Two recent independent studies tested different pharmacological strategies of HIF1 activators; both found a protective role for HIF1 in murine colitis . Taken together, these studies identify HIF1 as a critical factor for attenuating mucosal inflammation during experimental intestinal ischemia. Collectively, our results contribute to the current understanding of adenosine PLK signaling via HIF regulation in intestinal ischemia and hypoxia. Given the importance of HIFa as a mediator of adaptation to low oxygen levels, pharmacological strategies to stabilize HIF under conditions of intestinal ischemia or inflammation may represent a novel therapeutic approach to treat mesenteric IR injury. Present challenges involve the translation of these findings from the research laboratory to a clinical setting, as well studying the potential side effects of HIF activators .
The objective of this study was to investigate the oxidative metabolism pathways of 1717demethoxygeldanamycin Gemcitabine , a geldanamycin derivative and 90 kDa heat shock protein inhibitor. In vitro metabolic profiles of 17DMAG were examined by using pooled human liver microsomes and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17DMAG hydroquinone and 19glutathionyl 17DMAG, several oxidative metabolites of 17DMAG were detected and characterized by liquid chromatography tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17 DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs.
In contrast, the primary biotransformations of 17DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in eukaryotic the oxidative metabolism of 17DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17DMAG in HLMs were proposed.Molecular imaging is likely to become increasingly important in the drug development process, both preclinically and clinically, and eventually in treatment response monitoring in routine clinical practice.
Treatment monitoring is of key importance in patient management and drug development. As contemporary drug development is particularly focused on targeted drugs, which are often more cytostatic than cytotoxic, response to treatment as determined by changes in the anatomy, for example, shrinkage of tumor size on computed tomography as commonly assessed by the Response Evaluation Criteria in Solid Tumors , is insufficient. Furthermore, any anatomic changes occur relatively late in the treatment process and do not necessarily provide specific information on tissue function and viability. MRI can provide additional functional information on blood flow and water diffusion, but no specific molecular information on early treatment response . Radionuclide imaging techniques such as positron emission tomography and single photon emission CT with the use of selective radiotracers could partly offer a solution.