semaxinib and Liver-Neoplasms

To evaluate variability of a simplified method for measuring semiquantitative DCE-MRI parameters in patients with cancer and to explore effects of treatment with a putative anti-angiogenic compound.. A total of 19 patients enrolled on treatment trials with the putative anti-angiogenic agent SU5416 underwent contrast enhanced examinations, and 11 had a second examination eight weeks post therapy. Contrast media concentration as a function of time was calculated using changes in signal and literature baseline T(1) values in normal muscle or liver reference tissue. Semiquantitative DCE-MRI parameters, including the area under the contrast concentration vs. time curve (AUC), were calculated for regions-of-interest in normal liver and muscle, and in tumors.. The coefficients of variation for pretherapy parameters in normal tissue were 11% to 37%. No significant changes were detected in normal liver over two months of therapy. In tumors and muscle, a significant decrease in the AUC and maximum contrast concentration was observed.. Variability of semiquantitative DCE-MRI parameters utilizing a method based on known T(1) values in a reference tissue is low enough to detect changes in tumors during therapy. Use of this method as a pharmacodynamic marker should be further investigated.

Topics: Angiogenesis Inhibitors; Colonic Neoplasms; Contrast Media; Gadolinium DTPA; Humans; Indoles; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Melanoma; Mesothelioma; Muscle, Skeletal; Protein-Tyrosine Kinases; Pyrroles

The aryl hydrocarbon receptor (AhR) is a potential clinical target for cancer and autoimmune dysfunction. Identifying selective AhR modulators that produce desirable clinical outcomes represents an opportunity for developing new anti-cancer agents. Repurposing clinically-used drugs with established safety profiles that activate the AhR represents a good starting place to pursue this goal. In this study, we characterized the AhR-dependent effects of SU5416 (Semaxanib) following its identification in a small-molecule library screen. SU5416 potently activated AhR-dependent reporter genes, induced AhR nuclear localization, facilitated AhR-DNA binding, and increased, expression of its endogenous target genes. SU5416 significantly inhibited proliferation of Hepa1 hepatoma cells in an AhR-dependent manner, but did not induce apoptosis. SU5416 also inhibited the growth of human HepG2 liver cancer cells. The effects of SU5416 correlated with an increased G1 population and increased expression of cell cycle inhibitor p21cip1/waf1 at both the mRNA and protein level. Increased expression of p21cip1/waf1 by SU5416 required expression of both AhR and Arnt. In addition, evidence for long-term activation of the AhR in vivo by a single dose of SU5416 was identified by analyzing published microarray data. Our results provide support for continued investigation of the AhR as therapeutic for cancers such as hepatocellular carcinoma. In addition, our findings raise the possibility that some of the previously observed anti-proliferative effects of SU5416 may be due to activation of the AhR.

Topics: Antineoplastic Agents; Aryl Hydrocarbon Receptor Nuclear Translocator; Cell Line; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indoles; Liver Neoplasms; Protein Kinase Inhibitors; Pyrroles; Receptors, Aryl Hydrocarbon; Signal Transduction

3-Substituted indolin-2-ones are an important class of compounds that display a wide range of biological activities. Sunitinib is an orally available multiple tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration (FDA) for the treatment of renal cell cancer. Sunitinib and a related compound, semaxanib, exist as thermodynamically stable Z isomers, which photoisomerize to E isomers in solution. In this study, 17 3-substituted indolin-2-ones were synthesized, and the kinetics of their photoisomerization were studied by (1)H NMR spectroscopy. The rate constants for photoisomerization ranged from 0.009 to 0.048 h(-1). Selected compounds were tested for cytotoxicity in the TAMH liver cell line. E/Z mixtures of four compounds were also assessed for toxicity in the TAMH and HepG2 cell lines. In some cases, the stereochemically pure drug was more toxic than the E/Z mixtures, but a general statement cannot be made. Our studies show that each stereoisomer could contribute differently to toxicity, suggesting that stereochemical purity issues that could arise from isomerization cannot be ignored.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Indoles; Liver Neoplasms; Molecular Structure; Photochemical Processes; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrroles; Stereoisomerism; Structure-Activity Relationship; Sunitinib

