Vascular Endothelial Growth Factor Polymorphisms: Role in Response and Toxicity of Tyrosine Kinase Inhibitors

Vaziri, S. A.; Kim, Jenny; Ganapathi, Mahrukh K.; Ganapathi, Ram

doi:10.1007/s11912-010-0085-4

Cited by 34 publications

(33 citation statements)

References 51 publications

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“…29 Therefore, we propose that VEGFR-2 genetic polymorphisms may cause structural changes in the receptor and lead to aberrant activation of multiple pathways, including its interaction with P2Y(2)R, with an overall influence on platelet aggregation, which is correlated with CR. [30][31][32] Patients carrying the TT genotype of VEGFR-2 +1192C.T (rs2305948) polymorphism exhibited significantly higher MACE, whereas the GG genotype of …”

Section: Discussionmentioning

confidence: 99%

“…The underlying mechanism may be that VEGFR-2 rs2305948 polymorphism, resulting in an amino acid change at the 297th codon, alters VEGFR-2-specific intracellular signaling, resulting in increased incidence of MACE. 30,33,34 VEGF and VEGFR-2 may enhance the pathophysiologic mechanism of plaque formation and plaque destabilization and suggested to be precise triggers for inflammation and neovascularization in atherosclerosis. 35,36 The 2271G.A polymorphism of the VEGFR-2 gene is a functional polymorphism related to the regulation of gene transcription.…”

Section: Vegfr-2 Snp and Clopidogrel Resistancementioning

confidence: 99%

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Association of VEGFR-2 Gene Polymorphisms With Clopidogrel Resistance in Patients With Coronary Heart Disease

Zhang¹,

Zhang

Han³

et al. 2016

American Journal of Therapeutics

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Vascular endothelial growth factor receptor 2 (VEGFR-2) plays a central role in atherogenesis. We investigated the correlation between VEGFR-2 polymorphisms and the risk of clopidogrel resistance (CR) in patients with coronary heart disease (CHD). The study involved 275 patients with CHD undergoing percutaneous coronary intervention and on antiplatelet clopidogrel therapy. The participants were divided into CR group (n = 59) and non-CR group (NCR, n = 216) based on maximum platelet aggregation measurements. VEGFR-2 gene polymorphisms, +1192C>T (rs2305948), +1416T>A (rs1870377), and -271A>G (rs7667298), were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Enzyme-linked immunosorbent assay was used to measure serum transforming growth factor, beta receptor 2 levels. CR was found in 59 patients (20.45%). A significantly higher proportion of patients in the CR group had a history of diabetes mellitus compared with the NCR group (P < 0.05). Genotype and allele frequency of VEGFR-2 +1192C>T (rs2305948) was significantly higher in the CR group than in the NCR group (all P < 0.01). In the VEGFR-2 +1192C>T (rs2305948), the angina pectoris, recurrent myocardial infarction, and combined end point events were significantly more prevalent in the TT carriers than in the CC + CT carriers. In VEGFR-2 -271A>G (rs7667298), the GG carriers had a lower proportion of target lesion revascularization and angina pectoris in contrast to the AA + AG carriers (all P < 0.05). Based on our results, VEGFR-2 +1192C>T (rs2305948) polymorphism is strongly associated with increased CR and main adverse cardiovascular event incidence in patients with CHD undergoing percutaneous coronary intervention. Additionally, patients with CHD with diabetes mellitus history were more likely to develop CR. The associations of +1416T>A (rs1870377) and -271A>G (rs7667298) polymorphisms with CR were inconclusive and will need to be examined further.

