-
British Journal of Cancer Oct 2013This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment.
METHODS
Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS).
RESULTS
Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP.
CONCLUSION
Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.
Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Drug Combinations; Female; Humans; Indoles; Male; Middle Aged; Oxindoles; Oxonic Acid; Propionates; Pyrroles; Stomach Neoplasms; Survival Rate; Tegafur
PubMed: 24045669
DOI: 10.1038/bjc.2013.555 -
Structure (London, England : 1993) Jul 2013Tank-binding kinase 1 (TBK1) is a serine/threonine protein-kinase mediating innate antimicrobial immunity. TBK1 is involved in the signaling of TLRs, RLRs, and...
Tank-binding kinase 1 (TBK1) is a serine/threonine protein-kinase mediating innate antimicrobial immunity. TBK1 is involved in the signaling of TLRs, RLRs, and STING-mediated sensing of cytosolic DNA. Stimulation of these receptors results in the activation of TBK1, which phosphorylates interferon regulatory factor (IRF)-3. Phosphorylated IRF-3 translocates into the nucleus to initiate the transcription of the interferon (IFN)-β gene. Here, we show that TBK1 is activated by autophosphorylation at residue Ser172. Structures of TBK1 bound to two inhibitors showed that TBK1 has the IκB kinase fold with three distinct domains: the kinase domain, the ubiquitin-like domain, and the scaffold and dimerization domain. However, the overall structures of the TBK1 monomer and its dimer are different from IKKβ in the arrangements of the three domains and in dimer formation. Phosphorylation of IRF-3 by TBK1 in vitro results in its oligomerization, and phosphorylation of residue Ser386 plays a key role in IRF-3 activation.
Topics: Amino Acid Sequence; Animals; Bacterial Infections; Catalytic Domain; Crystallography, X-Ray; Enzyme Activation; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Immunity, Innate; Indoles; Interferon Regulatory Factor-3; Mice; Models, Molecular; Molecular Sequence Data; Oxindoles; Phosphorylation; Propionates; Protein Binding; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors; Protein Multimerization; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Quaternary; Protein Structure, Secondary; Pyrroles; Structural Homology, Protein
PubMed: 23746807
DOI: 10.1016/j.str.2013.04.025 -
The American Journal of Pathology Jun 2002Basic and acidic fibroblast growth factor (bFGF and aFGF, respectively) and vascular endothelial growth factor (VEGF) exert angiogenic actions and have a role in wound...
Down-modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor: reversal by the anti-angiogenic agent SU6668.
Basic and acidic fibroblast growth factor (bFGF and aFGF, respectively) and vascular endothelial growth factor (VEGF) exert angiogenic actions and have a role in wound healing, inflammation, and tumor growth. Monocytes and endothelial cells are involved in these processes, but the effect of FGF and VEGF on monocyte-endothelial cell interactions has not been defined. We observed that monocyte adhesion to resting or cytokine (tumor necrosis factor-alpha or interleukin-1 alpha)-stimulated human umbilical vein endothelial cells (HUVECs) was markedly inhibited (40 to 65%) by culture (1 to 6 days) of HUVECs with aFGF or bFGF. Monocyte transendothelial migration induced by C5a and chemokines (MCP-1, SDF-1 alpha, RANTES, MIP-1 alpha) was also suppressed (by 50 to 75%) on bFGF-stimulated HUVECs. VEGF did not have these effects at the concentrations used (10 to 20 ng/ml), although like bFGF, it promoted HUVEC proliferation. Culture of HUVECs with bFGF and aFGF significantly down-regulated intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression on resting or tumor necrosis factor-alpha-stimulated HUVECs, but had no influence on platelet endothelial cell adhesion molecule (PECAM)-1 and VE-cadherin expression. bFGF also inhibited MCP-1 production by HUVECs. The inhibitory effects of bFGF on monocyte transendothelial migration and adhesion molecule expression were reversed by SU6668, an anti-angiogenic agent and bFGF receptor tyrosine kinase inhibitor. Our results suggest that bFGF and aFGF may suppress endothelial-dependent monocyte recruitment and thus have an anti-inflammatory action during angiogenesis in chronic inflammation but inhibit the immunoinflammatory tumor defense mechanism. However, SU6668 is an effective agent to prevent this down-regulatory action of bFGF on monocyte-endothelial cell interactions.
