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1.
Breast Cancer Res Treat ; 197(2): 435-447, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36414795

ABSTRACT

PURPOSE: The aim was to understand real-world cyclin-dependent kinase (CDK) 4 and 6 inhibitor use in Japan. METHODS: This retrospective observational study used a Japanese administrative claims database and included patients with presumptive hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) prescribed CDK4 and 6 inhibitor therapy between December 2017 and March 2021. Patient characteristics, treatment patterns, and selected clinical and safety outcomes were descriptively summarized. Time to discontinuation (TTD) and chemotherapy-free survival (CFS) were examined using Kaplan-Meier estimates. RESULTS: The study cohort (N = 6442) was predominantly female (99.4%; median [range] age 64 [26-99] years) with records of metastases (79.6%) within 1 year prior to initiating CDK4 and 6 inhibitor therapy. In total, 4463 (69.3%) and 1979 (30.7%) were prescribed palbociclib and abemaciclib, respectively, as their first CDK4 and 6 inhibitor, most commonly in combination with fulvestrant (n = 3801; 59.0%). Overall, 3756 patients initiated a subsequent anticancer treatment, of whom 748 (19.9%) initiated a different CDK4 and 6 inhibitor in combination with the same or different endocrine therapy. Median TTD (95% confidence interval) was 9.7 (9.3, 10.1) months for the first CDK4 and 6 inhibitor therapy. Median CFS was 26.1 (24.6, 27.8) months. Incidence of clinically relevant diarrhea was higher after abemaciclib initiation (9.8%) than after palbociclib initiation (1.5%). More patients experienced dose reduction with palbociclib (69.3%) than with abemaciclib (53.0%). CONCLUSION: The data provide insights into current clinical practices for CDK4 and 6 inhibitor use in Japan that could help establish future treatment strategies for ABC.


Subject(s)
Breast Neoplasms , Humans , Female , Middle Aged , Male , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/metabolism , Cyclin-Dependent Kinase 4 , East Asian People , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Protein Kinase Inhibitors/adverse effects
2.
Gan To Kagaku Ryoho ; 50(12): 1283-1294, 2023 12.
Article in English | MEDLINE | ID: mdl-38247066

ABSTRACT

Real-world evidence for clinical outcomes and treatment patterns in patients with hormone receptor-positive(HR+)and human epidermal growth factor receptor 2-negative(HER2-)early breast cancer(EBC)in Japan is limited. We aimed to provide recent evidence in this population using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan(NDB). Adults ≥20 years old who were diagnosed with HR+/HER2- breast cancer and underwent breast resection surgery were followed up. Patient characteristics and treatment patterns were evaluated. Durations of overall post-operative endocrine therapy(ET)and luteinizing hormone-releasing hormone(LH-RH)agonist therapy, and time to metastasis/recurrence after surgery were analyzed using Kaplan-Meier method. Overall, 294,904 patients were included. Cyclophosphamide and tamoxifen were the most common peri-operative chemotherapeutic and ET drugs. Median(95% confidence interval[CI])duration of post-operative ET and LH-RH agonist therapy was 5.01(5.01-5.01)years and 2.13 (2.12-2.14)years, respectively. Five-year cumulative rate(95% CI)of any recurrence was 8.6%(8.5-8.7), visceral metastasis being the most common. Nation-wide treatment patterns were described, which were consistent with guideline recommendations for patients with HR+, HER2- EBC. Further discussion is required to delay metastasis/recurrence and improve clinical outcomes(Fig. 1: Plain language summary of the study).


Subject(s)
Breast Neoplasms , Adult , Humans , Young Adult , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Japan , Cyclophosphamide , Tamoxifen , Gonadotropin-Releasing Hormone
3.
Gan To Kagaku Ryoho ; 49(10): 1077-1086, 2022 Oct.
Article in Japanese | MEDLINE | ID: mdl-36281599

ABSTRACT

The purpose of this study was to investigate adherence to adjuvant endocrine therapy (ET) and the factors affecting demotivation and motivation to continue adjuvant ET. In patients with hormone receptor-positive breast cancer in Japan, an online survey was conducted from June to July 2021 to investigate the treatment effects, side effects, concerns about side effects(for demotivation only), convenience of hospital visits, treatment duration, concerns about recurrence/progression, treatment cost, support from healthcare professionals, and support from family, the patient association, and peers(for motivation only). According to the responses from 263 patients, the most common factor affecting demotivation to continue adjuvant ET was the burden of side effects, and the most common factor affecting motivation to continue adjuvant ET was concerns about recurrence/progression. Continuous relief of the burden of side effects from the early stage of treatment, and mental support for concerns about recurrence/progression, as well as explaining and promoting the risks and benefits of continuing treatment, are considered to lead to motivation to continue adjuvant ET(Fig. 1: Summary of this survey).


