interacts_with DB05773?
RL66 a second-generation curcumin analog has potent in vivo and in vitro anticancer activity in ER‑negative breast cancer models . There is a need for the development of new safe and efficacious drug therapies for the treatment of estrogen receptor (ER)‑negative breast cancers . 1-Methyl-3,5-bis [ ( E ) -4-pyridyl ) methylidene ] -4-piperidone ( RL66 ) is a second generation curcumin analog that exhibits potent cytotoxicity towards a variety of ER-negative breast cancer cells . Therefore , we have further examined the mechanism of this novel drug in in vitro and in vivo models of ER-negative breast cancer . The mechanistic studies demonstrated that RL66 ( 2 µM ) induced cell cycle arrest in the G2/M phase of the cell cycle . Moreover , RL66 ( 2 µM ) caused 40 % of SKBr3 cells to undergo apoptosis after 48 h and this effect was time-dependent . This correlated with an increase in cleaved caspase-3 as shown by western blot analysis . RL66 ( 2 µM ) also decreased P04626 /neu phosphorylation and increased p27 in SKBr3 cells , while in MDA-MB-231 and MDA-MB-468 cells RL66 ( 2 µM ) significantly decreased Akt phosphorylation and transiently increased the stress kinases P45983 /2 and MAPK p38 . In addition , RL66 exhibited anti-angiogenic potential in vitro as it inhibited HUVEC cell migration 46 % and the ability of these cells to form tube‑like networks . RL66 ( 8.5 mg/kg ) suppressed the growth of MDA-MB-468 xenograft tumors by 48 % compared to vehicle control following 10 weeks of daily oral administration . Microvessel density in the tumors from treated mice was also decreased 57 % compared to control . Thus our findings demonstrate that RL66 has potent proapoptotic and anti-angiogenic properties in vivo and in vitro and has the potential to be further developed as a drug for the treatment of ER‑negative breast cancer . The effects of trastuzumab on the P01730 +CD25+FoxP3+ and P01730 + Q16552 + T-cell axis in patients with breast cancer . In addition to the direct targeting effects on P04626 -positive cells , trastuzumab may have a therapeutic role modulating the activity of the cellular immune system in patients with breast cancer . To investigate this further , the balance of T-regulatory ( T(reg) ) , Th17 , natural killer ( NK ) and NK T ( NKT ) cells before , during and after trastuzumab therapy was investigated . Sequential frequencies of circulating T(reg) cells , Th17 cells , NK and NKT cells were measured in peripheral blood of breast cancer patients and normal controls throughout therapy . Individuals with breast cancer had significantly higher T(reg) frequencies of peripheral blood compared with healthy controls ( 9.2 or 8.6 vs 6 % ; P < 0.05 ) , and no significant differences in T(reg) frequencies were observed between P04626 -positive and P04626 -negative individuals . The number of Th17 cells was lowest in P04626 -positive patients compared with both healthy controls and P04626 -negative patients ( 0.31 vs 0.75 % or 0.84 % ; P=0.01 ) . There appeared to be an inverse relationship between T(reg) and Th17 frequencies in metastatic breast cancer ( MBC ) with T(reg) levels significantly reduced during treatment with trastuzumab ( P=0.04 ) , whereas Th17 frequencies were concomitantly increased ( P=0.04 ) . This study supports earlier data that T(reg) cells are present at higher frequencies in breast cancer patients compared with healthy individuals . For the first time , we show that P04626 -positive individuals with breast carcinomas have reduced numbers of circulating Th17 cells , which appear , in turn to have an inverse relationship with T(reg) frequency in MBC . The change in balance of the T(reg) : Th17 ratio appears to characterise the cancer state , and furthermore , is disrupted by trastuzumab therapy . Genetic alterations and oncogenic pathways associated with breast cancer subtypes . Breast cancers can be divided into subtypes with important implications for prognosis and treatment . We set out to characterize the genetic alterations observed in different breast cancer subtypes and to identify specific candidate genes and pathways associated with subtype biology . mRNA expression levels of estrogen receptor , progesterone receptor , and P04626 were shown to predict marker status determined by immunohistochemistry and to be effective at assigning samples to subtypes . P04626 (+) cancers were shown to have the greatest frequency of high-level amplification ( independent of the P04626 amplicon itself ) , but triple-negative cancers had the highest overall frequencies of copy gain . Triple-negative cancers also were shown to have more frequent loss of phosphatase and tensin homologue and mutation of P06400 , which may contribute to genomic instability . We identified and validated seven regions of copy number alteration associated with different subtypes , and used integrative bioinformatics analysis to identify candidate oncogenes and tumor suppressors , including P04626 , Q14451 , O95251 , O15297 , P24385 , Q92769 , P55317 , and P20936 . We tested the candidate oncogene O95251 and showed that it enhances the anchorage-independent growth of breast cancer cells . The genome-wide and region-specific differences between subtypes suggest the differential activation of oncogenic pathways . Carcinomatous meningitis : Leptomeningeal metastases in solid tumors . Leptomeningeal metastasis ( LM ) results from metastatic spread of cancer to the leptomeninges , giving rise to central nervous system dysfunction . Breast cancer , lung cancer , and melanoma are the most frequent causes of LM among solid tumors in adults . An early diagnosis of LM , before fixed neurologic deficits are manifest , permits earlier and potentially more effective treatment , thus leading to a better quality of life in patients so affected . Apart from a clinical suspicion of LM , diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid ( P04141 ) or radiographic manifestations as revealed by neuraxis imaging . Potentially of use , though not commonly employed , today are use of biomarkers and protein profiling in the P04141 . Symptomatic treatment is directed at pain including headache , nausea , and vomiting , whereas more specific LM-directed therapies include intra- P04141 chemotherapy , systemic chemotherapy , and site-specific radiotherapy . A special emphasis in the review discusses novel agents including targeted therapies , that may be promising in the future management of LM . These new therapies include anti-epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer , anti- P04626 monoclonal antibody trastuzumab in breast cancer , anti- P16410 ipilimumab and anti- P15056 tyrosine kinase inhibitors such as vermurafenib in melanoma , and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM . Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra- P04141 drug therapy . Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine ( DB05773 ) . The antibody trastuzumab ( Herceptin ) has substantially improved overall survival for patients with aggressive P04626 -positive breast cancer . However , about 70 % of all treated patients will experience relapse or disease progression . This may be related to an insufficient targeting of the P16070 (high) P25063 (low) breast cancer stem cell subset , which is not only highly resistant to chemotherapy and radiotherapy but also a poor target for trastuzumab due to low P04626 surface expression . Hence , we explored whether the new antibody-drug conjugate DB05773 , which consists of the potent chemotherapeutic DM1 coupled to trastuzumab , could improve the targeting of these tumor-initiating or metastasis-initiating cells . To this aim , primary P04626 -overexpressing tumor cells as well as P04626 -positive and P04626 -negative breast cancer cell lines were treated with DB05773 , and effects on survival , colony formation , gene and protein expression as well as antibody internalization were assessed . This revealed that P16070 (high) P25063 (low) P04626 (low) stem cell-like breast cancer cells show high endocytic activity and are thus particularly sensitive towards the antibody-drug conjugate DB05773 . Consequently , preexisting P16070 (high) P25063 (low) cancer stem cells were depleted by concentrations of DB05773 that did not affect the bulk of the tumor cells . Likewise , colony formation was efficiently suppressed . Moreover , when tumor cells were cocultured with natural killer cells , antibody-dependent cell-mediated cytotoxicity was enhanced , and EMT-mediated induction of stem cell-like properties was prevented in differentiated tumor cells . Thus our study reveals an unanticipated targeting of stem cell-like breast cancer cells by DB05773 that may contribute to the clinical efficacy of this recently approved antibody-drug conjugate . A phase 1 study of weekly dosing of trastuzumab emtansine ( DB05773 ) in patients with advanced human epidermal growth factor 2-positive breast cancer . BACKGROUND : We conducted a phase 1 , multicenter , open-label , dose-escalation study ( TDM3569g ) to assess the safety , tolerability , and pharmacokinetics of single-agent trastuzumab emtansine ( DB05773 ) administered weekly and once every 3 weeks in patients with P04626 -positive metastatic breast cancer previously treated with trastuzumab . The weekly dose results are described here . METHODS : Patients were administered escalating doses of DB05773 weekly , starting at 1.2 mg/kg . Additional patients were enrolled at the maximum tolerated dose ( MTD ) to better characterize tolerability and pharmacokinetics . RESULTS : Twenty-eight patients received weekly DB05773 , and the MTD was determined to be 2.4 mg/kg . In general , DB05773 was well tolerated , requiring few dose modifications or discontinuations because of adverse events ( AEs ) . Grade ≥ 3 AEs were reported in 19 patients ( 67.9 % ) ; treatment-related AEs occurred in 25 ( 89.3 % ) patients . Exposure to weekly DB05773 was dose-proportional at ≥ 1.2 mg/kg , and accumulation of DB05773 and total trastuzumab was observed . Objective partial tumor responses were reported in 13 ( 46.4 % ) patients ; the median duration of response was 18.6 months , and the 6-month clinical benefit rate was 57.1 % . CONCLUSION : The results suggest that a weekly dose of DB05773 2.4 mg/kg has antitumor activity and is well tolerated in patients with P04626 -positive metastatic breast cancer . Endometrial regenerative cells : a novel stem cell population . Angiogenesis is a critical component of the proliferative endometrial phase of the menstrual cycle . Thus , we hypothesized that a stem cell-like population exist and can be isolated from menstrual blood . Mononuclear cells collected from the menstrual blood contained a subpopulation of adherent cells which could be maintained in tissue culture for > 68 doublings and retained expression of the markers P21926 , CD29 , CD41a , P16070 , P13987 , CD73 , CD90 and CD105 , without karyotypic abnormalities . Proliferative rate of the cells was significantly higher than control umbilical cord derived DB05914 , with doubling occurring every 19.4 hours . These cells , which we termed " Endometrial Regenerative Cells " ( ERC ) were capable of differentiating into 9 lineages : cardiomyocytic , respiratory epithelial , neurocytic , myocytic , endothelial , pancreatic , hepatic , adipocytic , and osteogenic . Additionally , ERC produced P08254 , P09238 , GM- P04141 , angiopoietin-2 and DB00102 at 10-100,000 fold higher levels than two control cord blood derived mesenchymal stem cell lines . Given the ease of extraction and pluripotency of this cell population , we propose ERC as a novel alternative to current stem cells sources . Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of P00533 signaling . BACKGROUND : The aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases ( P48444 ) on the pathogenesis of non-small cell lung cancer ( NSCLC ) . MATERIALS AND METHODS : The methylation profiles of 12 genes , and the epidermal growth factor receptor ( P00533 ) and P01116 mutations were determined for samples from 229 NSCLC patients . In addition , protein expression of P00533 and P04626 in 116 NSCLCs was analyzed based on the presence or absence of P48444 . RESULTS : IL-12Rbeta2 and Wif-1 methylation and P04626 overexpression were more frequent events in the P48444 group . Eighty nonmalignant lung tissues had no correlation with any molecular changes between the P48444 and the non- P48444 group . P00533 mutation was significantly higher in the non- P48444 group , while P00533 expression was inversely correlated with % FEV1.0 . In the P48444 group , unmethylated P09486 and Q96HF1 genes or a negative CpG island methylator phenotype ( CIMP ) was a negative prognostic factor , while methylation of p16(INK4A) and WNT antagonist genes was a negative prognostic factor in the non- P48444 group . CONCLUSIONS : Novel characteristics of P48444 -related NSCLC were identified by examination of methylation profiles and alterations of P00533 signaling . In consideration of the high sensitivity to smoking in patients with P48444 , NSCLC with P48444 might be a distinct population of smoke-related NSCLC , the genetic profile of which is quite different from non- P48444 NSCLC . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . Letter to the editor concerning ' DB00072 emtansine ( DB05773 ) versus lapatinib plus capecitabine in patients with P04626 -positive metastatic breast cancer and central nervous system metastases : a retrospective , exploratory analysis in EMILIA ' . DB06366 protects the achilles ' heel of trastuzumab -- emtansine . DB00072 emtansine ( DB05773 ) represents a significant advancement in the treatment of P04626 (+) breast cancers . Its clinical efficacy however will be limited by the development of therapeutic resistance . In this report , the P21860 ligand neuregulin is shown to mediate DB05773 resistance , which was overcome by administration of pertuzumab , a steric inhibitor of P04626 dimerization . Treatment of P04626 -overexpressing breast cancer . The HER family of receptors consists of four closely related type 1 transmembrane TK receptors : P00533 ( P00533 ) , P04626 , P21860 and Q15303 . Signalling via the HER family of receptors underpins the majority of the intricate array of cellular activities on which cell survival and functionality depend . Aberrant P04626 expression and/or functionality have been implicated in the evolution of breast cancer and this receptor has proved to be a potent target for anticancer therapies , including antibody-based therapies to prevent ligand binding , dimer formation or the recruitment of antibody-dependent cell-mediated cytotoxicity , and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners . Novel strategies against P04626 include HER tyrosine kinase inhibitors , HSP90 inhibitors and antibody-chemotherapy conjugates . This latter approach is exemplified by DB05773 , a potent antibody that has a good safety profile and that has shown remarkable activity in patients with advanced disease . In addition , pertuzumab , an mAb that directly inhibits the formation of P04626 dimers including the P04626 : P21860 dimer , offers a unique mechanism of P21860 inhibition . All these approaches have shown substantial clinical activity in patients refractory to trastuzumab . It is anticipated that with the increased availability of novel anti- P04626 agents together with a better understanding of the mechanisms of resistance to anti- P04626 agents we should be able to further improve the outcome of patients with P04626 breast cancer . There will also be an increasing tendency towards moving the study of these agents to earlier stages of the disease , namely in the adjuvant and neoadjuvant setting . A tumour necrosis factor alpha autocrine loop contributes to proliferation and nuclear factor-kappaB activation of Theileria parva-transformed B cells . Theileria infection of bovine leucocytes induces uncontrolled proliferation and a transformed phenotype comparable to tumour cells . Infected cells have many characteristics of activated leucocytes and use autocrine loops to augment proliferation . We have shown previously that , in infected B cells , P19957 -K controls a granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) autocrine loop to increase both proliferation and activation of the activator protein 1 ( AP-1 ) transcription factor . We show here that the same infected B cells also use a tumour necrosis factor ( P01375 ) alpha autocrine loop that again contributes to proliferation and augments nuclear factor ( NF ) -kappaB activation . Interestingly , both pharmacological inhibition of P01375 synthesis and neutralizing anti- P01375 antibodies lead to a reduction in proliferation and a 50 % drop in NF-kappaB activation , without inducing apoptosis . DB01095 inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : DB01095 is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti-cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 /2 ) and P45983 and 2 ( JNK 1/2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound-healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC(50) = 8.6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p- P27361 /2 expression , upregulation of p- P45983 /2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma . A transcription-independent function of Q12778 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells . Increasing evidence suggests that aberrant activation of the androgen receptor ( AR ) plays a pivotal role in the development and progression of androgen depletion-independent prostate cancer ( PCa ) after androgen deprivation therapy . Here , we show that loss of the P60484 tumor suppressor gene is associated with hyperactivation of the AR in human PCa cell lines . This effect is mediated primarily by its downstream effector Q12778 . In addition to the inhibition of androgenic activation of the AR , forced expression of Q12778 in P60484 -negative PCa cells also inhibits androgen-independent activation of the AR in a manner independent of Q12778 transcriptional function . In contrast , silencing of Q12778 in P60484 -positive cells not only increases the basal activity of the AR in the absence of androgens , it also markedly sensitizes the AR activation by low levels of androgens or nonandrogenic factors such as interleukin-6 . Q12778 -mediated inhibition of the AR is partially attenuated by the histone deacetylase ( HDAC ) inhibitor trichostatin A . Accordingly , Q12778 interacts