semaxinib and Neoplasm-Metastasis

Cancer progression is attained by uncontrolled cell division and metastasis. Increase in tumor size triggers different vascular channel formation to address cell nutritional demands. These channels are responsible for transferring of nutrients and gaseous to the cancer cells. Cancer vascularization is regulated by numerous factors including vascular endothelial growth factors (VEGFs). These factors play an important role during embryonic development. Members included in this group are VEGFA, VEGFB, VEGFC, PIGF and VEGFD which markedly influence cellular growth and apoptosis. Being freely diffusible these proteins act in both autocrine and paracrine fashions. In this review, genetic characterization these molecules and their putative role in cancer staging has been elaborated. Prognostic significance of these molecules along with different stages of cancer has also been summarized. Brief outline of ongoing efforts to target hot spot target sites against these VEGFs and their cognate limitations for therapeutic implications are also highlighted.

Topics: Angiogenesis Inhibitors; Bevacizumab; Humans; Indoles; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Neovascularization, Pathologic; Prognosis; Protein Kinase Inhibitors; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factors

The vascularization is a very important part of a structure of each tissue both normal, including bone marrow stroma, and pathologically changed. Neoplastic tissues secure supplying in necessary substances for growth and expansion through regulated by its own cells neovasculation. Key role in multipotential cell's differentiation to endothelial cells plays regulatory system consisted of vascular-epithelial growth factor's family (VEGF B, C, D), receptors VEGFR-1, -2, -3, and system Tie2/angiopoetins. Stimulation and importance of angiogenesis for expansion of neoplastic diseases is a current problem in oncology. It is pointed to importance of neovascularization in pathogenesis of acute and chronic leukemias, lymphomas and multiple myeloma. The knowledge of the importance ofvascularization of neoplastic tissues is availing in therapy (researching of substances inhibiting angiogenesis--semaxinib, SU6668, ZD 6474, thalidomid, cetuximab, gefitinib, interferon-alpha, irradiation and others), in diagnostics as a monitoring of a success of the therapy, and in prognosis. Inhibitors ofangiogenesis are antineoplastic drugs with relatively lower toxicity, and lower risk of drug-resistance than conventional chemotherapy what has the importance especially during prolong administration, so they can be an alternative way of therapeutic process. During qualification for antiangiogenic therapy it is necessary to have a consciousness of its limited efficiency.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Angiopoietin-1; Angiopoietin-2; Hematologic Neoplasms; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasm Metastasis; Neovascularization, Pathologic; Oxindoles; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Propionates; Pyrroles; Receptor, TIE-2; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factors

This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination.. Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib.. Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months.. The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.

Topics: Adult; Aged; Angiogenesis Inhibitors; Area Under Curve; Asthenia; Dose-Response Relationship, Drug; Edema; Female; Half-Life; Headache; Humans; Indoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Protein Kinase Inhibitors; Pyrroles; Thalidomide; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Venous Thrombosis

Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer.. SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion.. Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease.. Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Indoles; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pyrroles; Vascular Endothelial Growth Factor Receptor-2

Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion.. Patients with documented progressive disease and

Topics: Adult; Aged; Angiogenesis Inhibitors; Female; Glucose; Humans; Indoles; Lymphocytes; Magnetic Resonance Imaging; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyrroles; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Endoglin, a transforming growth factor-β co-receptor, is highly expressed on angiogenic endothelial cells in solid tumors. Therefore, targeting endoglin is currently being explored in clinical trials for anti-angiogenic therapy. In this project, the redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis and the effects of targeting both pathways on breast cancer metastasis were explored. In patient samples, increased endoglin signaling after VEGF inhibition was observed. In vitro TRC105, an endoglin-neutralizing antibody, increased VEGF signaling in endothelial cells. Moreover, combined targeting of the endoglin and VEGF pathway, with the VEGF receptor kinase inhibitor SU5416, increased antiangiogenic effects in vitro and in a zebrafish angiogenesis model. Next, in a mouse model for invasive lobular breast cancer, the effects of TRC105 and SU5416 on tumor growth and metastasis were explored. Although TRC105 and SU5416 decreased tumor vascular density, tumor volume was unaffected. Strikingly, in mice treated with TRC105, or TRC105 and SU5416 combined, a strong inhibition in the number of metastases was seen. Moreover, upon resection of the primary tumor, strong inhibition of metastatic spread by TRC105 was observed in an adjuvant setting. To confirm these data, we assessed the effects of endoglin-Fc (an endoglin ligand trap) on metastasis formation. Similar to treatment with TRC105 in the resection model, endoglin-Fc-expressing tumors showed strong inhibition of distant metastases. These results show, for the first time, that targeting endoglin, either with neutralizing antibodies or a ligand trap, strongly inhibits metastatic spread of breast cancer in vivo.

Topics: Animals; Antibodies, Monoclonal; Breast Neoplasms; Endoglin; Female; Humans; Indoles; Neoplasm Metastasis; Neovascularization, Pathologic; Pyrroles; Smad1 Protein; Vascular Endothelial Growth Factor A; Zebrafish

The WASF3 (WAVE3) gene is an important mediator of cell motility, invasion and metastasis and is expressed at high levels in some advanced stage tumors. In our survey of breast cancer cells, we now demonstrate that exposure to hypoxic conditions increases WASF3 expression levels in MDA231, SKBR3 and MCF7 cells. The WASF3 promoter region contains HIF1A response elements (HRE). ChIP assays demonstrate that HIF1A binds to these HRE elements in the promoter region, and luciferase reporter assays using the WASF3 gene minimal promoter shows that hypoxia results in its upregulation. Phosphorylation of WASF3 is required for its ability to affect invasion and increased phosphoactivation of WASF3 is also seen in cells challenged with hypoxia. These cells also show increased motility in the scratch wound assay. Cells in which WASF3 has been knocked down show no response to hypoxia as expected, implicating the specificity of the hypoxic response to WASF3. Overall, these experiments demonstrate WASF3 is a HIF1A-regulated gene and suggests a mechanism to explain the observation of elevated expression of WASF3 in advanced stage tumors.

