semaxinib and Colonic-Neoplasms

The realization that the growth and spread of tumors are dependent on angiogenesis has created new avenues of research designed to help us to better understand cancer biology and to facilitate the development of new therapeutic strategies. However, the process of angiogenesis consists of multiple sequential and interdependent steps with a myriad of positive and negative regulators of angiogenesis being involved. The survival of tumors and thus their metastases are dependent on the balance of endogenous angiogenic and antiangiogenic factors such that the outcome favors increased angiogenesis. Several growth factors have been identified that regulate angiogenesis in colon cancer; the most important of these is vascular endothelial growth factor. In addition, specific integrins such as alphavbeta3 and alpha5beta1 mediate endothelial cell survival and have been shown to be overexpressed on the endothelium of colon cancer. These angiogenic mediators thus serve as targets for therapy of metastatic colon cancer and have shown promise in preclinical trials.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Colonic Neoplasms; Colorectal Neoplasms; Endothelial Growth Factors; Extracellular Matrix; Humans; Indoles; Integrins; Intercellular Signaling Peptides and Proteins; Lymphokines; Neovascularization, Pathologic; Oxindoles; Propionates; Pyrroles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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

Colorectal cancer is one of the most common cancers worldwide. Previous studies suggest that chemoradiotherapy is more effective for the treatment of colorectal cancer than is radiotherapy or chemotherapy alone. To enhance the radiosensitivity of tumor cells, several investigators have used targeted therapeutic agents that act as radiosensitizers. In the present study, we provide a scientific rationale for the clinical application of SU5416, an inhibitor of vascular endothelial growth factor receptor-2, as a radiosensitizer for colorectal cancer. Two human colorectal adenocarcinoma cell lines, HCT116 and HT-29, were treated with SU5416 and radiation alone or radiation followed by SU5416. In vitro tests were performed using colony forming assays, flow cytometric analysis, immunohistochemistry, senescence-associated β-galactosidase, tumor cell motility and invasion assays. The combination of radiation and SU5416 synergistically inhibited cell survival and induced apoptosis through reactive oxygen species, enhanced IR-induced premature senescence, and inhibited DNA repair activity, cell migration and invasion. Collectively, our results favor the use of SU5416 and radiotherapy as a combination therapy for the treatment of colon cancer and it can be combined successfully with a radiation regimen to potentiate its antitumor and antimetastatic activities for future clinical trials.

Topics: Adenocarcinoma; Aging; Antineoplastic Agents; Apoptosis; beta-Galactosidase; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; DNA Repair; HCT116 Cells; HT29 Cells; Humans; Indoles; Neoplasm Invasiveness; Pyrroles; Radiation Tolerance; Radiation-Sensitizing Agents; Reactive Oxygen Species; Receptors, Vascular Endothelial Growth Factor

The recently emerged concept of "vessel normalization" implies that judicious blockade of vascular endothelial growth factor (VEGF) signaling may transiently "normalize" the tumor vasculature, making it more suitable for tumor disposition of subsequently administered drugs. In this study, therefore, the effect of pretreatment with SU5416, a selective VEGF receptor-2 inhibitor, on tumor disposition and in vivo antitumor activity of polyethylene glycol (PEG)-modified liposomal paclitaxel (PL-PTX) was evaluated in Colon-26 solid tumor-bearing mice. To improve the solubility and in vivo disposition characteristics of SU5416, the inhibitor was formulated in PEGylated O/W emulsion (PE-SU5416). Pretreatment with PE-SU5416 significantly enhanced the in vivo antitumor effect of PL-PTX, although PE-SU5416 administration alone did not show any antitumor effect. Immunostaining for endothelial cells and pericytes demonstrated that the pretreatment with PE-SU5416 enhanced the pericyte coverage of the tumor vasculature. In addition, tumors treated with PE-SU5416 contained significantly smaller hypoxic regions compared with the nontreated control group, demonstrating that structural normalization of the tumor vasculature resulted in an improvement in tumor vessel functions, including oxygen supply. Furthermore, the pretreatment with PE-SU5416 increased the distribution of PEG liposomes and included PTX in the core region of the tumor, as well as conversely decreasing the ratio of their peripheral distribution. These results suggest that the structural and functional normalization of the tumor vasculature by the pretreatment with PE-SU5416 enabled liposomes to reach the deeper regions within tumor tissues, leading to more potent antitumor activity of PL-PTX.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Colonic Neoplasms; Humans; Immunoenzyme Techniques; Indoles; Liposomes; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Paclitaxel; Pericytes; Polyethylene Glycols; Pyrroles; Solubility; Tumor Cells, Cultured; Vascular Endothelial Growth Factor Receptor-2

Previously, we identified angiogenic vessel-homing peptide Ala-Pro-Arg-Pro-Gly (APRPG), and showed that APRPG-modified liposomes could selectively target to tumor neovasculature. Here, we designed an APRPG-modified liposome encapsulating SU5416, an angiogenesis inhibitor, to overcome the solubility problem, and to enhance the antiangiogenic activity of SU5416. Liposomal SU5416 appeared to have the appropriate characteristics, such as particle size and stability in serum. It showed a significantly lower hemoglobin release than SU5416 dissolved in a Cremophor EL-containing solvent. Compared with peptide-unmodified liposomal SU5416, the APRPG-modified liposomal SU5416 significantly suppressed tumor growth and with no remarkable side effects. Thus, targeted delivery of antiangiogenic drugs with tumor vasculature-targeted liposomes may be useful for antiangiogenic cancer therapy.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Compounding; Drug Stability; Endothelial Cells; Hemolysis; Humans; Indoles; Lipids; Liposomes; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Particle Size; Pyrroles; Solubility; Time Factors; Vascular Endothelial Growth Factor A

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