Disease relevance of Semaxinib

• Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema [1].
• Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis [1].
• Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation) [2].
• We observed, after 3 to 4 months of treatment, secondary paradoxical polycythemia in 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416 [3].
• A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia [4].

High impact information on Semaxinib

• An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors [5].
• Treatment with the caspase inhibitor Z-Asp-CH(2)-DCB prevented SU5416-induced septal cell apoptosis and emphysema development [1].
• The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation [1].
• Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416 [4].
• SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3 [2].

Chemical compound and disease context of Semaxinib

• Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia [6].
• The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts [7].
• We report that antiangiogenic agents (arginine deiminase, SU5416 and DC101) inhibit in vivo growth of neuroblastomas with unfavorable properties and that these effects are potentiated by simultaneous irradiation [8].
• Pharmacodynamic-mediated effects of the angiogenesis inhibitor SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral glioma xenograft models [9].
• METHODS AND MATERIALS: Primary isolated human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC), and human glioblastoma (U87) and prostate cancer cells (PC3) were exposed to pemetrexed (2 h) alone and in combination with SU5416 (2 h) [10].

Biological context of Semaxinib

• After 12 weeks of treatment with SU5416, the blast cell counts (blood and bone marrow) decreased to undetectable levels and the peripheral blood cell counts normalized with the exception of the platelet count (50-80 x 10(9)/L [50-80 x 10(3)/microL]) [6].
• Both sFlk-1 and the Flk-1-specifc inhibitor SU5416 eliminated the resistance phenotype in GBM and melanoma microvasculature as determined by both the vascular window and Doppler blood flow methods [11].
• The selective flk-1 inhibitor SU5416 partially rescued the flt-1-/- mutant phenotype, and this rescue was accompanied by a decrease in the relative amount of flk-1 tyrosine phosphorylation [12].
• PURPOSE: To determine the biological modulatory dose of SU5416, we employed a novel trial design, where "dose de-escalation" was based on demonstrable biological changes observed at the maximum tolerated dose [13].
• 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 [14].

Anatomical context of Semaxinib

• FLT3 inhibition by SU5416 and SU5614 resulted in reduced proliferation (IC(50), 250 nM and 100 nM, respectively) and induction of apoptosis of FLT3 ITD-positive leukemic cell lines [15].
• Microvessel density in the patient's bone marrow dropped from 33.4 to 12.3 microvessels/x500-field 8 weeks after SU5416 administration and remains in the normal range [6].
• The small molecule receptor tyrosine kinase (RTK) inhibitor SU5416 targets the vascular endothelial growth factor receptor 2 and the stem cell factor receptor c-kit [6].
• Polycythemia has never been reported in current SU5416 trials for advanced malignancies and could express a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene [3].
• 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 [16].

Associations of Semaxinib with other chemical compounds

• These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML [7].
• Moreover, ZD1839 almost completely blocked EGF-induced neovascularization of mice cornea, and SU5416 partially blocked neovascularization [17].
• The inhibition of VEGFR-2 by epigallocatechin-3 gallate was similar to that induced by Semaxanib (SU5416), a specific VEGFR-2 inhibitor [18].
• Finally, nephrin protein by immunofluorescence was decreased in the db/db mice but was significantly restored by SU5416 [19].
• Design: SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay [20].

Gene context of Semaxinib

• Our results suggest that inhibition of NADPH oxidase activity, blocking of COX-2 expression, and PGE(2) synthesis may represent novel targets for SU5416 [21].
• MMP9-released VEGF was biologically active, because it induced endothelial cell motility, and its activity was prevented by the VEGF inhibitor SU5416 [22].
• Moreover, conditioned medium from SH-SY5Y cells collected at different stages of differentiation induced progressive in vitro up-regulation of CEACAM1 expression in human umbilical vein endothelial cells (HUVECs) that was abrogated by the specific VEGF receptor-2/KDR inhibitor SU5416 [23].
• We induced apoptosis of microvascular EC using shear stress and the combined VEGF receptor (VEGFR-1 and -2) inhibitor SU-5416 [24].
• Treatment with the VEGF receptor inhibitor SU5416 (25 mg/kg ip at 3 h) had no effect on toxicity at 6 or 24 h [25].

Analytical, diagnostic and therapeutic context of Semaxinib

• Herein is described the successful treatment of a 65-year-old woman with SU5416, in second relapse of acute myeloid leukemia (AML) and refractory toward standard chemotherapy regimens [6].
• 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 [26].
• SU5416 (5 micro M) inhibited endogenous as well as PMA-mediated induction of COX-2 expression when analyzed by immunoblot and Northern blot analysis [21].
• Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416-treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL [27].
• Similarly, SU 5416, a potent kinase inhibitor of the vascular endothelial growth factor receptor/kinase domain receptor/Flk-1, is currently in clinical trials as an anticancer agent by virtue of its strong anti-angiogenic activity [28].

References