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Section: Discussionmentioning

confidence: 99%

Section: Vegfr-2 Snp and Clopidogrel Resistancementioning

confidence: 99%

Association of VEGFR-2 Gene Polymorphisms With Clopidogrel Resistance in Patients With Coronary Heart Disease

Zhang¹,

Zhang

Han³

et al. 2016

American Journal of Therapeutics

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“…Attention has been drawn to the possible role of VEGF-A, HIF1 or VEGFR polymorphisms in influencing the response of tumor cells, mainly to antibody-based therapies [70,71], but also to tyrosine kinase inhibitors [72], or in modulating the risk of treatment-related complications [73]. This possibility has been explored, with controversial results, in various cancer types, including colon [74] and breast cancers [75], but not NETs.…”

Section: Anti-angiogenic Treatments In Netsmentioning

confidence: 99%

Angiogenesis in Neuroendocrine Tumors: Therapeutic Applications

Scoazec

2012

Neuroendocrinology

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The considerable research efforts devoted to the understanding of the mechanisms of tumor angiogenesis have resulted in the development of targeted anti-angiogenic therapies and finally in their introduction in clinical practice. Neuroendocrine tumors (NETs), which are characterized by a high vascular supply and a strong expression of VEGF-A, one of the most potent pro-angiogenic factors, are an attractive indication for these new treatments. However, several lines of evidence show that the dense vascular networks associated with low-grade NETs are more likely to be a marker of differentiation than a marker of aggressiveness, as in other epithelial tumors. These observations form the basis for the so-called ‘neuroendocrine paradox’, according to which the most vascularized are the most differentiated and the less angiogenic NETs. This must be kept in mind when discussing the role of anti-angiogenic strategies in the treatment of NETs. Nevertheless, several targeted therapies, with direct or indirect anti-angiogenic properties, including anti-VEGF antibodies, tyrosine kinase inhibitors (sunitinib) and mTOR inhibitors (everolimus), have recently proven to be of clinical benefit. In addition, some drugs already used in NET treatment, such as somatostatin analogues and interferon-α, may also have anti-angiogenic properties. The main challenges for the next future are to validate biomarkers for the selection of patients and the prediction of their response to refine the indications of anti-angiogenic targeted therapies and to overcome the mechanisms of resistance, which explain the limited duration of action of most of these treatments.

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“…This idea is supported by recent genetic studies on colon cancers that revealed those patients with reduced COX expression and/or polymorphisms in both COX and PGDH genes may not benefit from NSAID treatment [155-157]. Likewise, screening the same patients for polymorphisms in components of the VEGF-C/VEGF-D signalling pathway may assist in the type of anti-lymphangiogenic therapy administered to improve patient outcome [158, 159]. The interaction of the VEGF-C/VEGF-D and PG signalling axes may provide additional biomarkers such as circulating levels of VEGF-C, VEGF-D and PG for predicting which patients respond to anti-metastatic therapies and/or assessing response during treatment.…”

Section: Introductionmentioning

confidence: 97%

The connection between lymphangiogenic signalling and prostaglandin biology: A missing link in the metastatic pathway

et al. 2012

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Substantial evidence supports important independent roles for lymphangiogenic growth factor signaling and prostaglandins in the metastatic spread of cancer. The significance of the lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, is well established in animal models of metastasis, and a strong correlation exits between an increase in expression of VEGF-C and VEGF-D, and metastatic spread in various solid human cancers. Similarly, key enzymes that control the production of prostaglandins, cyclooxygenases (COX-1 and COX-2, prototypic targets of Non-steroidal anti-inflammatory drugs (NSAIDs)), are frequently over-expressed or de-regulated in the progression of cancer. Recent data have suggested an intersection of lymphangiogenic growth factor signaling and the prostaglandin pathways in the control of metastatic spread via the lymphatic vasculature. Furthermore, this correlates with current clinical data showing that some NSAIDs enhance the survival of cancer patients through reducing metastasis. Here, we discuss the potential biochemical and cellular basis for such anti-cancer effects of NSAIDs through the prostaglandin and VEGF signaling pathways.

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Vascular Endothelial Growth Factor Polymorphisms: Role in Response and Toxicity of Tyrosine Kinase Inhibitors

Cited by 34 publications

References 51 publications

Association of VEGFR-2 Gene Polymorphisms With Clopidogrel Resistance in Patients With Coronary Heart Disease

Association of VEGFR-2 Gene Polymorphisms With Clopidogrel Resistance in Patients With Coronary Heart Disease

Angiogenesis in Neuroendocrine Tumors: Therapeutic Applications

The connection between lymphangiogenic signalling and prostaglandin biology: A missing link in the metastatic pathway

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