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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 -
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 -
The Journal of Clinical Investigation May 2003Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting...
Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors. In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity. Importantly, PDGFRs were expressed only in perivascular cells of this tumor type, suggesting that PDGFR(+) pericytes in tumors present a complimentary target to endothelial cells for efficacious antiangiogenic therapy. Therapeutic regimes combining the two kinase inhibitors (SU5416 and SU6668) were more efficacious against all stages of islet carcinogenesis than either single agent. Combination of the VEGFR inhibitor with another distinctive kinase inhibitor targeting PDGFR activity (Gleevec) was also able to regress late-stage tumors. Thus, combinatorial targeting of receptor tyrosine kinases shows promise for treating multiple stages in tumorigenesis, most notably the often-intractable late-stage solid tumor.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Blood Vessels; Carcinoma, Islet Cell; Endothelium, Vascular; Female; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Pathologic; Oxindoles; Pericytes; Platelet-Derived Growth Factor; Propionates; Protein-Tyrosine Kinases; Pyrroles; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor
PubMed: 12727920
DOI: 10.1172/JCI17929 -
Cancer Research Aug 2005Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach...
Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1-mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.
Topics: Angiogenesis Inhibitors; Animals; Aurora Kinases; COS Cells; Cell Division; Chlorocebus aethiops; HeLa Cells; Humans; Indoles; Oxindoles; Propionates; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrroles; Transfection
PubMed: 16061676
DOI: 10.1158/0008-5472.CAN-05-0574 -
Anticancer Research 2005Peritoneal dissemination of cancer involves several steps, including tumor cell attachment, invasion and growth in the peritoneum. Tumor angiogenesis is a prerequisite...
BACKGROUND
Peritoneal dissemination of cancer involves several steps, including tumor cell attachment, invasion and growth in the peritoneum. Tumor angiogenesis is a prerequisite for the growth of disseminated tumor. Vascular endothelial growth factor (VEGF) and its receptor are major regulators of angiogenesis.
PURPOSE
We examined the cytotoxic effects of SU6668, an inhibitor of VEGF tyrosine kinase receptors, on in vitro gastric cancer cell lines and human umbilical vascular endothelial cells (HUVEC); we also examined the antitumor effects of SU6668 on human gastric cancer cells administered intraperitoneally into nude mice.
MATERIALS AND METHODS
Direct cytotoxicity to gastric cancer cells (TMK-1, MKN-45 and MKN-74) and normal cells (HUVEC) was determined by the MTT assay and the bromodeoxyuridine (BrdU) incorporation assay, with and without VEGF-evoked growth stimulation in vitro. TMK-1 cells were transplanted intraperitoneally into nude mice, followed by twice daily oral administration of SU6668 (200 mg/kg/day) for two weeks starting on the first day after transplantation. Both the number and the wet weight of disseminated peritoneal tumor nodules were assessed.
RESULTS
In the MTT assay, SU6668 demonstrated low-grade cytotoxicity to the cell growth of three gastric cancer cells, with a 50% inhibitory concentration (IC50) of 22.6 microg/ml for TMK-1, 31.8 microg/ml for MKN-45 and 26.7 microg/ml for MKN-74; HUVEC was sensitive to SU6668 with an IC50 of 8.9 microg/ml. In the BrdU assay, VEGF stimulated DNA synthesis in HUVEC, while the incorporation of BrdU was not affected by VEGF in gastric cancer cell lines. SU6668 inhibited VEGF-induced DNA synthesis in HUVEC, while BrdU incorporation of gastric cancer cell lines was inhibited by SU6668 without correlation to VEGF stimulation. Peritoneal dissemination of cancer in nude mice was significantly suppressed by SU6668 compared with a control group at the p<0.05 level.
CONCLUSION
The mechanism of the antitumor activity of SU6668 may not involve direct toxicity to cancer cells, but may rather be an inhibitory effect on tumor angiogenesis, resulting in the inhibition of tumor dissemination in the peritoneum.
Topics: Adult; Animals; Cell Growth Processes; Cell Line, Tumor; DNA; Endothelial Cells; Humans; Indoles; Male; Mice; Mice, Nude; Mice, SCID; Neovascularization, Pathologic; Oxindoles; Peritoneal Neoplasms; Propionates; Protein-Tyrosine Kinases; Pyrroles; Stomach Neoplasms; Tetrazolium Salts; Thiazoles; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays
PubMed: 15816514
DOI: No ID Found -
Blood Mar 2001SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of receptor tyrosine kinases, including those of the vascular endothelial growth factor and...
The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts.
SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of receptor tyrosine kinases, including those of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors and, although not expressed on mature peripheral blood cells, is expressed in leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) patients. The c-kit kinase inhibitory activity of SU5416 and SU6668 was evaluated in MO7E cells, a human myeloid leukemia cell line. Tyrosine autophosphorylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC(50)] 0.1-1 microM). Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, a signaling event downstream of c-kit activation, was also inhibited in a dose-dependent manner. Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC(50) 0.1 microM for SU5416; 0.29 microM for SU6668). Furthermore, both SU5416 and SU6668 induced apoptosis in a dose- and time-dependent manner as measured by the increase in activated caspase-3 and the enhanced cleavage of its substrate poly(ADP-ribose) polymerase. These findings with MO7E cells were extended to leukemic blasts from c-kit(+) patients. In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis. These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML.
Topics: Angiogenesis Inhibitors; Apoptosis; Caspase 3; Caspases; Cell Division; Dose-Response Relationship, Drug; Humans; Indoles; Leukemia, Myeloid; Mitogen-Activated Protein Kinases; Oxindoles; Phosphorylation; Propionates; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Pyrroles; Stem Cell Factor; Tumor Cells, Cultured
PubMed: 11222388
DOI: 10.1182/blood.v97.5.1413 -
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 -
British Journal of Cancer May 2009Dynamic contrast-enhanced (albumin-Gd-DTPA) magnetic resonance imaging, performed during 2 weeks of daily administration of an inhibitor of tyrosine kinase receptors...
Dynamic contrast-enhanced (albumin-Gd-DTPA) magnetic resonance imaging, performed during 2 weeks of daily administration of an inhibitor of tyrosine kinase receptors (SU6668) in an HT-29 colon carcinoma model, revealed the onset of a hyper-enhancing rim, not observed in untreated tumours. To account for tissue heterogeneity in the quantitative analysis, we segmented tumours into three subunits automatically identified by cluster analysis of the enhancement curves using a k-means algorithm. Transendothelial permeability (Kps) and fractional plasma volume (fPV) were calculated in each subunit. An avascular and necrotic region, an intermediate zone and a well-vascularised periphery were reliably identified. During untreated tumour growth, the identified sub-regions did not substantially change their enhancement pattern. Treatment with SU6668 induced major changes at tumour periphery where a significant increase of Kps and fPV was observed with respect to control tumours. Histology revealed a sub-capsular layer composed of hyper-dense viable tumour cells in the periphery of untreated tumours. The rim of viable neoplastic cells was reduced in treated tumours, and replaced by loose connective tissue characterised by numerous vessels, which explains the observed hyper-enhancement. The present data show a peripheral abnormal development of cancer-associated stroma, indicative of an adaptive response to anti-angiogenic treatment.
Topics: Animals; Carcinoma; Cell Proliferation; Colonic Neoplasms; Disease Progression; HT29 Cells; Humans; Indoles; Magnetic Resonance Imaging; Mice; Mice, Nude; Neovascularization, Pathologic; Oxindoles; Propionates; Pyrroles; Receptor Protein-Tyrosine Kinases; Stromal Cells; Up-Regulation; Xenograft Model Antitumor Assays
PubMed: 19384298
DOI: 10.1038/sj.bjc.6605041