia , leukopenia , skin changes , and hyperlipidemia by adding everolimus ; and more diarrhea , skin changes , and hot flushes but no cardiac events by substituting trastuzumab by lapatinib . CONCLUSIONS : Adding bevacizumab and everolimus to chemotherapy appeared feasible . DB01259 at 1250 mg resulted in an increased rate of treatment discontinuations and was subsequently dose reduced to 1000 mg . Identification of cell surface targets for HIV-1 therapeutics using genetic screens . Human immunodeficiency virus ( HIV ) drugs designed to interfere with obligatory utilization of certain host cell factors by virus are less likely to encounter development of resistant strains than drugs directed against viral components . Several cellular genes required for productive infection by HIV were identified by the use of genetic suppressor element ( GSE ) technology as potential targets for anti-HIV drug development . Fragmented cDNA libraries from various pools of human peripheral blood mononuclear cells ( PBMC ) were expressed in vitro in human immunodeficiency virus type 1 ( HIV-1 ) -susceptible cell lines and subjected to genetic screens to identify GSEs that interfered with viral replication . After three rounds of selection , more than 15000 GSEs were sequenced , and the cognate genes were identified . The GSEs that inhibited the virus were derived from a diverse set of genes including cell surface receptors , cytokines , signaling proteins , transcription factors , as well as genes with unknown function . Approximately 2.5 % of the identified genes were previously shown to play a role in the HIV-1 life cycle ; this finding supports the biological relevance of the assay . GSEs were derived from the following 12 cell surface proteins : P61073 , CCR4 , P32248 , P20702 , P16070 , Q08722 , P34810 , Q07108 , P04233 , Q99062 , Q9UBS5 , and P20333 . Requirement of some of these genes for viral infection was also investigated by using RNA interference ( RNAi ) technology ; accordingly , 10 genes were implicated in early events of the viral life cycle , before viral DNA synthesis . Thus , these cell surface proteins represent novel targets for the development of therapeutics against HIV-1 infection and AIDS . Phase II study of weekly intravenous oxaliplatin combined with oral daily capecitabine and radiotherapy with biologic correlates in neoadjuvant treatment of rectal adenocarcinoma . PURPOSE : To evaluate the efficacy of a combination of capecitabine , oxaliplatin , and radiotherapy ( RT ) in the neoadjuvant treatment of Stage II and III rectal cancers . METHODS : DB01101 was given at 725 mg/m(2) orally twice daily Monday through Friday concurrently with RT . DB00526 was given intravenously at 50 mg/m(2) once weekly five times starting the first day of RT . The radiation dose was 50.4 Gy in 28 fractions ( 1.8 Gy/fraction ) , five fractions weekly . Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase , thymidylate synthase , excision repair cross-complementing rodent repair deficiency complementation group 1 ( P07992 ) , and apoptosis . RESULTS : A total of 25 patients were enrolled in this study ; 6 patients ( 24 % ) had a complete pathologic response . T-downstaging occurred in 52 % of patients , and N-downstaging occurred in 53 % . Grade 3 diarrhea was the most common Grade 3-4 toxicity , occurring in 20 % of patients . Only 2 patients experienced disease recurrence , with a median of 20 months of follow-up . P04818 , thymidine phosphorylase , P07992 , and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies , nor did they predict for T-downstaging or a complete pathologic response . CONCLUSION : DB01101 at 725 mg/m(2) orally twice daily , oxaliplatin 50 mg/m(2)/wk , and RT at 50.4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls . Novel P00533 inhibitors prepared by combination of dithiocarbamic acid esters and 4-anilinoquinazolines . On the basis of combination strategy , a novel series of P00533 inhibitors were designed and synthesized by combination of dithiocarbamic acid esters and 4-anilinoquinazolines . The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay in three human cancer cell lines : MDA-MB-468 , SK-BR-3 and HCT-116 . Two compounds ( 11d and 11f ) were found more potent against all three cell lines and five compounds ( 11a , 11d-11g ) were found more potent against both MDA-MB-468 and SK-BR-3 than DB01259 . SAR studies revealed that the substituents on P13671 and P10643 positions of quinazoline , the amine component of dithiocarbamate moiety and the linker greatly affected the activity . This work provides a promising new strategy for the preparation of potent tyrosine kinase inhibitors . Induction of DNA methylation and gene silencing by short interfering RNAs in human cells . Double-stranded RNAs ( dsRNAs ) induce post-transcriptional gene silencing in several species of animal and plant . In plants , dsRNAs targeted to CpG islands within a promoter can also induce RNA-directed DNA methylation ; however , it remains unclear whether gene silencing mediated by DNA methylation can be induced by dsRNAs in mammalian cells . Here , we demonstrate that short interfering RNAs ( siRNAs ; 21-25-nucleotide RNA molecules ) induce DNA methylation and histone H3 methylation in human cells . Synthetic siRNAs targeted to CpG islands of an P12830 promoter induced significant DNA methylation and histone H3 lysine 9 methylation in both MCF-7 and normal mammary epithelial cells . As a result , these siRNAs repressed expression of the P12830 gene at the transcriptional level . In addition , disrupting the expression of either one of two DNA methyltransferases ( P26358 or Q9UBC3 ) by specific siRNAs abolished the siRNA-mediated methylation of DNA . Moreover , vector-based siRNAs targeted to the erbB2 ( also known as P04626 ) promoter also induced DNA methylation in MCF-7 cells . Thus , siRNAs targeted to CpG islands within the promoter of a specific gene can induce transcriptional gene silencing by means of DNA-methyltransferase-dependent methylation of DNA in human cells , and might have potential as a new type of gene therapeutic agent . Molecular-based choice of cancer therapy : realities and expectations . Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success . Molecular research provides some opportunities to personalize antitumor treatment . For example , life-threatening toxic reactions can be avoided by the identification of subjects , who carry susceptible genotypes of drug-metabolizing genes ( e.g. P51580 , P22309 , P42898 , Q12882 ) . Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response . Tailoring of antiestrogen and trastuzumab therapy based on hormone and P04626 receptor status has already become a classical example of customized medicine . Other predictive markers have been identified both for cytotoxic and for targeted therapies , and include , for example , expression of TS , TP , Q12882 , OPRT , P07992 , P16455 , P11388 , class III beta-tubulin molecules as well as genomic alterations of P00533 , P10721 , P00519 oncogenes . Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity . Signaling through the receptor for epidermal growth factor receptor ( P00533 ) is frequently deregulated in solid tumors . Erlotinib ( Tarceva , DB00530 , OSI Pharmaceuticals , Inc. , Melville , NY ) is a low molecular weight , orally bioavailable inhibitor of the P00533 that has been approved for both non-small cell lung cancer and pancreatic cancers . Previous studies have indicated that sensitivity to P00533 antagonists correlated with HER-3 signaling for non-small cell lung cancer . Herein , we have sought to understand the signaling pathways that mediate erlotinib sensitivity for pancreatic and colorectal cancers . In a panel of 12 pancreatic tumor cell lines , we find that P00533 is coexpressed with HER-3 in all cell lines sensitive to erlotinib but not in insensitive cell lines . Erlotinib can block HER-3 phosphorylation in these sensitive cell lines , suggesting that HER-3 is transactivated by P00533 . Knockdown of HER-3 in BxPC3 , an erlotinib-sensitive pancreatic tumor cell line , results in inhibition of the phosphorylation for both Akt and S6 and is associated with a decrease in cell proliferation and reduced sensitivity to erlotinib . Therefore , P00533 transactivation of HER-3 mediates Akt signaling and can contribute to erlotinib sensitivity for pancreatic tumors . We extended our analysis to a panel of 13 colorectal tumor cell lines and find that , like pancreatic , HER-3 is coexpressed with P00533 in the most erlotinib-sensitive cell lines but not in erlotinib-insensitive cell lines . These studies suggest that HER-3 could be used as a biomarker to select patients who are most likely to respond to erlotinib therapy . Anticancer drug discovery targeting DNA hypermethylation . DNA methyltransferases ( DNMTs ) are important regulators of gene transcription and their roles in carcinogenesis have been a topic of considerable interest in the last few years . Diverse classes of chemical compounds including nucleotide analogues , adenosine analogues , aminobenzoic derivatives , polyphenols , hydrazines , phthalides , disulfides and antisenses are being discovered and evaluated as P26358 inhibitors targeting DNA hypermethylation . Among them , DB00928 5 and Decitabine 6 were launched recently . Several other compounds are under clinical trials . Some of these compounds were discovered from structure-based drug design . These compounds exert their DNA methylation inhibitory by different mechanisms . This review will present a brief account of various DNA methyltransferases and their biological functions , with focus on actuality of design and synthesis of various inhibitors of DNA hypermethylation as anticancer drugs . Endothelial permeability in vitro and in vivo : protective actions of P01160 and omapatrilat in experimental atherosclerosis . Increased arterial endothelial cell permeability ( P12724 ) is considered an initial step in atherosclerosis . Atrial natriuretic peptide ( P01160 ) which is rapidly degraded by neprilysin ( NEP ) may reduce injury-induced endothelial cell leakiness . DB00886 represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme ( P12821 ) . We hypothesized that P01160 prevents thrombin-induced increases of P12724 in human aortic ECs ( HAECs ) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance P01160 mediated vasorelaxation of isolated aortas . Thrombin induced P12724 determined by I(125) albumin flux was assessed in HAECs with and without P01160 pretreatment . Next we examined the effects of chronic oral administration of omapatrilat ( 12 mg/kg/day , n=13 ) or placebo ( n=13 ) for 8 weeks on aortic leakiness , atherogenesis and P01160 -mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet . In HAECs , thrombin-induced increases in P12724 were prevented by P01160 . DB00886 reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo . In isolated arterial rings , omapatrilat enhanced vasorelaxation to P01160 compared to placebo with and without the endothelium . P01160 prevents thrombin-induced increases in P12724 in HAECs . Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to P01160 . These studies support the therapeutic potential of dual inhibition of NEP and P12821 in the prevention of increased arterial P12724 and atherogenesis which may be linked to the P01160 /cGMP system . Circulating apoptotic proteins are increased in long-term disease-free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis-related proteins and inflammation markers are increased in long-term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF-receptor ( sTNF-R ) 1 and 2 , sFas , sFas ligand , sTNF-related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High-sensitivity P02741 ( HS-CRP ) , fibrinogen , plasma B-type and N-terminal atrial natriuretic peptide ( NT- P01160 and DB04899 ) were also determined . Thirty-four patients with median 6.0 years follow-up and 12 healthy age-matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg/m(2) ) , cyclophosphamide ( FEC ) ( n=14 ) or four cycles FEC followed by myeloablation with high-dose carboplatin , cyclophosphamide , thiotepa ( n=20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high-dose than in the standard-dose group . In conclusion , we observed increased circulating apoptotic protein levels in long-term disease-free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study . Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her-2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab-based chemotherapy . DB01259 will likely be effective against trastuzumab-resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 -VEGFR- associated tumor growth . Src and P61073 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib . DB01259 is a dual P00533 and ErbB-2 tyrosine kinase inhibitor that has significantly improved the clinical outcome of ErbB-2-overexpressing breast cancer patients . However , patients inexorably develop mechanisms of resistance that limit the efficacy of the drug . In order to identify potential targets for therapeutic intervention in lapatinib-resistant patients , we isolated , from ErbB-2-overexpressing SK-Br-3 breast cancer cells , the SK-Br-3 Lap-R-resistant subclone , which is able to routinely grow in 1 µM lapatinib . Resistant cells have a more aggressive phenotype compared with parental cells , as they show a higher ability to invade through a matrigel-coated membrane . DB01259 -resistant cells have an increased Src kinase activity and persistent levels of activation of P27361 /2 and AKT compared with parental cells . Treatment with the Src inhibitor saracatinib in combination with lapatinib reduces AKT and P27361 /2 phosphorylation and restores the sensitivity of resistant cells to lapatinib . SK-Br-3 Lap-R cells also show levels of expression of P61073 that are higher compared with parental cells and are not affected by Src inhibition . Treatment with saracatinib or a specific P61073 antibody reduces the invasive ability of SK-Br-3 Lap-R cells , with the two drugs showing cooperative effects . Finally , blockade of Src signaling significantly increases P50591 -induced cell death in SK-Br-3 Lap-R cells . Taken together , our results demonstrate that breast cancer cells with acquired resistance to lapatinib have a more aggressive phenotype compared with their parental counterpart , and that Src signaling and P61073 play an important role in this phenomenon , thus representing potential targets for therapeutic intervention in lapatinib-resistant breast cancer patients . 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 . Expression and transactivating functions of the bZIP transcription factor P35638 in mammary epithelial cells . Heregulin-beta1 ( P04196 ) , a combinatorial ligand for human epidermal growth factor receptor 3 ( P21860 ) and Q15303 , is a regulatory polypeptide having distinct biological effects , such as growth stimulation , differentiation , invasiveness , and migration in mammary epithelial cells . The mechanism underlying the diverse functions of P04196 is not well established but is believed to depend on induced changes in the expression of specific cellular gene products , their modification , or both . Here , we identified the basic leucine zipper transcription factor , the growth-arrest and DNA-damage 153 ( P35638 ) /CCAAT-enhancer binding protein ( C/EBP ) homologous protein ( P35638 ) as one of the P04196 -inducible genes . We demonstrated that P04196 stimulation of mammary epithelial cells induces the expression of P35638 mRNA and protein and transcription of P35638 promoter . The transcriptional activity of the P35638 promoter as well as transcription from the C/EBP-activating transcription factor ( P39905 ) composite motif in the P35638 promoter was also stimulated by P04196 -inducible P39905 -4 and activated P04626 but not wild-type P04626 . P35638 expression was upregulated by the lactogenic hormones insulin and progesterone and associated with differentiation of normal mammary epithelial cells . Consistent with its role as transcriptional modifier , P35638 stimulated transcription of beta-casein promoter activity in a STAT5a-sensitive manner in mammary epithelial cells . Analysis of mouse mammary gland development revealed that P35638 expression was predominantly restricted in the early lactating stages . Because cyclic AMP responsive element and P39905 binding sites are present in a variety of growth-regulating cellular genes , these findings suggest that stimulation of P35638 expression and its transactivating functions may constitute an important mechanism of regulation of putative genes having diverse functions during cell growth and differentiation . [ Measurement of rifampicin and clarithromycin in serum by high-performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug-metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high-performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r=0.975 , p < 0.01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC/MS/MS analysis ( r=0.995 , p < 0.01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations . Autocrine stimulation of P35968 activates human leukemic cell growth and migration . Emerging data suggest that P15692 receptors are expressed by endothelial cells as well as hematopoietic stem cells . Therefore , we hypothesized that functional P15692 receptors may also be expressed in malignant counterparts of hematopoietic stem cells such as leukemias . We demonstrate that certain leukemias not only produce P15692 but also express functional P35968 in vivo and in vitro , resulting in the generation of an autocrine loop that may support leukemic cell survival and proliferation . Approximately 50 % of freshly isolated leukemias expressed mRNA and protein for P35968 . P15692 (165) induced phosphorylation of P35968 and increased proliferation of leukemic cells , demonstrating these receptors were functional . P15692 (165) also induced the expression of P14780 by leukemic cells and promoted their migration through reconstituted basement membrane . The neutralizing mAb DB06101 , specific to human P35968 , inhibited leukemic cell survival in vitro and blocked P15692 (165)-mediated proliferation of leukemic cells and P15692 -induced leukemic cell migration . Xenotransplantation of primary leukemias and leukemic cell lines into immunocompromised nonobese diabetic mice resulted in significant elevation of human , but not murine , P15692 in plasma and death of inoculated mice within 3 weeks . Injection of DB06101 inhibited proliferation of xenotransplanted human leukemias and significantly increased the survival of inoculated mice . Interruption of signaling by VEGFRs , particularly P35968 , may provide a novel strategy for inhibiting leukemic cell proliferation . Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER-2 and P00533 . DB01259 is a potent dual inhibitor of HER-2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side-effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER-2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER-2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab-refractory metastatic breast cancer . DB01259 may have a specific role in treating HER-2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated . Molecular identification of the human O75899 : cell surface expression and coupling to adenylyl cyclase in the absence of Q9UBS5 . We have identified a gene encoding a GABAB receptor , the human O75899 , located on chromosome 9q22.1 , that is distinct from the recently reported rat Q9UBS5 . O75899 structurally resembles Q9UBS5 ( 35 % identity ) , having seven transmembrane domains and a large extracellular region , but differs in having a longer carboxy-terminal tail . O75899 is localized to the cell surface in transfected COS cells , and negatively couples to adenylyl cyclase in response to GABA , baclofen , and 3-aminopropyl(methyl)phosphinic acid in CHO cells lacking Q9UBS5 . DB00181 action is inhibited by the GABABR antagonist , 2-hydroxysaclofen . The human O75899 and Q9UBS5 genes are differentially expressed in the nervous system , with the greatest difference being detected in the striatum in which Q9UBS5 but not O75899 mRNA transcripts are detected . O75899 and Q9UBS5 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum . Identification of a functional homomeric O75899 coupled to adenylyl cyclase suggests that the complexity of GABAB pharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms . Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with DB01259 and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 -positive breast cancer . We report a patient with breast cancer overexpressing HER-2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine . The glial cell modulator and phosphodiesterase inhibitor , DB05066 ( ibudilast ) , attenuates prime- and stress-induced methamphetamine relapse . Stress and renewed contact with drug ( a " slip " ) have been linked to persisting relapse of methamphetamine abuse . Human brain microglial activation has been linked with methamphetamine abuse , and inhibitors of glial cell activation , certain phosphodiesterase ( PDE ) inhibitors , and glial cell derived neurotrophic factor ( P39905 ) have been reported to modulate drug abuse effects . Our objective was to determine whether the glial cell attenuator , 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine ( DB05066 , ibudilast ) , a non-selective PDE inhibitor and promoter of P39905 , could reduce stress- and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior . Male Long-Evans hooded rats were trained to lever press reinforced with 0.1 mg/kg i.v. methamphetamine infusion according to fixed-ratio 1 ( FR1 ) reinforcement schedules during daily , 2-hour experimental sessions . After performance had stabilized , lever pressing was extinguished for 12 consecutive sessions and doses of 0 ( vehicle ) , 2.5 and 7.5 mg/kg DB05066 were then administered intraperitoneally b.i.d. on the last 2 days of extinction and then once on the testday to separate groups of 12 rats . During testing , the rats were given 15 min of intermittent footshock or a 1 mg/kg i.p. methamphetamine prime followed by a 2-hour reinstatement test session . DB05066 significantly reduced response levels of footshock-induced ( 2.5 and 7.5 mg/kg ) and prime-induced ( 7.5 mg/kg ) reinstatement of extinguished methamphetamine-maintained responding . DB05066 has properties consistent with the ability to attenuate relapse precipitated by stress and methamphetamine " slips " during abstinence . These results thus reinforce interest in atypical neurobiological mechanisms which could be exploited for developing novel medications for treating drug abuse disorders .