ISIGNAL INTENSITY on a magnetic resonance (MR) image is mainly determined by proton density and T1 and T2. Image contrast, described as the difference in signal intensity between two tissues, is dependent on a number of physical parameters and can be altered by changing these parameters. Contrast agents are pharmaceuticals that can accentuate the difference in signal intensity between two adjacent tissue compartments by directly interfering with the proton relaxation times in one more than in the other. Such agents are designed with the purpose of improving image contrast between normal and abnormal tissues and may enhance the contrast positively or negatively, depending on their relative T1, T2, or T2* effects. Effec tive MR imaging contrast agents include paramagnetic (metal ions such as gadolinium, manganese, dysprosium, iron; free radicals: nitrous oxides), magnetic (superparamagnetic or ferromagnetic iron oxide particles), or diamagnetic (substances that displace hydrogen nuclei such as gases, deuterated water, perfluorocarbons) materials.The clinical effect of an MR imaging contrast medium is determined not only by the contrast-enhancing properties of the compound but also by its pharmacokinetic properties, which determine where the agent is distributed in the body and the length of time adequate concentrations are maintained in target organs. Furthermore, it is of crucial importance that the drug be well tolerated when given in doses necessary to achieve the clinical effect. Before a new chemical entity is introduced into humans as a drug, it is extensively studied in animals with respect to properties mentioned above. When the re1axivit.y effect of a contrast agent can be measured in vitro, the most important factors to study preclinically in animal experimental models are tolerance, distribution, and elimination in relevant species. The tolerance is riormally assessed during acute and subacute toxicity studies, in addition to more specific safety studies in critical organ systems such as cardiovascular, hepatobiliary, and renal systems. The safety profile is further extended through studies that examine effects on overall reproduction and on specific genetic modifications (mutagenicity), while ADME (absorbtion, distribution, metabolism, excretion) studies are performed to investigate pharmacokinetic properties. In this article, the main principles of the pharmacokinetic and toxicologic properties of the most important classes of contrast media are discussed. We focus on groups of contrast media in clinical use or under investigation; future developments such as immuno-and disease-specific concepts are not included. AGENTS DISTRIBUTED IN THE EXTRACELLULAR FLUID (ECF)Gadolinium: General Aspects the largest number of unpaired electrons and is thus, theoretically, the most efficient T1 relaxation metal that can be used in contrast media for MR imaging. However, when administered as the free gadolinium ion, the metal is not suitable as a contrast medium for three reasons: ( a ) its toxicity, ( b ) its pharmac...
Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependen cy on variably expressed nucleoside transporters for cellular uptake. We show here that CP-4200, an elaidic acid derivative of azacytidine, has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation, and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, however, the cellular uptake of CP-4200 was substantially less dependent on the nucleoside transporters that are known to be involved in azacytidine uptake. In agreement with this notion, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. Together, these data represent a detailed characterization of the CP-4200 mode of action and suggest that elaidic acid modification improves the therapeutic efficacy of azacytidine. Mol Cancer Ther; 9(5); 1256-64. ©2010 AACR.
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