semaxinib and Adenocarcinoma

Photodynamic therapy (PDT) is a promising therapeutic modality using a tumor localizing photosensitizer and light to destroy tumor cells. A major limitation of PDT is tumor recurrence, which is partly due to neovascularization.. The objective of the present study was to determine whether combination therapy with PDT and antiangiogenic agents (i.e. SU5416 and SU6668) would be more effective in controlling tumor recurrence in a mouse model of human CNE2 poorly differentiated nasopharyngeal carcinoma compared with PDT or antiangiogenic agents administered alone.. Athymic mice bearing CNE2 tumor xenografts received daily i.p. injections of 20 mg/kg SU5416 or 100 mg/kg SU6668 for 28 consecutive days either alone or following a single hypericin-PDT treatment.. Significant inhibition of CNE2 tumor growth was observed in all treatment groups. Differences in 4x tumor growth time, the number of mice with 4x tumor growth, tumor growth inhibition as well as the percent of mice surviving were not statistically significant among individual treatment groups. However, the number of mice with 4x tumor growth observed in SU6668 monotherapy and combined PDT and SU6668 treatment groups was significantly less than that in the control group (P<0.05 and 0.01, respectively). Moreover, compared with the control group, only the combined PDT and SU6668 treatment significantly extended survival of tumor-bearing host mice (P<0.05). The semiquantitative RT-PCR results showed that the expression of HIF-1alpha, VEGF, COX-2 and bFGF were increased in PDT-treated tumor samples collected 24 h post-PDT, suggesting that PDT-induced damage to tumor microvasculature and the resultant hypoxia upregulate the expression of certain proangiogenic factors.. The effectiveness of PDT can be enhanced by antiangiogenic treatment with the synthetic RTK inhibitors. Of the two synthetic RTK inhibitors tested, SU6668 was more effective than SU5416 in enhancing tumor responsiveness to PDT.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Anthracenes; Antineoplastic Agents; Chemotherapy, Adjuvant; Drug Screening Assays, Antitumor; Gene Expression; Indoles; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Neoplasms; Neoplasm Transplantation; Neoplasms, Experimental; Oxindoles; Perylene; Photochemotherapy; Propionates; Protein-Tyrosine Kinases; Proteins; Pyrroles; Survival Rate

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

Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model.. Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count.. Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride.. Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Angiogenesis Inhibitors; Animals; Blotting, Western; Cyclohexanes; Disease Models, Animal; Endostatins; Fibroblast Growth Factor 2; Finasteride; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Indoles; Male; Mice; Mice, Transgenic; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prostatic Neoplasms; Pyrroles; Sesquiterpenes; Tumor Microenvironment; Vascular Endothelial Growth Factor A

The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (PC3), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Division; Cell Movement; Cell Survival; Drug Synergism; Endostatins; Endothelium, Vascular; Female; Glioblastoma; Humans; Indoles; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Neoplasms; Neovascularization, Pathologic; Prostatic Neoplasms; Pyrroles; Ultrasonography; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays