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Bioorganic & Medicinal Chemistry Apr 2012With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized...
With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).
Topics: Animals; Binding Sites; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Drug Design; Humans; Indoles; Mice; Mice, Nude; Molecular Dynamics Simulation; Neoplasms; Oxindoles; Propionates; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyrimidines; Pyrroles; Receptor, Platelet-Derived Growth Factor beta; Transplantation, Heterologous; Vascular Endothelial Growth Factor Receptor-2
PubMed: 22370340
DOI: 10.1016/j.bmc.2012.01.029 -
Journal of Thoracic Oncology : Official... Feb 2012TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth...
Phase I clinical study of the angiogenesis inhibitor TSU-68 combined with carboplatin and paclitaxel in chemotherapy-naive patients with advanced non-small cell lung cancer.
INTRODUCTION
TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factor receptor 1. An open-label, single-arm, phase I study was performed to evaluate escalating doses of TSU-68 in combination with standard chemotherapy in patients with advanced non-small cell lung cancer.
METHODS
Eligible patients received TSU-68 at 200 or 400 mg twice daily and continuously in combination with carboplatin (area under the curve, 6 mg · min/mL) plus paclitaxel (200 mg/m2) on day 1 every 21 days.
RESULTS
Thirty-seven patients were enrolled at the two dose levels of TSU-68. No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level. At 400 mg twice a day, one of six patients experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle. The 400 mg twice a day dose level was determined to be the recommended dose, and a total of 34 patients were treated at this dose. Overall, adverse events were mild to moderate in severity, with the most frequently observed such events being myelosuppression, neuropathy, and gastrointestinal disorders. No drug-related bleeding was observed. The objective response rate was 39.4% (95% confidence interval, 22.9-57.9%), and median progression-free survival was 5.6 months (95% confidence interval, 3.6-7.2 months). Coadministration of TSU-68, carboplatin, and paclitaxel had no substantial impact on the pharmacokinetics of these drugs.
CONCLUSIONS
TSU-68 can be safely combined with standard doses of carboplatin-paclitaxel, with the combination manifesting promising antitumor activity.
Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Feasibility Studies; Female; Follow-Up Studies; Humans; Indoles; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Oxindoles; Paclitaxel; Propionates; Pyrroles; Tissue Distribution; Treatment Outcome; Young Adult
PubMed: 22071785
DOI: 10.1097/JTO.0b013e318238154d -
Journal of Gastroenterology Jan 2012We evaluated the usefulness of tumor marker doubling time (DT) as an efficacy indicator of a molecular targeted anticancer agent.
BACKGROUND
We evaluated the usefulness of tumor marker doubling time (DT) as an efficacy indicator of a molecular targeted anticancer agent.
METHODS
Twenty-five patients with advanced hepatocellular carcinoma (HCC) received TSU-68, a multiple tyrosine kinase inhibitor. Exponential increase in HCC-specific tumor marker levels (alpha-fetoprotein or des-gamma-carboxyprothrombin) was seen in 15 of them prior to TSU-68 administration. The relationship between tumor marker DT and tumor volume DT was evaluated. Next, tumor marker DT in the first 8 weeks of TSU-68 administration was compared with tumor marker DT before treatment. Efficacy evaluation based on changes in tumor marker DT was compared with Response Evaluation Criteria In Solid Tumors (RECIST).
RESULTS
Tumor marker DT and tumor volume DT were almost identical (r(2) = 0.94, P < 0.001) in each patient before TSU-68 administration. Efficacy evaluation based on changes in tumor marker DT on TSU-68 administration was in accordance with RECIST in 12/15 cases. Discordance was observed in three cases, for which RECIST indicated disease progression in spite of elongated tumor marker DT. Those cases showed substantial tumor necrosis without volume shrinkage or appearance of new lesions in spite of apparent effects on target lesions.
CONCLUSIONS
Serum tumor marker DT can be used to evaluate viable tumor burden irrespective of the presence of tumor necrosis which can compromise radiographic evaluation. This approach may be applicable to the evaluation of responses to chemotherapy, particularly to cytostatic agents (ClinicalTrials.gov number, NCT00784290).
Topics: Aged; Antineoplastic Agents; Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular; Disease Progression; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Oxindoles; Propionates; Protein Kinase Inhibitors; Protein Precursors; Prothrombin; Pyrroles; Time Factors; Treatment Outcome; Tumor Burden; alpha-Fetoproteins
PubMed: 21935635
DOI: 10.1007/s00535-011-0462-2 -
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 -
Investigational New Drugs Aug 2012TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. We conducted a phase I study to evaluate the safety and...
A phase I pharmacokinetic study of TSU-68 (a multiple tyrosine kinase inhibitor of VEGFR-2, FGF and PDFG) in combination with S-1 and oxaliplatin in metastatic colorectal cancer patients previously treated with chemotherapy.
TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. We conducted a phase I study to evaluate the safety and pharmacokinetic of TSU-68 when used with S-1 and oxaliplatin (SOX) in metastatic colorectal cancer (mCRC) patients. Patients with mCRC were treated with TSU-68 200 mg (Level 1) or 400 mg (Level 2) b.i.d. daily, S-1 35 mg/m(2) b.i.d. on Days 1-14 and oxaliplatin 130 mg/m(2) i.v. on Day 1 repeatedly every 3 weeks. Of eleven patients enrolled, two patients were excluded from dose limiting toxicity (DLT) assessment. Six patients at Level 1 experienced no DLT. Of three patients at Level 2, two patients experienced DLTs (one patient: grade 3 hiccup and palmar-plantar erythrodysaesthesia syndrome, another one: grade 2 neutropenia which prevented the initiation of next cycle within 14 days). The maximal tolerated dose (MTD) and recommended dose (RD) of TSU-68 was 200 mg b.i.d. C(max) and AUC(0-t) of TSU-68 at Level 2 were higher than those at Level 1, but doubling the dose of TSU-68 increased C(max) and AUC(0-t) less than two-fold. There was no appreciable difference in the PK of S-1 components (FT, CDHP and Oxo), 5-FU and oxaliplatin-derived platinum between Levels 1 and 2. A significant decrease in PDGF after TSU-68 treatment was identified and it might serve as pharmacodynamic marker of TSU-68. Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 200 mg b.i.d. daily.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Fibroblast Growth Factors; Humans; Indoles; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxindoles; Oxonic Acid; Platelet-Derived Growth Factor; Propionates; Protein Kinase Inhibitors; Pyrroles; Tegafur; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2
PubMed: 21567184
DOI: 10.1007/s10637-011-9683-8 -
Tissue Engineering. Part C, Methods Sep 2011Angiogenesis is of major interest because of its involvement in numerous pathologies or for promoting tissue repair. It is often assessed by the ability of endothelial... (Comparative Study)
Comparative Study
Angiogenesis is of major interest because of its involvement in numerous pathologies or for promoting tissue repair. It is often assessed by the ability of endothelial cells to sprout, migrate, and form vascular tubules in Matrigel in vitro. Matrigel contains a mixture of basement membrane components, which stimulate endothelial cells to form capillary-like hexagonal structures, and is often preferred over other in vitro assays because of its ease of use, rapidity and the ability to measure key steps in angiogenesis, including migration, protease activity, and tubule formation. Various methods have been used to quantitate tubule formation, yet no consensus has been reached regarding the best quantification method for evaluating the efficacy of angiogenic stimulants or inhibitors in this Matrigel assay. Here, we have measured the ability of umbilical cord blood endothelial colony-forming cell-derived cells to form tubules in growth factor reduced Matrigel in the presence or absence of two angiogenic inhibitors, suramin and SU6668, to compare the benefits and limitations of two quantification methods-Angiosys and Wimasis. These comparative analyses revealed that both Angiosys and Wimasis are easy to use, accurately quantify angiogenesis, and will suit the needs of different types of users.
Topics: Angiogenesis Inhibitors; Biological Assay; Collagen; Colony-Forming Units Assay; Drug Combinations; Endothelial Cells; Endothelium, Vascular; Fetal Blood; Humans; Image Processing, Computer-Assisted; Indoles; Intercellular Signaling Peptides and Proteins; Laminin; Neovascularization, Physiologic; Oxindoles; Phenotype; Propionates; Proteoglycans; Pyrroles; Software; Suramin
PubMed: 21517696
DOI: 10.1089/ten.TEC.2011.0150 -
Cardiovascular and Interventional... Feb 2012This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model.
PURPOSE
This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model.
METHODS
This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performed before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections.
RESULTS
According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02).
CONCLUSIONS
Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.
Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Disease Models, Animal; Doxorubicin; Drug Therapy, Combination; Ethiodized Oil; Indoles; Infusions, Intravenous; Liver Neoplasms, Experimental; Neovascularization, Pathologic; Oxindoles; Propionates; Pyrroles; Rabbits; Statistics, Nonparametric; Tomography, X-Ray Computed
PubMed: 21184227
DOI: 10.1007/s00270-010-0081-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 -
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 Feb 2011We studied the safety and effectiveness of TSU-68, an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, platelet-derived growth factor...
PURPOSE
We studied the safety and effectiveness of TSU-68, an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor and fibroblast growth factor receptor, in patients with advanced hepatocellular carcinoma (HCC).
METHODS
Patients with unresectable or metastatic HCC were eligible for enrollment. In phase I, the safety, tolerability and pharmacokinetics were assessed in patients stratified based on liver function, from no cirrhosis to Child-Pugh class B. The safety and effectiveness were assessed in phase II at the dose determined in phase I.
RESULTS
Twelve patients were enrolled in phase I. Dose-limiting toxicities were found with TSU-68 at the dose of 400 mg bid in Child-Pugh B patients, and 200 mg bid was established as the phase II dose. Phase II included 23 additional patients, and the safety and efficacy were evaluated in a total of 35 patients. One patient (2.9%) had a complete response. Two patients (5.7%) had a partial response, and 15 patients (42.8%) showed a stable disease. The median time to progression was 2.1 months, and the median overall survival was 13.1 months. Common adverse events were hypoalbuminemia, diarrhea, anorexia, abdominal pain, malaise, edema and AST/ALT elevation. The analysis of angiogenesis-related parameters suggests that serum-soluble vascular cell adhesion molecule-1 is a possible marker to show the response.
CONCLUSIONS
TSU-68 at a dose of 200 mg bid determined by stratification into liver function, showed promising preliminary efficacy with a high safety profile in patients with HCC who had been heavily pre-treated.
Topics: Administration, Oral; Aged; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Area Under Curve; Biomarkers; Carcinoma, Hepatocellular; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Necrosis; Oxindoles; Propionates; Pyrroles; Survival Analysis; Treatment Outcome; Vascular Cell Adhesion Molecule-1
PubMed: 20390419
DOI: 10.1007/s00280-010-1320-2