The side-chain conformation of the proposed catalytic residue, His144, changes upon complex formation. Lineweaver-Burk plots indicate that the inhibitor binds competitively with respect to NADH, and uncompetitively with respect to crotonoyl coenzyme A. We propose that the primary basis of the inhibitory activity is competition with NADH for binding to FabK, which is the first step of the two-step ping-pong catalytic
mechanism.”
“p53 missense mutations observed in human cancers are often associated with an increased level of p53 protein in the tumour. Using mouse models, Terzian et al. recently showed that this accumulation of mutant p53 protein is www.selleckchem.com/products/sch772984.html CX-5461 supplier not associated with specific properties of the protein itself but instead depends on the endogenous genetic
background of the tumours and on two important genes, mouse double minute 2 (Mdm2) and the cyclin kinase inhibitor p16(INK4a). Mice expressing mutant p53 in the absence of Mdm2 display more aggressive metastatic tumours. In light of these observations, targeting the MDM2-p53 interaction for therapy of human cancer could be more complicated than previously anticipated.”
“Purpose: To evaluate the usefulness of [F-18]-6-fluorodopamine ([F-18]-DA) and [F-18]-L-6-fluoro-3,4-dihydroxyphenylalanine ([F-18-DOPA) positron emission tomography (PET) in the detection of subcutaneous (s.c.) and metastatic pheochromocytoma in mice; to assess the expression
of the norepinephrine transporter (NET) and vesicular monoamine transporters I and 2 (VMAT1 and VMAT2), all important for [F-18]-DA and [F-18]-DOPA uptake. Furthermore, to compare tumor detection by micro-computed tomography (microCT) to magnetic resonance imaging (MRI) in individual mouse.
Methods: SUVmax values Electron transport chain were calculated from [F-18]-DA and [F-18]-DOPA PET, tumor-to-liver ratios (TLR) were obtained and expression of NET, VMAT1 and VMAT2 was evaluated.
Results: [F-18]-DA detected less metastatic lesions compared to [F-18]-DOPA. TLR values for liver metastases were 2.26-2.71 for [F-18]-DOPA and 1.83-2.83 for [F-18]-DA. A limited uptake of [F-18]-DA was found in s.c. tumors (TLR=0.22-0.27) compared to [F-18]-DOPA (TLR=1.56-2.24). Overall, NET and VMAT2 were expressed in all organ and s.c. tumors. However, s.c. tumors lacked expression of VMAT1. We confirmed [F-18]-DA’s high affinity for the NET for its uptake and VMAT1 and VMAT2 for its storage and retention in pheochromocytoma cell vesicles. In contrast, [F-18]-DOPA was found to utilize only VMAT2.
Conclusion: MRI was superior in the detection of all organ tumors compared to microCT and PET. [F-18]-DOPA had overall better sensitivity than [F-18]-DA for the detection of metastases.