Topics: Breast Neoplasms; Cell Hypoxia; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Neoplasm Metastasis; Pyrroles; Transcription, Genetic; Tumor Microenvironment; Vascular Endothelial Growth Factor A; Wiskott-Aldrich Syndrome Protein Family

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

Anti-angiogenesis is a promising strategy for cancer therapy currently evaluated in clinical trials. The aim of the study was to investigate the effects of an antiangiogenic combination therapy inhibiting alpha(v)-integrins by a c(yclic)RGD-peptide (EMD270179) and blocking VEGFR-2 by SU5416 on tumor angiogenesis and progression in vivo. Experiments were performed in dorsal skinfold chamber preparations of Syrian golden hamsters (60 +/- 5 g) bearing A-Mel-3 tumors. From day 3-10 after tumor-cell implantation, animals (n = 6 per group) were treated by monotherapies using the cRGD-peptide (114 mg/kg/day; i.p.), the VEGFR-2 antagonist (6 mg/kg/day; i.p.) or by the combination of both monotherapies. A control group received only the solvent DMSO. Using intravital microscopy parameters of intratumoral microcirculation were analyzed on day 5, 7 and 10. In separate experiments subcutaneous tumor growth and metastasis formation was evaluated starting therapy on day 0. Functional vessel density was significantly reduced by the combination therapy compared to that by all other groups on day 10. Although intratumoral red blood cell velocity and vessel diameters were less affected, blood flow in vessel segments and the microcirculatory perfusion index were lower after combined therapy compared to controls. In addition, we observed a significantly stronger inhibition of subcutaneous tumor growth and metastasis formation using the combination therapy. These data clearly support the concept of antiangiogenic combination therapy and demonstrate that it may especially be effective when scheduled as an early or prophylactic treatment regimen, thus avoiding angiogenesis-dependent tumor and metastasis initiation or tumor recurrence.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Cricetinae; Disease Progression; Indoles; Integrin alphaV; Male; Mesocricetus; Microcirculation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Pyrroles; Vascular Endothelial Growth Factor Receptor-2

The cancer process in a combination of two kinds of events: a multistep cellular genetic defects giving cells independent growth and great adaptation capability, a multistep interactions profiles with what is called the stromal reaction from the original in situ tumor to the invasive metastatic and angiogenic tumor. The immune system plays an important role in the control of the cancer process but always must be seen as a part integrated in the stromal reaction. In order to boost the immune system capability to treat a cancer we must never forget these cellular and tissular dimensions. Interleukins, growth factors and monoclonal antibodies are new agents are able to bring immunotherapy of cancer to reality. Interleukin 2 did not match our dreams of the ideal factor which can stimulate the defective immune system and bring the cancer evolution to an end. The little but real remissions obtained with the IL-2 high dose protocols still sustains our trust of the immune system as a critical barrier to cancer evolution but the numerous side effects reminds us that cytokines are not to be used as antibiotics and hormones. IL-2 is a regulator of the immune system at the microenvironment level, therefore flooding the blood circulation with high IL-2 doses is not appropriate. We have also to understand that IL-2 can interact directly with cancer cells and also with stromal cells (endothelial and fibroblastic cells), the outcome of IL-2 immunotherapy is not restricted to the interactions with immune cells.

Topics: Cytokines; Humans; Immunotherapy; Indoles; Interleukin-2; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oxindoles; Propionates; Protein-Tyrosine Kinases; Pyrroles; Receptors, Interleukin-2

Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.. Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.. Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion.. These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

Topics: Aged; Angiogenesis Inhibitors; Antigens, CD; Biomarkers, Tumor; CD24 Antigen; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lactoferrin; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Membrane Glycoproteins; Middle Aged; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Protein-Tyrosine Kinases; Pyrroles; Reverse Transcriptase Polymerase Chain Reaction

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Colorectal Neoplasms; Disease Progression; Extracellular Matrix; Humans; Indoles; Matrix Metalloproteinases; Neoplasm Metastasis; Neovascularization, Pathologic; Pyrroles

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

Neurogenic sarcomas are incurable, common malignant human peripheral nerve tumors subject to local recurrence and systemic metastasis. In this study, the vascularity, vascular endothelial growth factor (VEGF) expression, and effects of inhibiting VEGF receptor on growth of neurogenic sarcomas were examined. Vascularization and VEGF expression were 6.4- and 15-fold higher in tumors than in normal nerves. The small molecule inhibitor (SU5416) of VEGF receptor 2 had no effect on neurogenic sarcoma cell lines in vitro, but the growth of a human tumor explant xenograft model was reduced by 54.8% compared to vehicle. Reduction in tumor growth was due to decreased tumor angiogenesis, leading to reduction of tumor cell proliferation and increased apoptosis. Inhibiting VEGF function may therefore be a useful adjuvant therapy for neurogenic sarcomas.

Topics: Angiogenesis Inhibitors; Animals; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Indoles; Lymphokines; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Transplantation; Neovascularization, Pathologic; Neurofibromatosis 1; Neurons; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Time Factors; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors