Aflibercept. Una aproximación a la farmacología / Aflibercept. An approach to pharmacology

Aflibercept es una proteina de fusion que combina en su estructura quimica, la fraccion constante de cualquier IgG con una fraccion variable construida con partes fundamentales de los receptores del factor de crecimiento del endotelio vascular, por ello es capaz de fijar a diversas isoformas del factor de crecimiento del endotelio vascular y tambien al factor de crecimiento placentario, lo que se ha puesto en relacion con un posible efecto sinergico en la eficacia. La afinidad es mayor que la que presentan ranibizumab y bevacizumab. Ademas produce un efecto antiinflamatorio intraocular. La administracion por via intravitrea cursa con la presencia de trazos del farmaco en el plasma del paciente; de hecho, las concentraciones son tan reducidas que la presencia de efectos adversos sistemicos, incluida la hipertension arterial, es practicamente nula. Una semivida de eliminacion intraocular prolongada unida a la afinidad elevada supone que sea posible la utilizacion en pautas posologicas comodas, ya que tras una inyeccion mensual para las 3 primeras dosis se aumenta el intervalo a una inyeccion cada 2 meses, que tras los primeros 12 meses puede vincularse a los resultados visuales y anatómicos (AU)

Aflibercept is a fusion protein whose chemical structure combines the constant fraction of any IgG with a variable fraction constructed with fundamental parts of VEGF receptors. Consequently, it is able to bind to various VEGF as well as to placental growth factor (PIGF), which has been related to a possible synergistic effect in efficacy. The affinity of this drug is higher than that of ranibizumab and bevacizumab. Moreover, it has an intraocular antiinflammatory effect. Intravitreal administration leads to the presence of traces of the drug in plasma but the concentrations are so reduced that the presence of systemic adverse effects, including arterial hypertension, is practically nil. Because of its prolonged intraocular elimination half-life and high affinity, the drug can be administered in convenient regimens, since, after an initial monthly injection for the first three doses, the interval between injections is increased to one every two months and, after the first 12 months, the dosing will depend on the visual and anatomical results (AU)

The VEGF signaling pathway in cancer: the road ahead.

The vascular endothelial growth factor (VEGF) family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF), VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF), play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin) and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.

A probable novel splicing isoform of human vascular endothelial growth factor.

OBJECTIVE: To characterize a new alternative splicing isoform of human vascular endothelial growth factor (VEGF) gene. METHODS: The total RNA was extracted from the lung tissue of a legally aborted 4-month-old fetus and amplified by RT-PCR. The amplified product was cloned into the plasmid pMD18-T and plasmid pcDNA3.1- for sequence analysis. RESULTS: Electrophoresis of the RT-PCR products displayed one short band for VEGF(121) (487 bp) and a long band. The latter was characterized to contain two fragments: one was normal VEGF(165) (619 bp), and the other (639 bp) had an identical nucleotide sequence to VEGF(165) with a 20 bp fragment inserted between exons 3 and 4. Sequence analysis showed that this 20-bp nucleotide was inserted from the 3' end of the third intron containing a splicing signal, thus causing shift mutation in the reading frame of VEGF gene and early appearance of the stop codon UAG in the middle of exon 4. CONCLUSION: A new alternative splicing isoform of VEGF probably exists in the lung tissue of a legally aborted human fetus, and its biological significance remains to be further investigated.

Angiogenesis inhibition in cancer therapy: platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) and their receptors: biological functions and role in malignancy.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. VEGF gene transcription is induced in particular in hypoxic cells. In developmental angiogenesis, the role of VEGF is demonstrated by the finding that the loss of a single VEGF allele results in defective vascularization and early embryonic lethality. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Platelet-derived growth factor (PDGF) is mainly believed to be an important mitogen for connective tissue, and also has important roles during embryonal development. Its overexpression has been linked to different types of malignancies. Thus, it is important to understand the physiology of VEGF and PDGF and their receptors as well as their roles in malignancies in order to develop antiangiogenic strategies for the treatment of malignant disease.

[VEGF and central nervous system diseases].

Vascular endothelial growth factor (VEGF or VEGF-A) is a hypoxia induced angiogenic growth factor that is potent in neurotrophy,neuroprotection, anti-apoptosis and cell proliferation. Recent reports suggest that VEGF is related to many central nervous system diseases, such as cerebral ischemic disease, Alzheimer's disease and Parkinson's disease. Further study of the relationship between VEGF and central nervous system diseases,and investigation of VEGF related drugs will shed light on a new way for treatment of central nervous system diseases.

Expression levels of vascular endothelial growth factor and its receptors in Parkinson's disease.

Recently, we confirmed the presence of enhanced neural reconstruction in Parkinson's disease and in an animal model of Parkinson's disease based on increased polysialic acid-like immunoreactivity. Changes in neurogenesis often appear parallel to changes in angiogenesis. Moreover, both these processes share similar modulating factors, like vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1). Using immunohistochemistry, we identified in this study upregulation of VEGF in the substantia nigra but not in the striatum of patients with Parkinson's disease by enzyme-linked immunosorbent assay. Such overexpression may participate in vascular remodeling and neurogenesis in the substantia nigra of Parkinson's disease.

Biology of vascular endothelial growth factors.

Angiogenesis is the process by which new blood vessels are formed from existing vessels. The vascular endothelial growth factors (VEGFs) are considered as key molecules in the process of angiogenesis. The VEGF family currently includes VEGF-A, -B, -C, -D, -E, -F and placenta growth factor (PlGF), that bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. VEGF-C and VEGF-D also play a crucial role in the process of lymphangiogenesis. Here, we review the biology of VEGFs and evaluate their role in pathological angiogenesis and lymphangiogenesis.

Angiogenesis in gynecological oncology-mechanism of tumor progression and therapeutic targets.

The purpose of this article is to review the current literature pertaining to various angiogenic stimulators and angiogenesis inhibitors in gynecological malignancies and the relevance of these markers in the prognosis of these diseases. We also summarize the antiangiogenic drugs currently in development and in clinical use in gynecological oncology. The information was obtained from a computer search of MEDLINE for studies published in the English language regarding angiogenesis and angiogenesis inhibitors in gynecological malignancies between 1970 and December 2003; additional sources were identified through cross-referencing. In ovarian cancer, various different angiogenic activators have been found to correlate with microvessed density (MVD), stage, lymph node and peritoneal metastasis, and survival. In cervical cancer, correlation has been seen between increased angiogenic markers and stage, grade, tumor size, and survival. Studies in endometriat cancer show correlation of angiogenic markers with stage, grade, MVD, and survival. Whereas, in gestational trophoblastic neoplasm (GTD) only few markers have been studied, and some correlated with progression. Information on anti angiogenic drugs currently in ongoing and upcoming trials in gynecological malignancies is also presented. Angiogenesis factors may have a prognostic role to play in patients with gynecological cancers and should continue to be investigated as clinically useful tumor markers. Antiangiogenic-targeted therapies offer an attractive strategy for clinical investigation in gynecologic oncology.

The vascular endothelial growth factor family and its receptors.

This article focuses on describing the biology of vascular endothelial growth factor (VEGF) and its receptors as well as the regulation of their expression. A thorough understanding of the VEGF system is paramount in optimizing antiangiogenic therapies as a component of antineoplastic regimens.

Homologs of vascular endothelial growth factor and receptor, VEGF and VEGFR, in the jellyfish Podocoryne carnea.

Vascular endothelial growth factors (VEGF) are the major inducers of vasculogenesis and angiogenesis in vertebrates. Their effects are mediated by receptor tyrosine kinases of the VEGF receptor (VEGFR) family located on endothelial cells and include stimulation of cell survival, proliferation, migration, and tube formation as well as regulation of vascular permeability. Here, we report the presence of VEGF and VEGFR homologous genes in a basal invertebrate of the phylum Cnidaria. The marine jellyfish Podocoryne carnea features a gastrovascular system consisting of the feeding organ, or manubrium, the radial and ring canals, and the tentacle bulbs. Expression analysis indicates that both genes are involved in tentacle and gastrovascular canal formation, indicating an early recruitment of the VEGF signalling pathway for morphogenetic processes leading to tube formation in metazoans. The evolutionary origin of the VEGF signalling pathway resides in the common ancestor of the Cnidaria and Bilateria.

Vascular endothelial growth factor receptors: expression and function in solid tumors.

Vascular endothelial growth factor (VEGF) and its family members are important mediators of tumor angiogenesis. The multiple functions of the VEGF are mediated through complex and selective interactions between the ligands, their high-affinity tyrosine kinase receptors, and co-receptors (neuropilins). While these receptors are historically described as being exclusively expressed on endothelial cells, emerging evidence has documented expression of these receptors on a number of nonendothelial cells, including tumor cells. The VEGF receptors (VEGFR) have also been shown to be functional in a number of nonendothelial systems, where they may be targets for anti-VEGF therapy. This article will review the basic effects and interactions of the VEGFRs on endothelial cells and the evidence for their expression and function on tumor cells. The novel expression of VEGFRs on tumor cells contributes to the understanding of the complex roles of VEGF within the tumor microenvironment, potentially affecting both endothelial cells and tumor cells expressing the VEGFRs. This elucidation of VEGF activity may further refine antineoplastic regimens for solid malignancies.