semaxinib and Pancreatic-Neoplasms

To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies.. The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis.. Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly ( approximately 50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death.. SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

Topics: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Humans; Indoles; Male; Mice; Mice, Nude; Middle Aged; Neovascularization, Pathologic; Oxindoles; Pancreatic Neoplasms; Phosphorylation; Propionates; Pyrroles; Receptor, Platelet-Derived Growth Factor beta; Transplantation, Heterologous; Vascular Endothelial Growth Factor Receptor-2

Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem. The pharmacological control of angiogenesis might represent a novel approach to the management of pancreas cancer, since the pathological development of vascular supply is a critical step for tumor growth and may affect its prognosis. In order to test this hypothesis, SU5416 ([3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one]) a selective inhibitor of the vascular endothelial growth factor receptor-2 tyrosine kinase, and gemcitabine (2', 2'-difluorodeoxycytidine) were tested on endothelial (HUVEC) and pancreatic tumor cells (MIA PaCa-2) in vitro and in vivo alone and in simultaneous association. SU5416 inhibited HUVEC cells stimulated to proliferate by vascular endothelial growth factor but not MIA PaCa-2 cells; the drug concentration that decreased cell growth by 50% (IC50) was 0.14 microM. Furthermore, SU5416 reduced the development of microvessels from placental explants (IC50, 0.23 microM). Gemcitabine inhibited the growth of both HUVEC and MIA PaCa-2 cells with an IC50 of 0.08 and 0.1 microM, respectively. A synergistic effect (combination index <1 and dose reduction index >1) on anti-proliferative and pro-apoptotic activity was calculated with the simultaneous combination of the two drugs on endothelial cells. A marked in vivo antitumor effect on MIA PaCa-2 xenografts was observed with SU5416 at a protracted schedules, as well as with gemcitabine; furthermore, the combination between the two drugs resulted in an almost complete suppression of tumor growth and relapse. In conclusion, the present results provide the evidence of an effective anti-endothelial/antitumor activity of protracted administration of SU5416 on human pancreas cancer xenografts, which is comparable with the one obtained by gemcitabine; moreover, the synergistic combination between these drugs on endothelial cells and the promising association in pancreatic cancer xenografts could be used in future studies and translated into the clinical setting.

Topics: Angiogenesis Inhibitors; Animals; Antimetabolites, Antineoplastic; Apoptosis; Cell Division; Cell Line; Cell Line, Tumor; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Endothelial Cells; Female; Gemcitabine; Humans; Immunohistochemistry; Indoles; Male; Mice; Mice, Nude; Neovascularization, Pathologic; Pancreatic Neoplasms; Placenta; Pregnancy; Protein Kinase Inhibitors; Pyrroles; Time Factors; Tissue Culture Techniques; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Islet Cell; Chronotherapy; Indoles; Matrix Metalloproteinase Inhibitors; Mice; Neovascularization, Pathologic; Pancreatic Neoplasms; Phenylalanine; Protease Inhibitors; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Thiophenes