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Antineoplastic Agents, Hormonal/adverse effects , Chemotherapy, Adjuvant , Japan , Medication Adherence
4.
PLoS One ; 10(1): e0116135, 2015.
Article in English | MEDLINE | ID: mdl-25617756

ABSTRACT

Despite the recent advances in the treatment of multiple myeloma (MM), MM patients with high-risk cytogenetic changes such as t(4;14) translocation or deletion of chromosome 17 still have extremely poor prognoses. With the goal of helping these high-risk MM patients, we previously developed a novel phthalimide derivative, TC11. Here we report the further characterization of TC11 including anti-myeloma effects in vitro and in vivo, a pharmacokinetic study in mice, and anti-osteoclastogenic activity. Intraperitoneal injections of TC11 significantly delayed the growth of subcutaneous tumors in human myeloma-bearing SCID mice. Immunohistochemical analyses showed that TC11 induced apoptosis of MM cells in vivo. In the pharmacokinetic analyses, the Cmax was 2.1 µM at 1 h after the injection of TC11, with 1.2 h as the half-life. TC11 significantly inhibited the differentiation and function of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts in mouse osteoclast cultures using M-CSF and RANKL. We also revealed that TC11 induced the apoptosis of myeloma cells accompanied by α-tubulin fragmentation. In addition, TC11 and lenalidomide, another phthalimide derivative, directly bound to nucleophosmin 1 (NPM1), whose role in MM is unknown. Thus, through multiple molecular interactions, TC11 is a potentially effective drug for high-risk MM patients with bone lesions. The present results suggest the possibility of the further development of novel thalidomide derivatives by drug designing.


Subject(s)
Multiple Myeloma/pathology , Phthalimides/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Evaluation, Preclinical , Half-Life , Heterografts/drug effects , Humans , Lenalidomide , Male , Mice, Inbred ICR , Mice, SCID , Multiple Myeloma/genetics , Nuclear Proteins/chemistry , Nucleophosmin , Osteoclasts/drug effects , Phthalimides/chemistry , Phthalimides/pharmacokinetics , Thalidomide/analogs & derivatives , Thalidomide/chemistry , Thalidomide/pharmacology
5.
Biochem Biophys Res Commun ; 457(4): 589-94, 2015 Feb 20.
Article in English | MEDLINE | ID: mdl-25600804

ABSTRACT

BEN domain-containing protein 3 (BEND3) has recently been reported to function as a heterochromatin-associated protein in transcriptional repression in the nucleus. BEND3 should have nuclear localization signals (NLSs) to localize to the nucleus in light of its molecular weight, which is higher than that allowed to pass through nuclear pore complexes. We here analyzed the subcellular localization of deletion/site-directed mutants of human BEND3 by an immunofluorescence assay in an attempt to identify the amino acids essential for its nuclear localization. We found that three basic amino acid residues located in the N-terminal region of BEND3 (BEND356-58, KRK) are essential, suggesting that these residues play a role as a functional NLS. These results provide valuable information for progressing research on BEND3.


Subject(s)
Amino Acids, Basic/analysis , Cell Nucleus/chemistry , Repressor Proteins/analysis , Amino Acid Sequence , HeLa Cells , Humans , Molecular Sequence Data , Nuclear Localization Signals
6.
Immun Inflamm Dis ; 2(1): 35-43, 2014 Jun.
Article in English | MEDLINE | ID: mdl-25400923

ABSTRACT

BEN domain-containing protein 3 (BEND3) has no transmembrane region, is localized in the cytoplasm, and is involved in chromatin function and transcription. We here identified a novel subpopulation of human T cells that expressed BEND3 on their cell surface (BEND3(+) T cells). BEND3(+) T cells consisted of approximately 3% of T cells in the peripheral blood, were present in both CD4(+) and CD8(+) T cells, and were also observed in cord blood. The stimulation of BEND3(+) T cells through the TCR/CD3 complex led to the production of various kinds of cytokines; however, the levels of IL-6 and IL-8 produced by BEND3(+) T cells were higher than those by BEND3(-) T cells. The proportion of BEND3(+) T cells was also increased in some patients with inflammatory diseases. Taken together, these results indicate that BEND3(+) T cells are a new subpopulation of T cells in terms of their cytokine profile. Further analyses on BEND3(+) T cells may be of importance and useful in understanding human T cell immunology.

7.
PLoS One ; 9(10): e109163, 2014.
Article in English | MEDLINE | ID: mdl-25275651

ABSTRACT

The oncoprotein MDM2 binds to tumor suppressor protein p53 and inhibits its anticancer activity, which leads to promotion of tumor cell growth and tumor survival. Abrogation of the p53:MDM2 interaction reportedly results in reactivation of the p53 pathway and inhibition of tumor cell proliferation. We recently performed rigorous selection of MDM2-binding peptides by means of mRNA display and identified an optimal 12-mer peptide (PRFWEYWLRLME), named MDM2 Inhibitory Peptide (MIP), which shows higher affinity for MDM2 (and also its homolog, MDMX) and higher tumor cell proliferation suppression activity than known peptides. Here we determined the NMR solution structure of a MIP-MDM2 fusion protein to elucidate the structural basis of the tight binding of MIP to MDM2. A region spanning from Phe3 to Met11 of MIP forms a single α-helix, which is longer than those of the other MDM2-binding peptides. MIP shares a conserved Phe3-Trp7-Leu10 triad, whose side chains are oriented towards and fit into the hydrophobic pockets of MDM2. Additionally, hydrophobic surface patches that surround the hydrophobic pockets of MDM2 are covered by solvent-exposed MIP residues, Trp4, Tyr6, and Met11. Their hydrophobic interactions extend the interface of the two molecules and contribute to the strong binding. The potential MDM2 inhibition activity observed for MIP turned out to originate from its enlarged binding interface. The structural information obtained in the present study provides a road map for the rational design of strong inhibitors of MDM2:p53 binding.


Subject(s)
Peptides/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , RNA, Messenger/genetics , Tumor Suppressor Protein p53/antagonists & inhibitors , Humans , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Protein Conformation , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/genetics , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/genetics
8.
PLoS One ; 9(4): e94324, 2014.
Article in English | MEDLINE | ID: mdl-24710513

ABSTRACT

The agonistic anti-human CD3ε antibody (Ab), OKT3, has been used to control acute transplant rejection. The in vivo administration of OKT3 was previously shown to induce the partial depletion of T cells and unresponsiveness (anergy) in the remaining CD4+ T cells. However, this therapy is also associated with the systemic release of several cytokines, which leads to a series of adverse side effects. We established a novel anti-human CD3ε Ab, 20-2b2, which recognized a close, but different determinant on the CD3ε molecule from that recognized by OKT3. 20-2b2 was non-mitogenic for human CD4+ T cells, could inhibit the activation of T cells in vitro, and induced T cell anergy in in vivo experiments using humanized mice. Cytokine release in humanized mice induced by the administration of 20-2b2 was significantly less than that induced by OKT3. Our results indicated that the CD3ε molecule is still an attractive, effective, and useful target for the modulation of T cell responses. The establishment of other Abs that recognize CD3ε, even though the determinant recognized by those Abs may be close to or different from that recognized by OKT3, may represent a novel approach for the development of safer Ab therapies using anti-CD3 Abs, in addition to the modification of OKT3 in terms of the induction of cytokine production.


Subject(s)
Antibodies, Monoclonal/immunology , CD3 Complex/immunology , CD4-Positive T-Lymphocytes/immunology , Animals , CD4-Positive T-Lymphocytes/metabolism , Clonal Anergy , Cytokines/biosynthesis , Female , Humans , Lymphocyte Activation , Mice
9.
Eur J Immunol ; 44(6): 1770-80, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24595757

ABSTRACT

The activation of T cells is known to be accompanied by the temporary downmodulation of the TCR/CD3 complex on the cell surface. Here, we established a novel monoclonal antibody, Dow2, that temporarily induces downmodulation of the TCR/CD3 complex in mouse CD4(+) T cells without activating T cells. Dow2 recognized the determinant on CD3ε; however, differences were observed in the binding mode between Dow2 and the agonistic anti-CD3ε Ab, 145-2C11. An injection of Dow2 in vivo resulted in T-cell anergy, and prolonged the survival of cardiac allografts without a marked increase in cytokine release. The phosphorylated forms of the signaling proteins PLC-γ1 and LAT in Dow2-induced anergic T cells were markedly decreased upon stimulation. However, the levels of phosphorylated LAT and PLCγ1 in Dow2-induced anergic T cells could be rescued in the presence of the proteasome inhibitor MG-132. These results suggest that proteasome-mediated degradation is involved in hypophosphorylated LAT and PLCγ1 in Dow2-induced anergic T cells. The novel CD3-specific Ab, Dow2, may provide us with a unique tool for inducing immunosuppression.


Subject(s)
Adaptor Proteins, Signal Transducing/immunology , Antibodies, Monoclonal, Murine-Derived/pharmacology , CD3 Complex/immunology , Clonal Anergy/drug effects , Membrane Proteins/immunology , Phospholipase C gamma/immunology , Phosphoproteins/immunology , T-Lymphocytes/immunology , Animals , Antibodies, Monoclonal, Murine-Derived/immunology , Male , Mice , Mice, Inbred BALB C , Phosphorylation/drug effects , Phosphorylation/immunology , Proteasome Endopeptidase Complex/immunology , Proteolysis/drug effects
10.
PLoS One ; 8(9): e76774, 2013.
Article in English | MEDLINE | ID: mdl-24098805

ABSTRACT

We recently identified a novel anilinoquinazoline derivative, Q15, as a potent apoptosis inducer in a panel of human cancer cell lines and determined that Q15 targets hCAP-G2, a subunit of condensin II complex, leading to abnormal cell division. However, whether the defect in normal cell division directly results in cell death remains unclear. Here, we used an mRNA display method on a microfluidic chip to search for other Q15-binding proteins. We identified an additional Q15-binding protein, MIP-2A (MBP-1 interacting protein-2A), which has been reported to interact with MBP-1, a repressor of the c-Myc promoter. Our results indicate that Q15 inhibits the interaction between MIP-2A and MBP-1 as well as the expression of c-Myc protein, thereby inducing cell death. This study suggests that the simultaneous targeting of hCAP-G2 and MIP-2A is a promising strategy for the development of antitumor drugs as a treatment for intractable tumours.


Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Membrane Transport Proteins/metabolism , Quinazolines/pharmacology , Transcription Factors/metabolism , Adenosine Triphosphatases/metabolism , Amino Acid Sequence , Aniline Compounds/chemistry , Aniline Compounds/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , DNA-Binding Proteins/metabolism , Gene Expression Profiling , Humans , Microfluidic Analytical Techniques , Molecular Sequence Data , Molecular Structure , Multiprotein Complexes/metabolism , Quinazolines/chemistry , Quinazolines/metabolism , Reverse Transcriptase Polymerase Chain Reaction
11.
Chem Biol ; 20(7): 935-42, 2013 Jul 25.
Article in English | MEDLINE | ID: mdl-23890011

ABSTRACT

Here, we used mRNA display to search for proteins that bind to FK506, a potent immunosuppressant drug, and identified spartin, a hereditary spastic paraplegia protein, from a human brain cDNA library. We demonstrated that FK506 binds to the C-terminal region of spartin and thereby inhibits the interaction of spartin with TIP47, one of the lipid droplet-associated proteins. We further confirmed that FK506 inhibits localization of spartin and its binder, an E3 ubiquitin ligase AIP4, in lipid droplets and increases the protein level of ADRP (adipose differentiation-related protein), which is a regulator of lipid homeostasis. These results strongly suggest that FK506 suppresses the proteasomal degradation of ADRP, a substrate of AIP4, by inhibiting the spartin-TIP47 interaction and thereby blocking the localization of spartin and AIP4 in lipid droplets.


Subject(s)
Immunosuppressive Agents/metabolism , Proteins/genetics , Proteins/metabolism , RNA, Messenger/metabolism , Tacrolimus/metabolism , Cell Cycle Proteins , HEK293 Cells , HeLa Cells , Humans , Immunosuppressive Agents/pharmacology , Protein Binding , Protein Transport/drug effects , Proteins/chemistry , RNA, Messenger/genetics , Tacrolimus/pharmacology
12.
PLoS One ; 7(9): e44889, 2012.
Article in English | MEDLINE | ID: mdl-23028663

ABSTRACT

We screened 46 novel anilinoquinazoline derivatives for activity to inhibit proliferation of a panel of human cancer cell lines. Among them, Q15 showed potent in vitro growth-inhibitory activity towards cancer cell lines derived from colorectal cancer, lung cancer and multiple myeloma. It also showed antitumor activity towards multiple myeloma KMS34 tumor xenografts in lcr/scid mice in vivo. Unlike the known anilinoquinazoline derivative gefitinib, Q15 did not inhibit cytokine-mediated intracellular tyrosine phosphorylation. Using our mRNA display technology, we identified hCAP-G2, a subunit of condensin II complex, which is regarded as a key player in mitotic chromosome condensation, as a Q15 binding partner. Immunofluorescence study indicated that Q15 compromises normal segregation of chromosomes, and therefore might induce apoptosis. Thus, our results indicate that hCAP-G2 is a novel therapeutic target for development of drugs active against currently intractable neoplasms.


Subject(s)
Adenosine Triphosphatases/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , DNA-Binding Proteins/chemistry , Multiprotein Complexes/chemistry , Protein Subunits/metabolism , Thiazoles/metabolism , Thiazoles/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chromosome Segregation/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , Male , Mice , Mitosis/drug effects , Multiple Myeloma/pathology , Protein Binding , Risk , Xenograft Model Antitumor Assays
13.
PLoS One ; 7(6): e38878, 2012.
Article in English | MEDLINE | ID: mdl-22761710

ABSTRACT

Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma.


Subject(s)
Apoptosis , Cell Proliferation , Centrosome/drug effects , Multiple Myeloma/drug therapy , Nuclear Proteins/metabolism , Phthalimides/pharmacology , Amino Acid Sequence , Animals , Blotting, Western , Centrosome/metabolism , Centrosome/pathology , Flow Cytometry , Fluorescent Antibody Technique , Humans , Male , Mice , Mice, Inbred ICR , Mice, SCID , Microfluidics , Molecular Sequence Data , Molecular Structure , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Nucleophosmin , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Surface Plasmon Resonance , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
14.
PLoS One ; 6(3): e17898, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21423613

ABSTRACT

p53 is a tumor suppressor protein that prevents tumorigenesis through cell cycle arrest or apoptosis of cells in response to cellular stress such as DNA damage. Because the oncoprotein MDM2 interacts with p53 and inhibits its activity, MDM2-p53 interaction has been a major target for the development of anticancer drugs. While previous studies have used phage display to identify peptides (such as DI) that inhibit the MDM2-p53 interaction, these peptides were not sufficiently optimized because the size of the phage-displayed random peptide libraries did not cover all of the possible sequences. In this study, we performed selection of MDM2-binding peptides from large random peptide libraries in two stages using mRNA display. We identified an optimal peptide named MIP that inhibited the MDM2-p53 and MDMX-p53 interactions 29- and 13-fold more effectively than DI, respectively. Expression of MIP fused to the thioredoxin scaffold protein in living cells by adenovirus caused stabilization of p53 through its interaction with MDM2, resulting in activation of the p53 pathway. Furthermore, expression of MIP also inhibited tumor cell proliferation in a p53-dependent manner more potently than DI. These results show that two-stage, mRNA-displayed peptide selection is useful for the rapid identification of potent peptides that target oncoproteins.


Subject(s)
Peptide Library , Peptides/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Adenoviridae/drug effects , Adenoviridae/metabolism , Amino Acid Sequence , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Enzyme-Linked Immunosorbent Assay , Green Fluorescent Proteins/metabolism , Humans , Inhibitory Concentration 50 , Molecular Sequence Data , Peptides/chemistry , Peptides/pharmacology , Protein Binding/drug effects , RNA, Messenger/metabolism , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Signal Transduction/drug effects
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