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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: Days of Molecular Medicine 2007
Location: Harvard University
Date: 2007
Additional content: poster; 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 ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor. OlmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. 1), 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 VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. Nuclear ReceptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription.2), 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 genes3) 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 http://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.

References

1)
FDA CDER: NDA-21-286, Sankyo Pharma Inc Available from URL http://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm
2)
Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract presentation, DMM2006.
3)
Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes.
Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, Bourdeau V, Konstorum A, Lallemant B, Zhang R, Mader S, White JH
Mol Endocrinol19p2685-95(2005 Nov)
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