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That the identified SNP in exon 19 of PDGFRB may indeed What One Could Do About Dynasore
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Min have relevant biological implications is further supported by the fact that analysis of protein content in cell lines demonstrated the presence of the B19 SNP clearly correlated with higher protein levels of the PDGF receptor B, also in its phosphorylated state. PDGF path way constitutive activation maintains highly active MEK, thus phosphorylating Bad and inhibiting apoptosis. Increased PDGF pathway activation has been also shown to contribute to drug resistance by activating the PI3K pathway. Whether or not the presence of this SNP may portend particular sensitivity to PDGFR targeted agents is a matter of speculation but certainly deserves further investigation due to its rele vant potential clinical applications.
On the contrary, no relevant findings were identified in our series regarding VEGFR2 TK domain SNP analysis. As in other solid tumors, overexpression of VEGF mRNA and protein has been associated with tumor progression and poor prognosis of colon carcinoma. The VEGF A gene is known to be highly polymorphic and harbors numerous SNPs, especially in the promoter, 5 and 3 untranslated regions, which contain key regulatory elements that are sensitive to hypoxia. These SNPs contribute to the high variability in VEGF production among tissues and have been associated with cancer susceptibility, progression, and anti VEGF therapeutic response in subjects with a variety of solid tumors includ ing colorectal cancer.
For example, the 936 T allele has been associated with increased risk of CRC, advanced stage of disease and worse prognosis, whereas the 634 C allele was predictive of decreased risk and improved sur vival. SNPs have also been identified in the VEGF receptor genes, although the literature in this topic is still very sparse. Very recently, the VEGFR 1 319 C A SNP, located in the promoter region of the gene, has been reported to be associated with response to therapy in a cohort of 218 CRC patients treated with different bevacizumab containing regimens. In this study by Hansen et al, response rates were significantly higher in patients homozygous for the A allele than in patients with the C allele genotype. Simi lar results were also documented in bevacizumab treated pancreatic cancer patients. In addition, functional relevance has been demonstrated for several SNPs in the VEGFR 1 and VEGFR 2 genes, particularly SNPs 1192C T and 1719T A.
These SNPs are located in exons 7 and 11, and lead to amino acid changes potentially interfering with the recep tors binding affinity to VEGF A. In the current study, however, we aimed to explore potential genetic variations in the TK domain of the VEGFR 2, which would be expected to have relevant functional conse quences. No mutations were however detected in our study population in these gene domains.