with O15379 as shown by coimmunoprecipitation assays , and cotransfection of cells with Q12778 and O15379 , but not Q13547 and Q92769 , results in a greater inhibition of AR activity than in cells transfected with Q12778 or O15379 individually . Together , our findings define a novel corepressor function of Q12778 in inhibition of androgen-independent activation of the AR . Preclinical safety profile of trastuzumab emtansine ( DB05773 ) : mechanism of action of its cytotoxic component retained with improved tolerability . DB00072 emtansine ( DB05773 ) is the first antibody-drug conjugate ( ADC ) approved for patients with human epidermal growth factor receptor 2 ( P04626 ) -positive metastatic breast cancer . The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery , where poor tolerability can limit efficacious doses . Here , we present results from preclinical studies characterizing the toxicity profile of DB05773 , including limited assessment of unconjugated DM1 . DB05773 binds primate ErbB2 and human P04626 but not the rodent homolog c-neu . Therefore , antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats , respectively , in both single- and repeat-dose studies ; toxicity of DM1 was assessed in rats only . DB05773 was well tolerated at doses up to 40 mg/kg ( ~4400 μg DM1/m(2) ) and 30 mg/kg ( ~ 6000 μg DM1/m(2) ) in rats and monkeys , respectively . In contrast , DM1 was only tolerated up to 0.2mg/kg ( 1600 μg DM1/m(2) ) . This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in DB05773 , supporting the premise of ADCs to improve the therapeutic index . In addition , DB05773 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 ( i.e. , microtubule disruption ) . Findings included hepatic , bone marrow/hematologic ( primarily platelet ) , lymphoid organ , and neuronal toxicities , and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest . These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in DB05773 -treated patients to date . Targeting Q01196 / Q06455 -histone deacetylase repressor complex : a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in Q01196 / Q06455 -positive acute myeloid leukemia cells . In t(8;21) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) -containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( DB00313 ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . DB00313 causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i.e. , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that DB00313 treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i.e. , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase-dependent apoptosis . Taken together , these data support the notion that DB00313 might effectively target Q01196 / Q06455 -driven leukemogenesis through disruption of aberrant Q13547 function and that DB00313 should be integrated in novel therapeutic approaches for Q01196 / Q06455 -positive AML . Emerging therapeutic targets in bladder cancer . Treatment of muscle invasive urothelial bladder carcinoma ( BCa ) remains a major challenge . Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets . This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa . Small molecule pan-FGFR inhibitors have shown encouraging efficacy and safety results especially among patients with activating FGFR mutations or translocations . P42345 inhibitors for patients with Q92574 mutations and concomitant targeting of PI3K and MEK represent strategies to block PI3K/AKT/ P42345 pathway . Encouraging preclinical results with ado-trastuzumab emtansine ( DB05773 ) exemplifies a new potential treatment for P04626 -positive BCa along with innovative bispecific antibodies . Inhibitors of cell cycle regulators ( aurora kinase , polo-like kinase 1 , and cyclin-dependent kinase 4 ) are being investigated in combination with chemotherapy . Early results of clinical studies with anti- P16410 and anti- Q9NZQ7 are propelling immune modulating drugs to the forefront of emerging treatments for BCa . Collectively , these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy . Enhanced antitumor activity of trastuzumab emtansine ( DB05773 ) in combination with pertuzumab in a P04626 -positive gastric cancer model . Human epidermal growth factor receptor 2 ( P04626 ) -targeted therapy by trastuzumab has become increasingly important for treating P04626 -positive cancers , and trastuzumab emtansine ( DB05773 ) is expected to serve as an effective alternative to trastuzumab . DB06366 , a P04626 dimerization inhibitor , showed prolonged progression-free survival when used with trastuzumab for P04626 -positive breast cancer . In this study , we investigated the effect of combining DB05773 and pertuzumab on xenografted gastric tumors . DB05773 as a single agent showed significant antitumor activity in all the three P04626 -high expression tumor models tested ( NCI-N87 , P35240 and 4-1ST ) but was ineffective against two P04626 -low expression tumors ( SNU-16 and MKN-28 ) . Using the DB05773 -sensitive NCI-N87 model , the combination efficacy of DB05773 and pertuzumab was elucidated . The combination induced significant tumor regression , whereas DB05773 or pertuzumab alone did not . In cultured NCI-N87 cells stimulated with epidermal growth factor ( P01133 ) or heregulin-α , concomitant treatment of DB05773 and pertuzumab significantly inhibited proliferation and increased caspase 3/7 activity compared to either agent alone . Only the combination significantly inhibited the phosphorylation of P00533 or P21860 , and its downstream factor AKT . Suppressed P21860 phosphorylation by the combination was also seen in the NCI-N87 xenografted tumors . Compared to single agent treatments , the combination treatment significantly enhanced antibody-dependent cellular cytotoxicity ( ADCC ) against NCI-N87 cells . These findings suggest that DB05773 in combination with pertuzumab shows significant antitumor activity by increasing AKT signal inhibition and ADCC in P04626 -positive gastric cancers . New therapies in P04626 -positive breast cancer : a major step towards a cure of the disease ? Overexpression of the human epidermal growth factor receptor 2 ( P04626 ) predicts a poor prognosis in metastatic breast cancer . While the introduction of P04626 -targeted therapies , such as the monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib , has significantly improved outcomes in P04626 + breast cancer compared with previously available therapies , use of these targeted therapies is often limited by the development of drug resistance and tolerability issues . These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways . Recently , several agents have demonstrated promising activity in P04626 + metastatic breast cancer , either as monotherapy or in combination therapy , including the tyrosine-kinase inhibitors neratinib ( HKI-272 ) and afatinib ( BIBW-2992 ) and the anti- P04626 monoclonal antibodies pertuzumab and trastuzumab-DM1 ( DB05773 ) . Agents that target other molecular pathways , such as the vascular endothelial growth factor receptor , mammalian target of rapamycin , P19957 -kinases , insulin-like growth factor ( IGFR ) , HSP-90 , and other kinases also have potential , in combination with anti- P04626 and/or other systemic therapies , to be active in this subtype of breast cancer . Innovative clinical studies are required in well-characterized patient populations to define the true clinical value of these emerging new approaches . Responses to subsequent anti- P04626 therapy after treatment with trastuzumab-DM1 in women with P04626 -positive metastatic breast cancer . BACKGROUND : Women with human epidermal growth factor receptor 2 ( P04626 ) -positive metastatic breast cancer ( MBC ) can respond to multiple lines of anti- P04626 therapy . It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 ( DB05773 ) . PATIENTS AND METHODS : We retrospectively identified P04626 -positive MBC patients treated with DB05773 and characterized outcomes during subsequent lines of anti- P04626 therapy . Response was determined by a blinded radiology review . Time-dependent analyses were carried out using Kaplan-Meier estimates . RESULTS : We identified 23 patients treated with single-agent DB05773 and report on the 20 patients who discontinued protocol therapy . All patients received trastuzumab-based metastatic therapy before initiation of DB05773 [ median 7 regimens ( range 3-14 ) ] . Of these 20 patients , 75 % ( 15 of 20 ) received further therapy with or without anti- P04626 agents after discontinuing DB05773 . Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 ( 33 % ) treated patients , including 33 % ( 4 of 12 ) who received a regimen containing trastuzumab and/or lapatinib . Median durations of therapy to first- and second-subsequent regimens after DB05773 were 5.5 and 6.4 months , respectively . CONCLUSIONS : In heavily pretreated P04626 -positive MBC patients , prior exposure to DB05773 does not exhaust the potential benefit of ongoing anti- P04626 therapy with trastuzumab- and/or lapatinib-based regimens . P04626 -positive breast cancer : beyond trastuzumab . The outlook for patients with P04626 -positive breast cancer was revolutionized by the development of trastuzumab ( Herceptin ) , a humanized murine monoclonal antibody . Use of this agent led to improved overall survival when it was added to chemotherapy for the treatment of metastatic breast cancer . Improved understanding of mechanisms of resistance to trastuzumab has facilitated the development of novel agents for P04626 -positive breast cancer , and also resulted in superior outcomes when added to chemotherapy in the adjuvant setting . This review explores the use of several such agents , including lapatinib ( DB01259 ) , HSP90 inhibitors , DB05773 , and other tyrosine kinase inhibitors . Emerging data from trials of these agents indicate that the P04626 pathway remains a valid therapeutic target following disease progression on trastuzumab , and suggest a promising role for combined P04626 blockade with two or more agents . Potential mechanisms for thrombocytopenia development with trastuzumab emtansine ( DB05773 ) . PURPOSE : DB00072 -emtansine ( DB05773 ) is an antibody-drug conjugate ( ADC ) comprising the cytotoxic agent DM1 conjugated to trastuzumab with a stable linker . Thrombocytopenia was the dose-limiting toxicity in the phase I study , and grade ≥3 thrombocytopenia occurred in up to 13 % of patients receiving DB05773 in phase III studies . We investigated the mechanism of DB05773 -induced thrombocytopenia . EXPERIMENTAL DESIGN : The effect of DB05773 on platelet function was measured by aggregometry , and by flow cytometry to detect the markers of activation . The effect of DB05773 on differentiation and maturation of megakaryocytes ( MK ) from human hematopoietic stem cells was assessed by flow cytometry and microscopy . Binding , uptake , and catabolism of DB05773 in MKs , were assessed by various techniques including fluorescence microscopy , scintigraphy to detect T-[H(3)]-DM1 and (125)I- DB05773 , and mass spectrometry . The role of FcγRIIa was assessed using blocking antibodies and mutant constructs of trastuzumab that do not bind FcγR . RESULTS : DB05773 had no direct effect on platelet activation and aggregation , but it did markedly inhibit MK differentiation via a cytotoxic effect . Inhibition occurred with DM1-containing ADCs but not with trastuzumab demonstrating a role for DM1 . MKs internalized these ADCs in a P04626 -independent , FcγRIIa-dependent manner , resulting in intracellular release of DM1 . Binding and internalization of DB05773 diminished as MKs matured ; however , prolonged exposure of mature MKs to DB05773 resulted in a disrupted cytoskeletal structure . CONCLUSIONS : These data support the hypothesis that DB05773 -induced thrombocytopenia is mediated in large part by DM1-induced impairment of MK differentiation , with a less pronounced effect on mature MKs . DB05773 , a novel antibody-drug conjugate , is highly effective against uterine and ovarian carcinosarcomas overexpressing P04626 . Ovarian and uterine carcinosarcoma ( CS ) are characterized by their aggressive clinical behavior and poor prognosis . We evaluated the efficacy of trastuzumab-emtansine ( DB05773 ) , against primary P04626 positive and P04626 negative CS cell lines in vitro and in vivo . Eight primary CS cell lines were evaluated for P04626 amplification and protein expression by fluorescence in situ hybridization , immunohistochemistry , flow cytometry and qRT-PCR . Sensitivity to DB05773 -induced antibody-dependent-cell-mediated-cytotoxicity ( ADCC ) was evaluated in 4-h-chromium-release-assays . DB05773 cytostatic and apoptotic activities were evaluated using flow cytometry based proliferation assays . In vivo activity of DB05773 was also evaluated . P04626 protein overexpression and gene amplification were detected in 25 % ( 2/8 ) of the primary CS cell lines . DB05773 and T were similarly effective in inducing strong ADCC against CS overexpressing P04626 at 3+ levels . In contrast , DB05773 was dramatically more effective than T in inhibiting cell proliferation ( P < 0.0001 ) and in inducing G2/M phase cell cycle arrest in the P04626 expressing cell lines ( shift of G2/M : mean ± SEM from 14.87 ± 1.23 to 66.57 ± 4.56 % , P < 0.0001 ) . Importantly , DB05773 was highly active at reducing tumor formation in vivo in CS xenografts overexpressing P04626 ( P = 0.0001 and P < 0.0001 compared to T and vehicle respectively ) with a significantly longer survival when compared to T and vehicle mice ( P = 0.008 and P = 0.0001 respectively ) . DB05773 may represent a novel treatment option for the subset of P04626 positive CS patients with disease refractory to chemotherapy . Therapeutic targeting of P04626 in breast cancer : understanding resistance in the laboratory and combating it in the clinic . P04626 gene amplification occurs in about one quarter of breast carcinomas ( BCs ) and identifies a distinct clinical subset of BC . The introduction in the clinic of DB00072 , a humanized monoclonal antibody ( mAb ) directed to the P04626 extracellular domain , has had a great impact on the therapeutic management of P04626 + BC . Yet , not all patients respond to DB00072 and resistance develops also among patients that initially benefit from DB00072 -based regimens . Pre-clinical studies have discovered several mechanisms through which tumor cells may escape from DB00072 -mediated P04626 inhibition . These include rewiring of the ErbB signaling network , loss of P04626 expression , expression of P04626 isoforms refractory to DB00072 inhibition , vicarious signaling by non-ErbB tyrosine kinases and constitutive activation of downstream signaling routes , such as the PI3K pathway . While the relative contribution of each of these mechanisms to establishing DB00072 resistance in the clinical setting is not fully understood , much attention has been focused on abating resistance by achieving complete blockade of P04626 -containing dimers . This approach , propelled by the development of novel anti- P04626 therapeutics , has led to the recent approval of DB01259 , DB06366 and DB05773 as additional anti- P04626 therapeutics in BC . However , full success is far from being achieved and resistance to P04626 targeting remains a relevant problem in the clinical management of BC . Herein , we provide an overview of biological and molecular bases underpinning resistance to P04626 therapeutics in BC , discuss outstanding issues in the field of P04626 therapeutic targeting and elaborate on future directions of translational research on P04626 + breast cancer . Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5-hydroxytryptamine ; 5-HT ) , 5-HT receptors 1A ( 5-HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients , at 72 h post-challenge with the antigen . In addition , the effects of 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients , regarding their proliferation and interleukin ( IL ) -2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell-like line ( XS52 ) , regarding its IL-1beta production . Serotonin-positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0.01 ) in 5-HT1AR-positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5-HT2AR- and P31645 -positive cells were increased ( p < 0.001 for both ) in the eczematous skin . Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10(-5) mol/l of DOI inhibited ( p < 0.01 ) the proliferation of nickel-stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10(-6) mol/l tended to inhibit the production of IL-1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction . Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : DB01024 ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre- and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high-performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50-88 % , P < 0.0005 ) and decreased P12268 ( 42-56 % , P < 0.0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P=0.009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 -treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow-up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1.26 vs. 0.87 respectively , P=0.017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation . DB05773 : a P04626 -positive targeted antibody-drug conjugate . OBJECTIVE : To review the pharmacology , pharmacokinetics , efficacy , adverse effects , drug-drug interactions , dosage and administration , and formulary considerations for ado-trastuzumab emtansine . DATA SOURCES : Sources of information were identified through a PubMed search ( 1966 to June 2014 ) using the key terms ado-trastuzumab emtansine , trastuzumab-DM1 , trastuzumab-MCC-DM1 , and DB05773 . Other information was obtained from clinicaltrials.gov , product labeling , and press releases . STUDY SELECTION AND DATA EXTRACTION : All English-language clinical trials and abstracts evaluating ado-trastuzumab emtansine in humans were reviewed for inclusion . DATA SYNTHESIS : Overexpression or amplification of human epidermal growth factor receptor 2 ( P04626 ) occurs in approximately 20 % of breast cancers and is associated with more aggressive tumors and poorer prognosis in the absence of treatment . Although effective therapies for the initial management of P04626 -positive metastatic breast cancer ( MBC ) exist , many patients will experience disease progression . Most second-line therapies are associated with either significant toxicities or limited improvements in overall survival ( OS ) . DB05773 is a P04626 -positive directed antibody drug conjugate ( ADC ) approved in February 2013 . In phase III clinical trials comparing the efficacy and safety of ado-trastuzumab emtansine with lapatinib-capecitabine or physician 's choice , ado-trastuzumab emtansine had a better tolerability profile and improved progression-free survival compared with lapatinib-capecitabine or physician 's choice and increased OS compared with lapatinib-capecitabine . CONCLUSION : DB05773 is a novel ADC effective for P04626 -positive MBC in patients previously treated with trastuzumab , lapatinib , and a taxane . Further studies will determine its use in the adjuvant and neoadjuvant setting and in combination with pertuzumab . Characterization of P04626 status by fluorescence in situ hybridization ( Q5TCZ1 ) and immunohistochemistry ( IHC ) . The use of human epidermal growth factor receptor type 2 ( P04626 ) gene amplification and overexpression as a molecular predictive marker has become critically important for proper selection of breast cancer patients for treatment with targeted therapeutic agents such as trastuzumab , lapatinib , pertuzumab , and DB05773 . A high level of sensitivity and specificity of molecular tests for this alteration is desirable . The American Society of Clinical Oncology and College of American Pathology have jointly established consensus guidelines to standardize characterization of this alteration in breast cancers . This chapter provides a brief overview of pre-analytic and analytical processing of breast specimens as well as subsequent molecular evaluation for P04626 status . Treating metastatic breast cancer with systemic chemotherapies : current trends and future perspectives . Treatment selection for metastatic breast cancer ( MBC ) is guided by multiple factors , most importantly hormone receptor ( HR ) or P04626 expression , treatment history , and prognostic factors such as short disease-free interval , presence of visceral metastases , performance status , and degree of symptoms . Chemotherapy is indicated as initial therapy for patients with HR-negative disease and following failure of hormonal therapies in HR-positive disease . Patients treated with an anthracycline or a taxane in early-stage settings may no longer be candidates for those drugs in MBC , thus underscoring the need for alternative options . Sequential single-agent therapy or combination therapy are viable strategies . Trials have shown that ixabepilone plus capecitabine significantly improves progression-free survival compared with capecitabine alone in anthracycline- or taxane-pretreated or -resistant patients , and single-agent eribulin improves survival compared with the physician 's choice of treatment in patients treated previously with at least two regimens for MBC . Regardless of the regimen , proactive management to detect treatment-related adverse events in a timely manner remains important for ensuring effective delivery of treatment . Many promising investigational agents are in development , including DB05773 ( trastuzumab emtansine ) and pertuzumab for P04626 -positive disease , as well as P09874 ( poly [ adenosine diphosphate ribose ] polymerase-1 ) inhibitors and cetuximab for triple-negative disease . In addition , new options for the treatment of MBC following failure of an anthracycline and a taxane promise to improve patient outcomes . Nurses should remain vigilant for adverse events and remember that the goal of treatment remains control of the disease and palliation . Nursing perspectives on trastuzumab emtansine for the treatment of metastatic breast cancer . Increased understanding of the molecular composition of breast cancer tumors has led to the development of targeted anticancer agents . Novel therapies directed against human epidermal growth factor receptor 2 ( P04626 ) in breast cancer have been developed . One such agent , trastuzumab emtansine ( DB05773 ) , is an antibody drug conjugate that has been shown to be effective in the treatment of women with P04626 -positive breast cancer . Phase I and II studies have determined a maximum tolerated dose , and several phase Ib/II , II , and III studies have shown improved tolerability and efficacy compared with the combination of trastuzumab and chemotherapy . The most concerning grade 3 or higher adverse events associated with DB05773 include thrombocytopenia and transaminitis . To ensure that these adverse events do not delay or interrupt treatment , oncology nurses need to familiarize themselves with these risks and their management . This article reviews the clinical development of DB05773 and its usage , with a focus on the nurse 's role in preventing and managing adverse events associated with DB05773 therapy . Triple negative breast cancer : therapeutic and prognostic implications . Triple negative breast cancers ( TNBC ) lack oestrogen receptor ( ER ) , progesterone receptor ( PR ) , nor over-express human epidermal growth factor receptor 2 ( P04626 ) . Epidemiologic studies demonstrate that women diagnosed with TNBC manifest a significantly different set of clinic-pathologic features and risk factors when compared to women with other subtypes of breast cancer . They are associated with poor prognosis , as defined by low five-year survival . To date many studies have examined the utility of traditional chemotherapy for the treatment of patients with TNBC and have confirmed the benefits of these agents in both the adjuvant and neoadjuvant settings . Targeted therapy options involving P09874 and P00533 inhibition , are currently in different phases of development and will hopefully change the paradigm of how patients with TNBC are treated . The present commentary aims to summarize the latest findings on chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents . A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine ( DB05773 ) , an antibody-drug conjugate ( ADC ) for treatment of metastatic breast cancer . DB00072 emtansine ( DB05773 ) is an antibody-drug conjugate ( ADC ) therapeutic for treatment of human epidermal growth factor receptor 2 ( P04626 ) -positive cancers . The DB05773 dose product contains a mixture of drug-to-antibody ratio ( DAR ) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody . The pharmacokinetics ( PK ) underlying this system and other ADCs are complex and have not been elucidated . Accordingly , we have developed two PK modeling approaches from preclinical data to conceptualize and understand DB05773 PK , to quantify rates of DM1 deconjugation , and to elucidate the link between trastuzumab , DB05773 , and DAR measurements . Preclinical data included PK studies in rats ( n = 34 ) and cynomolgus monkeys ( n = 18 ) at doses ranging from 0.3 to 30 mg/kg and in vitro plasma stability . DB05773 and total trastuzumab ( TT ) plasma concentrations were measured by enzyme-linked immunosorbent assay . Individual DAR moieties were measured by affinity capture liquid chromatography-mass spectrophotometry . Two PK modeling approaches were developed for DB05773 using NONMEM 7.2 software : a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and DB05773 concentrations . DAR moieties were well described with a three-compartmental model and DM1 deconjugation in the central compartment . DM1 deconjugated fastest from the more highly loaded trastuzumab molecules ( i.e. , DAR moieties that are ≥3 DM1 per trastuzumab ) . DB05773 clearance ( CL ) was 2-fold faster than TT CL due to deconjugation . The two modeling approaches provide flexibility based on available analytical measurements for DB05773 and a framework for designing ADC studies and PK-pharmacodynamic modeling of ADC efficacy- and toxicity-related endpoints . Alloreactive memory T cells are responsible for the persistence of graft-versus-host disease . Graft-vs-host disease ( GVHD ) is caused by a donor T cell anti-host reaction that evolves over several weeks to months , suggesting a requirement for persistent alloreactive T cells . Using the C3H.SW anti-C57BL/6 ( B6 ) mouse model of human GVHD directed against minor histocompatibility Ags , we found that donor CD8(+) T cells secreting high levels of P01579 in GVHD B6 mice receiving C3H.SW naive CD8(+) T cells peaked by day 14 , declined by day 28 after transplantation , and persisted thereafter , corresponding to the kinetics of a memory T cell response . Donor CD8(+) T cells recovered on day 42 after allogeneic bone marrow transplantation expressed the phenotype of P16070 (high)CD122(high)CD25(low) , were able to homeostatically survive in response to P60568 , P13232 , and P40933 and rapidly proliferated upon restimulation with host dendritic cells . Both allogeneic effector memory ( P16070 (high)CD62L(low) ) and central memory ( P16070 (high)CD62L(high) ) CD8(+) T cells were identified in B6 mice with ongoing GVHD , with effector memory CD8(+) T cells as the dominant ( > 80 % ) population . Administration of these allogeneic memory CD8(+) T cells into secondary B6 recipients caused virulent GVHD . A similar allogeneic memory P01730 (+) T cell population with the ability to mediate persistent GVHD was also identified in BALB/b mice receiving minor histocompatibility Ag-mismatched B6 T cell-replete bone marrow transplantation . These results