The majority of patients with a diagnosis of cancer die from metastatic disease. Targeting specific steps in the metastatic process has the potential to improve patient outcomes. In this study, a novel lung metastasis model was developed by injecting DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbo-cyanine perchlorate)-labeled Lewis lung carcinoma cells into the tail vein of mice. The temporal development of tumor metastases was studied in the lung, liver and spleen. Additionally, the effects of vascular endothelial growth factor receptor inhibitor SU5416 and platelet activation inhibitor prostacyclin were tested in this metastasis model. Systemically injected Lewis lung carcinoma cells present in the lung at 15 min slowly accumulated in the liver and spleen reaching a peak at 4 days. After 8 days, tumor development was only evident in the lung. Use of SU5416 or prostacyclin lowered the initial density of Lewis lung carcinoma-labeled cells in the lung by a factor 1.8 and 2.3, respectively (P<0.05). Furthermore, treatment with prostacyclin or SU5416 decreased lung weight by over 50% and the number of visible metastatic nodes by over 90% (P<0.05). Combined treatment resulted in grossly normal lung tissue. Additionally, systemic treatment with prostacyclin reduced harvested metastatic cell adherence to endothelial cells by a factor of 10 and treatment with SU5416 attenuated vascular formation (P<0.001). In conclusion, SU5416 and prostacyclin effectively attenuated metastasis formation in this model. DiI labeling is an effective technique to monitor the temporal and spatial distribution of metastatic cells.

Topics: Animals; Carcinoma, Lewis Lung; Cell Adhesion; Cells, Cultured; Disease Progression; Epoprostenol; Indoles; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Splenic Neoplasms

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Hepatectomy; Humans; Indoles; Liver Neoplasms; Prognosis; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Survival Rate

SU5416 is a potent inhibitor of receptor tyrosine kinases, including those of the vascular endothelial growth factor receptor, stem cell factor receptor, and platelet-derived growth factor receptor. Because of the overwhelming evidence favoring the role of aberrant hepatocyte growth factor (HGF)/Met signaling in the pathogenesis of various human cancers, various inhibitor strategies have been employed to therapeutically target this receptor.. Cell proliferation was determined by incorporation of [(3)H] thymidine. Invasiveness was assayed in Boyden Chambers with 8 microm Matrigel coated filters. Phosphorylation of ERK1/2, Akt by HGF stimulation was detected by Western blotting.. We found that SU5416 inhibited motility scattering and the invasive activity of a hepatocellular carcinoma cell line HepG2 in vitro and growth in primary cultured hepatocytes induced by HGF. Consequently, tyrosine autophosphorylation of the c-met induced by HGF was inhibited in these cells by SU5416 in a dose-dependent manner. Furthermore, ERK1/2 and Akt phosphorylation, the signaling events down-stream of c-met activation were reduced. Moreover, SU5416 caused reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met.. Inhibition of various solid tumors growth and metastasis by SU5416 may be partially attributed to blocking activation of the hepatocyte growth factor receptor.

Topics: 3T3 Cells; Animals; Carcinoma, Hepatocellular; Cells, Cultured; DNA; Dose-Response Relationship, Drug; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Expression; Hepatocyte Growth Factor; Hepatocytes; Humans; Indoles; Liver Neoplasms; Mice; Neoplasm Invasiveness; Oncogene Proteins, Fusion; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyrroles; Tyrosine

Tumor growth and metastasis are dependent on angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in the angiogenesis of numerous solid malignancies including colon cancer. Evidence from preclinical and clinical studies indicates VEGF is the predominant angiogenic factor in human colon cancer and is associated with formation of metastases and poor prognosis. Based on these results, it was hypothesized that inhibition of VEGF receptor activity could inhibit colon cancer liver metastasis. To test this hypothesis, the authors evaluated the ability of a small molecule inhibitor specific for the tyrosine kinase VEGF receptor Flk-1/KDR (SU5416) or multiple tyrosine kinase receptors (SU6668) to inhibit tumor angiogenesis and metastasis in a model of colon cancer hepatic metastasis. Both SU5416 and SU6668 inhibited metastases, microvessel formation, and cell proliferation while increasing tumor cell and endothelial cell apoptosis. These results showed that targeting the VEGF receptor/ligand system is a rational approach to inhibiting tumor growth and prolonging survival.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Cell Division; Colonic Neoplasms; Disease Models, Animal; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Humans; Indoles; Liver Neoplasms; Lymphokines; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Prognosis; Protein Isoforms; Protein-Tyrosine Kinases; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Mitogen; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Increased vascular endothelial growth factor (VEGF) expression is associated with colon cancer metastases. We hypothesized that inhibition of VEGF receptor activity could inhibit colon cancer liver metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate metastases. Mice received daily i.p. injections of vehicle, tyrosine kinase inhibitor for Flk-1/KDR (SU5416) or tyrosine kinase inhibitor for VEGF, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). SU5416 and SU6668 respectively inhibited metastases (48.1% and 55.3%), microvessel formation (42.0% and 36.2%), and cell proliferation (24.4% and 27.3%) and increased tumor cell (by 2.6- and 4.3-fold) and endothelial cell (by 18.6- and 81.4-fold) apoptosis (P<0.001). VEGF receptor inhibitors increased endothelial cell apoptosis, suggesting that VEGF may serve as an endothelial survival factor.

Topics: Animals; Apoptosis; Colonic Neoplasms; Endothelium; Fluorescent Antibody Technique; In Situ Nick-End Labeling; Indoles; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Pyrroles; Random Allocation; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Tumor Cells, Cultured