Topics: Angiogenesis Inhibitors; Antigens, CD; Cadherins; Cell Adhesion; Cell Movement; Cells, Cultured; Chemokine CCL2; Chemokine CCL4; Chemokine CCL5; Chemokine CXCL12; Chemokines, CXC; Complement C5a; Down-Regulation; E-Selectin; Endothelial Growth Factors; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Humans; Indoles; Intercellular Adhesion Molecule-1; Lymphokines; Macrophage Inflammatory Proteins; Monocytes; Oxindoles; Platelet Endothelial Cell Adhesion Molecule-1; Propionates; Pyrroles; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Wound Healing
PubMed: 12057924
DOI: 10.1016/S0002-9440(10)61169-8 -
BMC Cancer Mar 2007As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore,... (Comparative Study)
Comparative Study
BACKGROUND
As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore, additional therapies such as antiangiogenesis represent a promising strategy for overcoming limitations in chondrosarcoma therapy. There is strong experimental evidence that SU6668, an inhibitor of the angiogenic tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1 can induce growth inhibition of various primary tumors. However, the effectiveness of SU6668 on malignant primary bone tumors such as chondrosarcomas has been rarely investigated. Therefore, the aim of this study was to investigate the effects of SU6668 on chondrosarcoma growth, angiogenesis and microcirculation in vivo.
METHODS
In 10 male severe combined immunodeficient (SCID) mice, pieces of SW1353 chondrosarcomas were implanted into a cranial window preparation where the calvaria serves as the site for the orthotopic implantation of bone tumors. From day 7 after tumor implantation, five animals were treated with SU6668 (250 mg/kg body weight, s.c.) at intervals of 48 hours (SU6668), and five animals with the equivalent amount of the CMC-based vehicle (Control). Angiogenesis, microcirculation, and growth of SW 1353 tumors were analyzed by means of intravital microscopy.
RESULTS
SU6668 induced a growth arrest of chondrosarcomas within 7 days after the initiation of the treatment. Compared to Controls, SU6668 decreased functional vessel density and tumor size, respectively, by 37% and 53% on day 28 after tumor implantation. The time course of the experiments demonstrated that the impact on angiogenesis preceded the anti-tumor effect. Histological and immunohistochemical results confirmed the intravital microscopy findings.
CONCLUSION
SU6668 is a potent inhibitor of chondrosarcoma tumor growth in vivo. This effect appears to be induced by the antiangiogenic effects of SU6668, which are mediated by the inhibition of the key angiogenic receptor tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1. The experimental data obtained provide rationale to further develop the strategy of the use of the angiogenesis inhibitor SU6668 in the treatment of chondrosarcomas in addition to established therapies such as surgery.
Topics: Angiogenesis Inhibitors; Animals; Chondrosarcoma; Disease Models, Animal; Indoles; Injections, Subcutaneous; Male; Mice; Mice, SCID; Microcirculation; Oxindoles; Propionates; Pyrroles; Treatment Outcome
PubMed: 17367541
DOI: 10.1186/1471-2407-7-49 -
Investigational New Drugs Oct 2014We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor...
Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.
PURPOSE
We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment.
PATIENTS AND METHODS
Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed.
RESULTS
Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively.
CONCLUSION
The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.
Topics: Administration, Oral; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Combinations; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Oxindoles; Oxonic Acid; Propionates; Pyrroles; Tegafur; Treatment Outcome
PubMed: 24829073
DOI: 10.1007/s10637-014-0109-2 -
The Journal of Investigative Dermatology Nov 2011Double-stranded RNA (dsRNA) causes keratinocytes to release thymic stromal lymphopoietin (TSLP), which plays a key role in allergic diseases. Endosomal Toll-like...
Double-stranded RNA (dsRNA) causes keratinocytes to release thymic stromal lymphopoietin (TSLP), which plays a key role in allergic diseases. Endosomal Toll-like receptor 3 (TLR3) and cytosolic RIG-like receptors (RLRs) and PKR have been reported to recognize dsRNA. Here, we demonstrate that dsRNA induces TSLP in keratinocytes via an endosomal acidification-dependent and NF-κB-mediated pathway. After treatment with pharmacologic inhibitors or transfection with small interfering RNAs (siRNAs), primary human keratinocytes were stimulated. Bafilomycin A1, which inhibits endosomal acidification to block the TLR3 pathway, blocked the dsRNA-induced expression of TSLP, IL-8, IFN-β, and other molecules including the dsRNA sensors, whereas it did not inhibit diacyllipopeptide-induced expression of TSLP and IL-8. The dsRNA-induced gene expression of TSLP depended on RelA, a component of NF-κB, but not IRF3, similar to IL-8 but different from IFN-β, which depended on both IRF3 and RelA. The results indicate that endosomal acidification and the subsequent activation of NF-κB are necessary to sense extracellular dsRNA, suggesting the importance of the TLR3-NF-κB axis to trigger production of TSLP against the self dsRNA released from damaged cells or viral dsRNA, in the epidermis, relating to skin inflammation including atopic dermatitis (AD).
Topics: Cells, Cultured; Cytokines; Endosomes; Humans; Indoles; Interferon Regulatory Factor-3; Interferon-beta; Interleukin-8; Keratinocytes; Macrolides; NF-kappa B; Oxindoles; Poly I-C; Propionates; Pyrroles; RNA, Double-Stranded; RNA, Small Interfering; Signal Transduction; Toll-Like Receptor 3; Transcription Factor RelA; Thymic Stromal Lymphopoietin
PubMed: 21716324
DOI: 10.1038/jid.2011.185 -
Cancer Chemotherapy and Pharmacology May 2011TSU-68 is a low molecular weight inhibitor of the tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and...
PURPOSE
TSU-68 is a low molecular weight inhibitor of the tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factors receptor 1. In this study, we assessed the recommended dose with TSU-68 administration of twice-daily (b.i.d.) or thrice-daily (t.i.d.) after meals for 4 weeks in Japanese patients with solid tumors based on the safety and tolerability and investigated the relationship between angiogenesis biomarker and clinical outcomes.
METHODS
The study design was a dose-escalation method with alternating enrollment of b.i.d. administration and t.i.d. administration after meal by traditional three-patient cohort.
RESULTS
We enrolled 24 patients at doses of 200, 400, and 500 mg/m(2) b.i.d. or 200 and 400 mg/m(2) t.i.d. No dose-limiting toxicity (DLT) occurred in the 200 mg/m(2) b.i.d. or t.i.d., and 3 patients experienced DLTs at 400 mg/m(2) b.i.d. or 400 mg/m(2) t.i.d. As main toxicity, blood albumin decreased, malaise, diarrhea, alkaline phosphatase increased, anorexia, abdominal pain, nausea, and vomiting were observed as almost all grade 1-2. There were no apparent differences in pharmacokinetic parameters between days 2 and 28 after the repeated b.i.d. and t.i.d. doses. Although tumor shrinkage was not observed, the disease control rate was 41.7%. As an angiogenesis-related factor of stratified analysis, plasma vascular endothelial growth factor and plasminogen activator inhibitor-1 were detected as a significant increase with progressive disease patients.
CONCLUSIONS
A recommended dosage of TSU-68 for this administration schedules was estimated to be 400 mg/m(2) or less b.i.d.
Topics: Administration, Oral; Adult; Aged; Angiogenesis Inhibitors; Biomarkers, Tumor; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indoles; Male; Middle Aged; Neoplasms; Oxindoles; Plasminogen Activator Inhibitor 1; Postprandial Period; Propionates; Protein-Tyrosine Kinases; Pyrroles; Vascular Endothelial Growth Factor A
PubMed: 20676674
DOI: 10.1007/s00280-010-1405-y -
Cancer Chemotherapy and Pharmacology May 2011A single-agent dose-escalating phase I and pharmacokinetic study on TSU-68, a novel multiple receptor tyrosine kinase inhibitor, was performed to determine the safety...
Phase I and pharmacokinetic study of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, by twice daily oral administration between meals in patients with advanced solid tumors.
PURPOSE
A single-agent dose-escalating phase I and pharmacokinetic study on TSU-68, a novel multiple receptor tyrosine kinase inhibitor, was performed to determine the safety profile, maximum-tolerated dose for Japanese patients with advanced solid tumors and to define the recommended dose of phase II studies.
METHODS
Study design was a dose escalation method on a three-patient cohort. TSU-68 was given orally twice daily (bid) between meals without interruption; the estimation of dose escalation was based on the toxicity within 4 week administration at each dose level.
RESULTS
Fifteen patients were enrolled into the study. Dose levels studied were 200, 400, 800, and 1,200 mg/m(2) bid. Grade 3 arrhythmia and anemia/thrombocytopenia were observed in 1 patient each at 800 mg/m(2) bid. Three patients discontinued continuous oral administration for 4 weeks at 400 and 800 mg/m(2) bid. At 1,200 mg/m(2) bid, 2 patients discontinued the treatment over 4 weeks for intolerable fatigue and abdominal pain, respectively. No serious drug-related toxicities have been observed. Grade 1-2 toxicity included urinary/feces discoloration, diarrhea, fatigue, anorexia, abdominal/chest pain, and edema. Tumor shrinkage was observed in 1 patient of NSCLC. In the pharmacokinetics, at any dose levels, C(max) and AUC(0-t) after repeated administration of TSU-68 on days 8 and 29 were ~2-fold lower that those after the first administration on day 1; these parameters are similar between days 8 and 28. In addition, no obvious dose-dependent increase in plasma exposure to TSU-68 repeatedly administered was observed over the four dose levels, including the higher dose levels.
CONCLUSIONS
The tolerable dose in this administration schedule for continuing treatment is thought to be 800 mg/m(2) or less bid.
Topics: Administration, Oral; Adult; Aged; Angiogenesis Inhibitors; Biomarkers, Tumor; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indoles; Male; Middle Aged; Neoplasms; Oxindoles; Postprandial Period; Propionates; Protein-Tyrosine Kinases; Pyrroles
PubMed: 20676675
DOI: 10.1007/s00280-010-1404-z -
Biochimica Et Biophysica Acta Apr 2014Observations that Glioma-associated transcription factors Gli1 and Gli2 (Gli1/2), executers of the Sonic Hedgehog (Shh) signaling pathway and targets of the Transforming...
Observations that Glioma-associated transcription factors Gli1 and Gli2 (Gli1/2), executers of the Sonic Hedgehog (Shh) signaling pathway and targets of the Transforming Growth Factor β (TGF-β) signaling axis, are involved in numerous developmental and pathological processes unveil them as attractive pharmaceutical targets. Unc-51-like serine/threonine kinase Ulk3 has been suggested to play kinase activity dependent and independent roles in the control of Gli proteins in the context of the Shh signaling pathway. This study aimed at investigating whether the mechanism of generation of Gli1/2 transcriptional activators has similarities regardless of the signaling cascade evoking their activation. We also elucidate further the role of Ulk3 kinase in regulation of Gli1/2 proteins and examine SU6668 as an inhibitor of Ulk3 catalytic activity and a compound targeting Gli1/2 proteins in different cell-based experimental models. Here we demonstrate that Ulk3 is required not only for maintenance of basal levels of Gli1/2 proteins but also for TGF-β or Shh dependent activation of endogenous Gli1/2 proteins in human adipose tissue derived multipotent stromal cells (ASCs) and mouse immortalized progenitor cells, respectively. We show that cultured ASCs possess the functional Shh signaling axis and differentiate towards osteoblasts in response to Shh. Also, we demonstrate that similarly to Ulk3 RNAi, SU6668 prevents de novo expression of Gli1/2 proteins and antagonizes the Gli-dependent activation of the gene expression programs induced by either Shh or TGF-β. Our data suggest SU6668 as an efficient inhibitor of Ulk3 kinase allowing manipulation of the Gli-dependent transcriptional outcome.
Topics: Animals; Cell Differentiation; Cells, Cultured; Gene Expression Regulation, Developmental; Hedgehog Proteins; Humans; Indoles; Kruppel-Like Transcription Factors; Leukocytes, Mononuclear; Mice; Multipotent Stem Cells; Neoplasms; Nuclear Proteins; Oxindoles; Propionates; Protein Serine-Threonine Kinases; Pyrroles; Signal Transduction; Transcription Factors; Transforming Growth Factor beta; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2
PubMed: 24418624
DOI: 10.1016/j.bbamcr.2014.01.003 -
Drug Metabolism and Pharmacokinetics 2008The anti-angiogenic agent TSU-68 is known to rapidly induce cytochrome P450 activity responsible for its own hydroxylation in rats. In this study, we identified CYP1A1... (Comparative Study)
Comparative Study
The anti-angiogenic agent TSU-68 is known to rapidly induce cytochrome P450 activity responsible for its own hydroxylation in rats. In this study, we identified CYP1A1 and CYP1A2 as the TSU-68-induced P450 and temporally characterized the rapid induction of these isoforms. Protein and mRNA levels of CYP1A1 and CYP1A2 along with CYP1A activities were examined in rat liver after a single oral administration of 500 mg/kg TSU-68. CYP1A-mediated ethoxyresorufin O-deethylation and TSU-68 hydroxylation activities reached the maximum at 12 hr. The activities were maintained up to 24 hr and then slowly decreased down to control levels. Protein levels of both CYP1A1 and CYP1A2 were also rapidly induced with temporal profiles similar to the profile of CYP1A activity. In contrast, unlike CYP1A2 mRNA levels, which peaked at 12 hr and almost returned to control levels by 48 hr, CYP1A1 mRNA levels peaked as early as 3 hr and returned to control levels by 24 hr. Thus, CYP1A1 showed more rapid elevation and turnover of its mRNA than CYP1A2. In conclusion, TSU-68 administered to rats rapidly induced mRNA and protein of CYP1A1 and CYP1A2 as well as CYP1A activity. Furthermore, the data showed a difference in the time-dependent induction between CYP1A1 and CYP1A2 mRNAs.
Topics: Angiogenesis Inhibitors; Animals; Base Sequence; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Enzyme Induction; Gene Expression Regulation, Enzymologic; Indoles; Male; Microsomes, Liver; Molecular Sequence Data; Oxindoles; Propionates; Pyrroles; RNA, Messenger; Rats; Rats, Sprague-Dawley; Time Factors
PubMed: 19122336
DOI: 10.2133/dmpk.23.421