Differences

This shows you the differences between two versions of the page.

@@ Line 1: / Line 1: @@
+~~NOTOC~~
+====== Poster - Molecular static and dynamic analyses reveal flaw in murine model used by US FDA to detect drug carcinogenicity ======
+**Type:** Abstract presentation\\
+**Presented by:**  Trevor Marshall, PhD\\
+**Conference:**  [[https://www.nature.com/nm/meetings/dmm2007/program.html|Days of Molecular Medicine 2007]]\\
+**Location:**  Harvard University\\
+**Date:**  2007\\
+**Additional content:** [[https://autoimmunityresearch.org/transcripts/dmm2007-harvard.pdf|poster]]; [[https://autoimmunityresearch.org/dmm2007/dmm2007.ram|video showing difference in steady-state ligand conformation between rat and human VDR]]
+===== Abstract =====
+The US FDA currently accepts carcinogenicity studies of
+pharmaceutical drugs based on murine models. In addition to 6 month
+studies with p53(+/-) and ras.H2 transgenic mice, lifetime studies
+(typically 2 years) in WT mice or rats are also considered as evidence
+that a drug lacks carcinogenic activity. This model is not always
+exhaustive. For example, during the acceptance testing of the ARB
+Olmesartan((FDA CDER: NDA-21-286, Sankyo Pharma Inc Available from URL
+https://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm)), possible carcinogenicity observed in hamsters was not
+able to be duplicated in rats, or in transgenic mice. We have previously
+used the static molecular modeling of AutoDock to demonstrate that
+Olmesartan has agonostic activity in the PDB:1DB1 model of the
+human VDR Nuclear Receptor((Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from
+Chronic Inflammatory and Autoimmune Disease.
+Abstract presentation, DMM2006.)), while it has antagonistic activity in
+the PDB:1RK3 model of the rat VDR. This agonism has now been
+confirmed with Molecular Dynamics, using GROMACS. The murine
+VDR indeed lost its ability to bind the DRIP 205 co activator when
+Olmesartan was the ligand, while the human VDR was activated by
+Olmesartan similarly to its native ligand (1,25-dihydroxyvitamin-D).
+Since the VDR is believed to express 913 genes(({{pmid>long:16002434}}))
+This video was created using the GROMACS Molecular
+Dynamics software on a small computing cluster assembled
+from PCs based on Core-2-duo CPU technologies. The
+difference in steady-state ligand conformation between
+human and rat VDR can clearly be seen at
+https://autoimmunityresearch.org/dmm2007/dmm2007.ram, many of which are
+known to be associated with cancer pathogenesis, good homology
+between human VDR, and the animal model VDR, is exceedingly
+important.
+==== Conclusion ====
+The murine environment is inadequate to accurately
+model drug carcinogenic activity in humans. A species should be
+chosen which has a VDR LBP homology closer to that of man. AutoDock
+and GROMACS molecular analyses are useful in resolving any
+remaining anomalies in the observed data.
+{{tag>posters Trevor_Marshall_PhD DMM 2007}}
+===== References =====