Effect of dipterinyl calcium pentahydrate on hepatitis B virus replication in transgenic mice.
BACKGROUND
Dipterinyl calcium pentahydrate (DCP) has previously been shown to inhibit MDA-MB-231 human breast cancer xenographs in nude mice in a manner correlated with increases in plasma IL-12 and IL-4 concentrations, and decreases in plasma IL-6 levels. DCP also inhibits indoleamine 2,3-dioxygenase (IDO), an immuno-inhibitory enzyme, in human PBMCs (Peripheral Blood Mononuclear Cells).


METHODS
In the present study, DCP was administered per os, once daily for 14 days to hepatitis B virus (HBV) transgenic mice at 23, 7.3, and 2.3 mg/(kg d). Multivariate stepwise regression and MANOVA analyses, by gender and treatment, of liver HBV DNA and RNA measures, liver core and serum HBe antigen assays, serum cytokine/chemokine profiles, and IDO metabolite measurements were performed.


RESULTS
DCP caused a significant dose-response reduction of log liver HBV DNA as measured by PCR in the female HBV mice. The gender dependence of the anti-HBV DNA activity was explained by the DCP Effects Model (DCP-EM) (p = .001) which includes three serum biomarker changes caused by DCP: 1) decreased MCP-1; 2) decreased Kyn/Trp (an estimation of IDO activity); and 3) increased GM-CSF.


CONCLUSIONS
Immunomodulation via IDO or TDO (tryptophan 2,3-dioxygenase) pathways, along with serum MCP-1 and GM-CSF are proposed to play roles in the anti-HBV mechanism of DCP based upon their coordinated modulation in the reduction of viral DNA replication in HBV mice.
Moheno
Phillip
P
SanRx Pharmaceuticals, Inc,, 603 Colima Street, La Jolla, California 92037-8032, USA. phil.moheno@sanrx.com
Morrey
John
J
Fuchs
Dietmar
D
D000818:Animals; D017610:Calcium Compounds / Q000737:chemistry / Q000494:pharmacology*; D004279:DNA, Viral / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D014366:Tryptophan Oxygenase / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D017610:Calcium Compounds; D004279:DNA, Viral; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014366:Tryptophan Oxygenase