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Cellular Physiology and Biochemistry :... 2017Recently, some small-molecule compounds that were designed for cancer therapy have acquired new roles in the treatment of pulmonary diseases. However, drug screening...
BACKGROUND/AIMS
Recently, some small-molecule compounds that were designed for cancer therapy have acquired new roles in the treatment of pulmonary diseases. However, drug screening aimed at abnormal muscle contraction is still limited. TSU-68 is a potent, orally administered, small-molecule agent that can reduce the vascular endothelial growth factor (VEGF)-induced Ca2+ increase in endothelial cells. We questioned whether TSU-68 could also affect calcium influx and relax airway smooth muscle (ASM) cells. The current study aimed to investigate these effects and to explore the underlying mechanisms.
METHODS
The effects of TSU-68 on ASM cells were studied in mice using a series of biophysiological techniques, including force measurement and patch-clamp experiments.
RESULTS
TSU-68 inhibited high K+ or acetylcholine chloride (ACh)-induced pre-contracted mouse tracheal rings in a concentration-dependent manner. Further research demonstrated that the TSU-68-induced ASM relaxation was mediated by calcium, which was decreased by blocking voltage-dependent Ca2+ channels (VDCCs) and non-selective cation channels (NSCCs).
CONCLUSION
Our data indicated that TSU-68 relaxes tense ASM by reducing the intracellular Ca2+ concentration through blocking VDCCs and NSCCs, which suggested that this small molecule might be useful in the treatment of abnormal smooth muscle.
Topics: Acetylcholine; Angiogenesis Inhibitors; Animals; Calcium; Calcium Channels; Cells, Cultured; Indoles; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Muscle Relaxation; Myocytes, Smooth Muscle; Oxindoles; Patch-Clamp Techniques; Potassium; Propionates; Pyrroles
PubMed: 28478457
DOI: 10.1159/000475653 -
International Journal of Oncology May 2017Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although...
Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although diagnosis modalities for primary prostate cancer have markedly improved, there are still no effective therapies for metastatic prostate cancer. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2, PDGFRβ and FGFR1. There is strong experimental evidence that SU6668 can induce growth inhibition of various primary tumors. However, the function and molecular mechanism of SU6668 in prostate cancer has not been fully elucidated. In the present study, we found that SU6668 inhibited the proliferation and invasion of prostate cancer cells. Functional studies also demonstrated that SU6668 inhibited epithelial-mesenchymal transition in DU145 and LNCap cells. After treatment with SU6668, MTDH protein, which has been reported to be significantly overexpressed in many human tumor tissues, was downregulated in DU145 and LNCap cells. siRNA-mediated silencing of MTDH in prostate cancer cells decreased their proliferation and invasive capabilities, suggesting that SU6668 may inhibit cell proliferation and invasion of prostate cancer cells partly through downstream targeting of MTDH. Mechanistic investigations showed that AKT signaling pathway was inhibited after SU6668 treatment in prostate cancer cells. Moreover, a combination of SU6668 and PI3K-AKT pathway inhibitor LY29004 resulted in increased inhibition of cell proliferation and invasion in DU145 cells. Taken together, our findings revealed that SU6668 suppressed prostate cancer progression by downregulating MTDH/AKT signaling pathway and identified a promising therapeutic strategy for prostate cancer.
Topics: Angiogenesis Inhibitors; Cell Adhesion Molecules; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Indoles; Male; Membrane Proteins; Neoplasm Invasiveness; Oxindoles; Propionates; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrroles; RNA-Binding Proteins; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2
PubMed: 28339027
DOI: 10.3892/ijo.2017.3926 -
Asia-Pacific Journal of Clinical... Dec 2017The aim of this study is to investigate whether the addition of TSU-68 would affect on the quality of life (QOL) of Korean metastatic breast cancer patients treated with...
Quality of life on TSU-68: Combination of docetaxel and TSU-68, an oral antiangiogenic agent, in patients with metastatic breast cancer previously treated with anthracycline.
AIM
The aim of this study is to investigate whether the addition of TSU-68 would affect on the quality of life (QOL) of Korean metastatic breast cancer patients treated with docetaxel.
METHODS
Sixty-three of 78 patients completed the baseline QOL questionnaires and at least one follow-up questionnaire comprising questions from the Korean Functional Assessment of Cancer Therapy-Breast (FACT-B), hospital anxiety and depression scale (HAD), the shortened form of the profile of mood states (BPOMS), and anticipation and anxiety for treatment scale. Changes in QOL scores from baseline were compared by analysis of covariance at each time point (6, 12 weeks, 9, 12 and 18 months) and at the end of treatment (EOT), and the longitudinal changes over time were evaluated by repeated measure analysis.
RESULTS
The two-treatment groups (TSU-68 plus docetaxel [A] vs docetaxel alone [B]) were well balanced regarding sociodemographic characteristics, including age (P = 0.450), religion (P = 1.000), education (P = 0.257), ECOG performance status (P = 0.261), and employment status (P = 0.325). The return rate at EOT was 61.9%. In analyses at each QOL measuring time, A group showed a higher FACT-B total score and FACT-G score than B at 12 months (P = 0.031 and P = 0.024, respectively). The anticipation and anxiety for treatment scale of A group was higher than that of B at 12 weeks and EOT (P = 0.046 and P = 0.022, respectively). However, repeated measure analysis for longitudinal changes over time showed no significant group wise differences.
CONCLUSIONS
The combination of TSU-68 with docetaxel showed no additional adverse effects on patient QOL during the study period, as compared with docetaxel monotherapy.
Topics: Angiogenesis Inhibitors; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Humans; Indoles; Middle Aged; Neoplasm Metastasis; Oxindoles; Propionates; Pyrroles; Quality of Life; Taxoids
PubMed: 28303646
DOI: 10.1111/ajco.12681 -
Cancer Research and Treatment Oct 2017Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer... (Review)
Review
Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Clinical Trials as Topic; Esophageal Neoplasms; Esophagogastric Junction; Humans; Molecular Targeted Therapy; Neoplasm Staging; Protein Kinase Inhibitors; Quality of Life; Receptor, ErbB-2; Stomach Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 28052652
DOI: 10.4143/crt.2016.176 -
Cancer Research and Treatment Apr 2016This study analyzed the role of plasma biomarkers for TSU-68 in a previous phase II trial comparing TSU-68 plus docetaxel and docetaxel alone in patients with metastatic...
PURPOSE
This study analyzed the role of plasma biomarkers for TSU-68 in a previous phase II trial comparing TSU-68 plus docetaxel and docetaxel alone in patients with metastatic breast cancer.
MATERIALS AND METHODS
A total of 77 patients were eligible for this study (38 in the TSU-68 plus docetaxel arm and 39 in the docetaxel alone arm). Blood samples were collected prior to the start of each cycle, and vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-AA, -AB, -BB, fibroblast growth factor, M30, C-reactive protein (CRP), and interleukin 6 (IL-6) levels were measured using enzyme linked immunosorbent assay. The primary endpoint was progression-free survival (PFS).
RESULTS
In patients with baseline PDGF-AA ≥ median, median PFS was significantly worse in the TSU-68 plus docetaxel group than in the docetaxel alone group (5.4 months vs. 13.7 months, p=0.049), while a trend toward a PFS benefit was observed in those with baseline PDGF-AA < median (9.7 months vs. 4.0 months, p=0.18; p for interaction=0.03). In the TSU-68 plus docetaxel group, PFS showed significant association with fold changes in CRP (p=0.001), IL-6 (p < .001), PDGF-BB (p=0.02), and VEGF (p=0.047) following the first treatment cycle.
CONCLUSION
Baseline PDGF-AA levels and dynamics of VEGF, PDGF-BB, CRP, and IL-6 levels were predictive for the efficacy of TSU-68.
Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Docetaxel; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factors; Humans; Indoles; Interleukin-6; Middle Aged; Neoplasm Metastasis; Oxindoles; Propionates; Pyrroles; Taxoids; Vascular Endothelial Growth Factor A
PubMed: 26194374
DOI: 10.4143/crt.2015.089 -
Anticancer Research Mar 2015TSU-68 is a multikinase inhibitor that targets platelet-derived growth factor receptors (PDGFRs). In the present study, we evaluated the effect of TSU-68 on the...
BACKGROUND
TSU-68 is a multikinase inhibitor that targets platelet-derived growth factor receptors (PDGFRs). In the present study, we evaluated the effect of TSU-68 on the tumor-microenvironment interaction in hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
HCC and fibroblast cell lines (HuH7, Hep3B, HuH1 and WI-38) were used to evaluate their interactions. Cancer characteristics were evaluated by spheroid formation and tumorigenicity in immunodeficient mice. Time-lapse image analysis was performed to monitor cell motility.
RESULTS
Although PDGFA was abundantly expressed, PDGFR-α was predominantly located in the cytoplasm and was not functional in HuH7 cells. Co-culture experiments demonstrated that HCC cells induced phosphorylation of PDGFR-α in WI-38 fibroblasts and that stimulated fibroblasts, in turn, boosted the spheroid formation capacity of HCC cells. TSU-68 inhibited phosphorylation of PDGFR-α in WI-38 cells and suppressed the growth of subcutaneously co-injected HuH7/WI-38 tumor xenografts.
CONCLUSION
TSU-68 inhibits stromal PDGF signaling activated by cancer cells and suppresses HCC growth.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Liver Neoplasms; Mice; Oxindoles; Platelet-Derived Growth Factor; Propionates; Pyrroles; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Transforming Growth Factor beta1
PubMed: 25750293
DOI: No ID Found -
Hepatology Research : the Official... Oct 2015Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic... (Review)
Review
Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic therapy that has demonstrated an overall survival benefit in patients with advanced HCC, and new agents for treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation and survival provide many opportunities for the development of molecularly targeted therapies. Molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for treatment of advanced HCC. Agents targeting vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-mesenchymal-epithelial transition factor-1 and mammalian target of rapamycin signaling have been actively explored. This article focuses on the evaluation of molecular agents targeting pathogenic HCC and provides a review of recently completed phase III drug studies (e.g. involving sorafenib, sunitinib, brivanib, linifanib, erlotinib, everolimus, ramucirumab or orantinib) and ongoing drug studies (e.g. involving lenvatinib, regorafenib, tivantinib or cabozantinib) of molecularly targeted agents in advanced HCC, including a brief description of the biologic rationale behind these agents.
PubMed: 25472913
DOI: 10.1111/hepr.12459 -
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 -
Investigational New Drugs Aug 2014The novel oral antiangiogenic agent TSU-68 was investigated in patients with metastatic breast cancer. Patients with anthracycline-pretreated metastatic breast cancer... (Randomized Controlled Trial)
Randomized Controlled Trial
Combination of docetaxel and TSU-68, an oral antiangiogenic agent, in patients with metastatic breast cancer previously treated with anthracycline: randomized phase II multicenter trial.
The novel oral antiangiogenic agent TSU-68 was investigated in patients with metastatic breast cancer. Patients with anthracycline-pretreated metastatic breast cancer were randomly assigned to receive either TSU-68 400 mg twice daily on days 1-21 plus docetaxel 60 mg/m(2) on day 1 every 3 weeks, or docetaxel 60 mg/m(2) on day 1 every 3 weeks. The primary endpoint was progression-free survival. Between November 2006 and December 2007, 81 patients were included in this study (41 for TSU-68 plus docetaxel and 40 for docetaxel alone). Median progression-free survival was 6.8 months (95 % confidence interval [CI] = 5.4-12.5 months) in the TSU-68 plus docetaxel group and 8.1 months (95 % CI = 4.0-13.7 months) in the docetaxel-alone group (hazard ratio [HR] = 1.0; 95 % CI = 0.6-1.8; p = 0.95). There were no significant differences in the overall response rates and overall survival between groups (p = 0.29 and p = 0.42, respectively). In subgroup analysis, TSU-68 plus docetaxel was associated with better overall survival than docetaxel alone in anthracycline-resistant patients (HR = 0.3; 95 % CI = 0.1-0.8; p = 0.02). The most frequent adverse events were neutropenia and anorexia in both arms. Although both regimens were well tolerated, grade 3/4 non-hematologic toxicity was more frequently observed in the TSU-68 plus docetaxel group. Combination of TSU-68 and docetaxel is well tolerated but failed to demonstrate superior efficacy over docetaxel alone in anthracycline-pretreated breast cancer patients. As TSU-68 was associated with better survival in the anthracycline-resistant subgroup, it should be further explored in this subgroup.
Topics: Adult; Aged; Angiogenesis Inhibitors; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Docetaxel; Female; Humans; Indoles; Middle Aged; Oxindoles; Propionates; Pyrroles; Taxoids
PubMed: 24715580
DOI: 10.1007/s10637-014-0093-6