indicate that allogeneic memory T cells are generated in vivo during GVH reactions and are able to cause GVHD , resulting in persistent host tissue injury . Thus , in vivo blockade of both alloreactive effector and memory T cell-mediated host tissue injury may prove to be valuable for GVHD prevention and treatment . Poly( DB02059 )polymerase-1 signalling of the DNA damage induced by P11387 poison in D54(p53wt) and U251(p53mut) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor-mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor DB01030 and the poly( DB02059 )polymerase-1 inhibitor DB02690 in D54(p53wt) and U251(p53mut) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti-proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2/M block of the cell cycle . We also evaluated , the influence of TPT+/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT-dependent increase of P09874 auto-modification level in both the cells . Moreover , in the D54(p53wt) cells we found that in co-treatments DB02690 incremented the TPT-dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251(p53mut) cells we found that DB02690 incremented the TPT-dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status . The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft-versus-host disease . The influence of Q13216 on T-cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 -treated cultures showed fewer CD56(+)CD16(+) P55040 (+) NK cells and a reciprocal increase in CD56(+)CD16(-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56(dim) NK-cell subpopulation and a relative resistance of CD56(bright) NK cells to Q13216 . Following coculture with K562 targets , Q13216 -exposed NK cells differed from controls and lacked Ca(2+) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand-expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL-12 and Q14116 stimulation , Q13216 -treated NK cells showed more P01579 -producing cells . Using in vitro NK-cell differentiation , progenitor cells gave rise to more CD56(+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK-cell function and phenotype , which may have important implications for graft-versus-leukemia effects . Systemic treatment of P04626 -positive metastatic breast cancer : a systematic review . AIM : We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of P04626 -positive metastatic breast cancer . METHODS : We reviewed phase 2 and 3 studies in which an anti- P04626 agent was used in one or both arms of the study . While formal meta-analysis was not possible for such a heterogeneous group of trials , resulting forest plots outline some generalizable findings . RESULTS : There is strong evidence that the addition of an anti- P04626 agent to standard chemo- or endocrine therapy improves clinically relevant measurable outcomes . There is also consistent evidence that initial treatment with trastuzumab alone ( and subsequent use of a cytotoxic ) is inferior to the initial combination of trastuzumab plus chemotherapy , and that either DB05773 or dual anti- P04626 agents are superior to single anti- P04626 agent regimens . There is no strong evidence that the use of more than one cytotoxic agent together with an anti- P04626 agent confers any benefit over a single cytotoxic , anti- P04626 combination . CONCLUSION : This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting . DB05773 ( DB05773 ) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer . DB00072 ( Herceptin(®) ) is currently used as a treatment for patients whose breast tumors overexpress P04626 /ErbB2 . DB05773 ( DB05773 , trastuzumab emtansine ) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug , DM1 ( a maytansine derivative ) . Currently DB05773 is being tested in multiple clinical trials . The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway , inhibition of HER-2 shedding and Fcγ receptor mediated engagement of immune cells , which may result in antibody-dependent cellular cytotoxicity ( ADCC ) . Here we report that DB05773 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors . P04626 -family signalling mechanisms , clinical implications and targeting in breast cancer . Approximately 20 % of human breast cancers ( BC ) overexpress P04626 protein , and P04626 -positivity is associated with a worse prognosis . Although P04626 -targeted therapies have significantly improved outcomes for P04626 -positive BC patients , resistance to trastuzumab-based therapy remains a clinical problem . In order to better understand resistance to P04626 -targeted therapies in P04626 -positive BC , it is necessary to examine HER family signalling as a whole . An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in P04626 -positive BC and response to P04626 -targeted therapy . Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding ( Q99102 , p95HER2 ) , increased signalling through alternative HER family receptor tyrosine kinases ( RTK ) , altered intracellular signalling involving loss of P60484 , reduced p27kip1 , or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as P08069 . Emerging strategies to circumvent resistance to P04626 -targeted therapies in P04626 -positive BC include co-targeting P04626 /PI3K , pan-HER family inhibition , and novel therapies such as DB05773 . There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy , and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies . With our rapidly expanding understanding of P04626 signalling mechanisms along with the repertoire of HER family and other targeted therapies , it is likely that the near future holds further dramatic improvements to the prognosis of women with P04626 -positive BC . DB00072 emtansine in human epidermal growth factor receptor 2-positive breast cancer : a review . PURPOSE OF REVIEW : In this review , we aim to update the clinical data of trastuzumab-DM1 ( DB05773 ) in terms of safety and efficacy , and describe ongoing and future trials evaluating its potential role in the management of patients with human epidermal growth factor receptor 2 ( P04626 ) -positive breast cancer . RECENT FINDINGS : DB00072 emtansine ( DB05773 ) is an antibody drug conjugate that optimizes delivery of chemotherapy with an anti- P04626 monoclonal antibody . As a conjugate , DB05773 's systemic side effects are significantly minimized due to its targeted delivery by trastuzumab to P04626 -positive cells . Phase I and II studies show that the maximum tolerated dose , and thus the recommended dose for DB05773 , is 3.6 mg/kg given intravenously every 3 weeks . Single arm phase Ib/II , II and a randomized phase II first-line study of DB05773 versus the combination of trastuzumab + docetaxel all showed improved tolerability , and at least equivalent efficacy , compared with our current standard of care . Two randomized phase III registration studies are now active , evaluating this agent in the refractory and first-line P04626 -positive settings . SUMMARY : DB05773 has been shown to be a very promising agent for the targeted delivery of chemotherapy and anti- P04626 monoclonal antibody therapy for patients with metastatic , P04626 -positive breast cancer . DB05773 will likely play a role in the management of patients with advanced and early stage P04626 -positive breast cancer , but this awaits further study . Exposure-response relationship of DB05773 : insight into dose optimization for patients with P04626 -positive metastatic breast cancer . Exposure-response ( E-R ) analyses for ado-trastuzumab emtansine ( DB05773 , Kadcyla ) were performed using data from a randomized , active control ( lapatinib plus capecitabine ) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer . Kaplan-Meier survival analyses stratified by DB05773 trough concentration on day 21 of cycle 1 ( Cmin,C1D21 ) were performed for overall survival ( OS ) and progression-free survival ( PFS ) . E-R analyses indicated that after adjusting for baseline risk factors , higher DB05773 exposure is associated with improved efficacy . DB05773 -treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm . The percentage of patients who received DB05773 dose adjustments was similar across the exposure range and was lower than that of the active control arm . Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low DB05773 exposure for improved efficacy with acceptable tolerability . Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17-1A and interleukin-2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co-medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin-2 ( P60568 ) induced cytotoxicity and P60568 -induced-ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 -induced-ADCC . DB00904 , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type-2 receptor antagonist augmented the P60568 -induced-ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type-2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC . Modeling the efficacy of trastuzumab-DM1 , an antibody drug conjugate , in mice . DB05773 ( DB05773 ) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 ( P04626 ) -positive metastatic breast cancer . One challenge in oncologic drug development is determining the optimal dose and treatment schedule . A novel dose regimen-finding strategy was developed for DB05773 using experimental data and pharmacokinetic/pharmacodynamic modeling . To characterize the disposition of DB05773 , pharmacokinetic studies were conducted in athymic nude and beige nude mice . The pharmacokinetics of DB05773 were described well by a two-compartment model . Tumor response data were obtained from single-dose , multiple-dose and time-dose-fractionation studies of DB05773 in animal models of P04626 -positive breast cancer , specifically engineered to be insensitive to trastuzumab . A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of DB05773 . A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of DB05773 . Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to DB05773 ; anti-tumor activity was schedule independent ; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis . DB00072 emtansine in the treatment of P04626 -positive metastatic breast cancer in Japanese patients . Anti- P04626 agents , such as trastuzumab , lapatinib , trastuzumab emtansine ( DB05773 ) , and pertuzumab , are standard agents in the treatment of breast cancer overexpressing the human epidermal growth factor receptor 2 ( P04626 ) . DB00072 is the first approved P04626 -targeted agent . Subsequent developments include agents with different mechanisms . In this paper , we review the results of clinical trials of DB05773 , a new anti- P04626 agent , with a focus on Japanese patients with breast cancer . On the basis of results from a Phase I study ( JO22591 ) , the maximum tolerated dose was determined to be 3.6 mg/kg every 3 weeks for both Japanese and western patients . In a Phase II study ( JO22997 ) , the overall response rate was 38.4 % ( 90 % confidence interval 28.8-48.6 ) . DB05773 was well tolerated in Japanese patients ; however , the incidence of grade 3 or 4 thrombocytopenia was higher than that observed in earlier western studies , but was not associated with clinically important symptoms . Pharmacokinetic parameters for DB05773 and its metabolites were consistent with those reported previously from a Phase I or II study in non-Japanese patients , and the data obtained showed no suggestion of ethnic differences . Several Phase III studies of DB05773 are ongoing throughout the world , including in Japanese patients with breast cancer . The adjuvant treatment of P04626 -positive breast cancer . About 15-20 % of patients with early stage breast cancer present with tumors that have overexpression or amplification of the human epidermal growth factor receptor 2 ( P04626 ) gene . Before 2005 , these individuals had an increased risk of recurrence and death , but since then their outcomes have substantially improved with the adoption in most countries of adjuvant trastuzumab as a standard component of therapy for P04626 -positive early-stage breast cancer . Consequently , access to high-quality and accurate P04626 testing methods is critical to accurately determine P04626 status , guide treatment decisions , and ultimately improve clinical outcomes . In 2012 , the humanized monoclonal anti-HER antibody trastuzumab was the only approved P04626 -targeted therapy in the adjuvant setting . Data from the first generation of trials combining it with various chemotherapy regimens showed significant improvements in disease-free and overall survival ( DFS/OS ) . Based on results from five randomized clinical trials , a trastuzumab-containing regimen for up to 1 year is now considered standard for all patients with P04626 -positive tumors larger than 1 cm in size who would have fulfilled eligibility to those studies , and this recommendation is sometimes extended to patients with stage I tumors greater than 0.5 cm ( T1b ) . Second generation adjuvant studies with other P04626 -targeted agents like lapatinib and pertuzumab are ongoing , and newer drugs like DB05773 and neratinib are being actively tested in the metastatic setting . A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 *3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol-sensitive patient was found to possess , in addition to P11712 *3 allele , a P11712 *11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions DB01418 sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare *11 allele . Population pharmacokinetics of trastuzumab emtansine ( DB05773 ) , a P04626 -targeted antibody-drug conjugate , in patients with P04626 -positive metastatic breast cancer : clinical implications of the effect of covariates . PURPOSE : DB00072 emtansine ( DB05773 ) is an antibody-drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1 , a highly potent cytotoxic agent . A population pharmacokinetic ( PK ) analysis was performed to estimate typical values and interindividual variability of DB05773 PK parameters and the effects of clinically relevant covariates . METHODS : Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer ( MBC ) who received single-agent DB05773 in five phase I to phase III studies . Nonlinear mixed-effects modeling with the first-order conditional estimation method was used . RESULTS : A linear two-compartment model with first-order elimination from the central compartment described DB05773 PKs in the clinical dose range . DB05773 elimination clearance was 0.676 L/day , volume of distribution in the central compartment ( V c ) was 3.127 L , and terminal elimination half-life was 3.94 days . Age , race , region , and renal function did not influence DB05773 PK . Given the low-to-moderate effect of all statistically significant covariates on DB05773 exposure , none of these covariates is expected to result in a clinically meaningful change in DB05773 exposure . CONCLUSIONS : DB05773 PK properties are consistent and predictable in patients . A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC . Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine , a P04626 -targeted antibody-drug conjugate , in patients with P04626 -positive metastatic breast cancer . DB00072 emtansine ( DB05773 ) is a P04626 -targeted antibody-drug conjugate in development for treatment of P04626 -positive cancers . DB05773 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer ( MBC ) , with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing . The authors present results from the population pharmacokinetics analysis for DB05773 . Population pharmacokinetics for DB05773 were characterized using a clinical database of 273 patients from the 3 studies . Pharmacokinetics was best described by a linear 2-compartment model . Population estimates ( interindividual variability [ IIV ] ) for pharmacokinetic parameters were clearance , 0.7 L/d ( 21.0 % ) ; central compartment volume ( V(c) ) , 3.33 L ( 13.2 % ) ; peripheral compartment volume ( V(p) ) , 0.89 L ( 50.4 % ) ; and intercompartmental clearance , 0.78 L/d . Body weight , albumin , tumor burden , and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in DB05773 pharmacokinetics , with body weight having a greater effect on IIV of clearance and V(c) than other covariates . DB05773 exposure was relatively consistent across the weight range following body weight-based dosing . This analysis suggests no further DB05773 dose adjustments are necessary in heavily pretreated patients with MBC . Targeting the P04626 receptor in metastatic breast cancer . The advent of targeted therapies has revolutionized the treatment of certain types of cancer . Identification of molecular targets on cancer cells has led to the design of novel drugs , which either used as single agents or in combination with chemotherapy , has prolonged survival in metastatic disease , or contributed to curative treatment in the adjuvant setting . A literature review was conducted to identify and present current knowledge on the molecular function of the P04626 receptor , its role in the pathogenesis of breast cancer and anti- P04626 targeted drugs in use or under development . Many molecular targets have been identified in breast cancer , with the HER family of receptors being the ones most extensively studied . DB00072 and lapatinib target the P04626 receptor and are approved drugs for the treatment of metastatic breast cancer . Several other targeted agents , including DB05773 , pertuzumab , neratinib , afatinib and ertumaxomab , are currently being tested in vivo as well as in clinical studies . The use of targeted therapies in metastatic breast cancer has improved prognosis , increased survival and dramatically changed the way we treat breast cancer patients today . Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with P04626 -positive metastatic breast cancer . OBJECTIVE : DB00072 emtansine ( DB05773 ) , an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker , has shown clinical activity in human epidermal growth factor receptor 2-positive metastatic breast cancer patients . This study evaluated the maximum tolerated dose , toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients . METHODS : Inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered trastuzumab emtansine intravenously at a dose of 1.8 , 2.4 or 3.6 mg/kg every 3 weeks . The maximum tolerated dose was estimated using the continual reassessment method . RESULTS : This study enrolled 10 patients who were administered trastuzumab emtansine for a median of seven cycles . The dose-limiting toxicity was Grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level . The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients , the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25 % at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that . The most frequent adverse events were nausea , arthralgia , fever , fatigue and decreased appetite . Adverse events were generally tolerable . The maximum concentration and area under the concentration-time curve increased linearly with the dose . CONCLUSIONS : DB00072 emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients . Although thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials , those adverse events recovered without special supportive treatment . Targeting of T lymphocytes to Neu/ P04626 -expressing cells using chimeric single chain Fv receptors . Cell surface molecules essential for the transformed phenotype or growth of malignant cells are attractive targets for anticancer immunotherapy . Antibodies specific to Neu/ P04626 , a human adenocarcinoma-associated growth factor receptor , were demonstrated to have tumor-inhibitory capacity . Yet , the inefficient accessibility of antibodies to solid tumors limits their clinical use . To redirect effector lymphocytes to adenocarcinomas , we constructed and functionally expressed in T cells chimeric single chain receptor genes incorporating both the Ag-binding domain of anti-Neu/ P04626 antibodies and the zeta-signal-transducing subunit of the TCR/CD3 complex or the gamma-signal-transducing subunit of the Ig Fc receptor complex . Surface expression of the anti-Neu/ P04626 chimeric genes in cytotoxic T cell hybridomas endowed them with specific Neu/ P04626 recognition enabling their activation for P60568 production and lysis of transformed cells overexpressing Neu/ P04626 . These chimeric genes hold promise for the immunotherapy of cancer . DB00072 emtansine in breast cancer . INTRODUCTION : DB00072 emtansine ( DB05773 ) is a human epidermal growth factor receptor 2 ( P04626 ) -targeted antibody-drug conjugate ( ADC ) composed of trastuzumab , a stable linker ( MCC ) , and the cytotoxic agent DM1 ( derivative of maytansine ) . Administration of DB05773 leads to limited systemic exposure of free DM1 , with no evidence of DM1 accumulation after repeated dosing . AREAS COVERED : Phase I and Phase II clinical trials with DB05773 as a single agent and in combination with paclitaxel , docetaxel , and pertuzumab have shown substantial clinical activity and a favorable safety profile . A randomized , open-label , first-line trial comparing trastuzumab and docetaxel with single agent DB05773 showed a significant improved progression-free survival for DB05773 . EXPERT OPINION : DB05773 has successfully completed second-line Phase III development for advanced P04626 -positive breast cancer . The Phase III EMILIA study demonstrated an overall survival benefit for DB05773 compared to the combination of lapatinib and capecitabine in taxane-trastuzumab pretreated patients . DB05773 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner . DB05773 : a clinical update of the novel antibody-drug conjugate for P04626 -overexpressing breast cancer . DB00072 is a monoclonal antibody targeted against the P04626 tyrosine kinase receptor . Although trastuzumab is a very active agent in P04626 -overexpressing breast cancer , the majority of patients with metastatic P04626 -overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and , in the adjuvant setting , progress despite trastuzumab-based therapy . The antibody-drug conjugate trastuzumab-DM1 ( DB05773 ) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent , DM1 ( N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol ) , a maytansine derivative , to P04626 -overexpressing breast cancer cells . DB05773 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials . Phase I and II clinical trials of DB05773 as a single agent and in combination with paclitaxel , docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with P04626 -positive metastatic breast cancer . Two randomized phase III trials of DB05773 are awaiting final results ; the EMILIA trial is evaluating DB05773 compared with lapatinib plus capecitabine , and early positive results have been reported . The MARIANNE trial is evaluating DB05773 plus placebo versus DB05773 plus pertuzumab versus trastuzumab plus a taxane . Here , we summarize evidence from clinical studies and discuss the potential clinical implications of DB05773 . Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes : evidence for in situ t-cell activation and therapeutic efficacy . After adoptive transfer of pre-activated lymphocytes into the operation cavity of glioma patients , tumor regression and improved survival have been reported in some patients . Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied . In this study , we attempted to avoid time-consuming pre-activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the P01133 receptor ( P00533 ) on tumor cells and to CD3 and P10747 on T cells . Eleven patients with high-grade malignant glioma received 3 injections of 2 bispecific antibody fragments ( P00533 x CD3 and P00533 x P10747 ) together with freshly isolated autologous lymphocytes via an Ommaya reservoir . Intracavitary fluid aspirated during immunotherapy was examined for markers of T-cell activation . Increased levels of soluble P60568 receptor and P01375 were detected in the intracavitary fluid of all patients tested . Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent Q9BWK5 scans and prolonged survival . Side effects were transient and consisted of fever , nausea , headache and aggravation of pre-existing neurologic deficits . These adverse effects were most likely due to the antibody construct containing anti-CD3 specificity . Two patients developed cerebral edema and required steroid treatment . Influence of a 3-day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . DB00207 was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg/day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C(max) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5/day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98,116 ) and 119 ( 104,136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg/dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together . Why your preferred targeted drugs may become unaffordable . DB00072 , a monoclonal antibody directed at the P04626 receptor , is one of the most impressive targeted drugs developed in the last two decades . Indeed , when given in conjunction with chemotherapy , it improves the survival of women with P04626 positive breast cancer , both in advanced and in early disease . Its optimal duration , however , is poorly defined in both settings with a significant economic impact in the adjuvant setting where the drug is arbitrarily given for 1 year . This article reviews current attempts at shortening this treatment duration , emphasizing the likelihood of inconclusive results and , therefore , the need to investigate this important variable as part of the initial pivotal trials and with the support of public health systems . Failure to do so has major consequences on treatment affordability . Ongoing adjuvant trials of dual P04626 blockade , using trastuzumab in combination with a second anti- P04626 agent , and trials of the antibody-drug conjugate DB05773 ( trastuzumab-emtansine ) have to all be designed with 12 months of targeted therapy . DB00072 emtansine : a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer . DB00072 emtansine ( DB05773 ) is a human epidermal growth factor receptor ( P04626 ) -targeted antibody-drug conjugate , composed of trastuzumab , a stable thioether linker , and the potent cytotoxic agent DM1 ( derivative of maytansine ) , in phase III development for P04626 -positive cancer . Extensive analysis of DB05773 in preclinical studies has shown that DB05773 combines the distinct mechanisms of action of both DM1 and trastuzumab , and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models . Clinically , DB05773 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1 , with no evidence of DM1 accumulation following repeated DB05773 doses . Although a few covariates were shown to affect interindividual variability in DB05773 exposure and clearance in population-pharmacokinetics analyses , the magnitude of their effect on DB05773 exposure was not clinically relevant . Phase I and phase II clinical trials of DB05773 as a single agent and in combination with paclitaxel , docetaxel , and pertuzumab have shown clinical activity and a favorable safety profile in patients with P04626 -positive metastatic breast cancer . Two randomized phase III trials of DB05773 are recruiting patients : EMILIA ( NCT00829166 ) is evaluating DB05773 compared with lapatinib plus capecitabine , and MARIANNE ( NCT01120184 ) is evaluating DB05773 plus placebo versus DB05773 plus pertuzumab versus trastuzumab plus a taxane . Additional combinations of DB05773 ( for example , with P16260 -0941 ) and additional disease settings ( early-stage P04626 -positive breast cancer ) are also under investigation . Data from the phase III trials and other studies of DB05773 -containing agents are eagerly awaited . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .