Abstract
BackgroundDipterinyl 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).MethodsIn 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.ResultsDCP 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.ConclusionsImmunomodulation 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.
Highlights
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
The following viral, IDO, and cytokine/chemokine measures were collected in this study: liver hepatitis B virus (HBV) DNA (Southern), liver HBV DNA (PCR), liver HBV RNA (PCR), HBe antigen (ELISA); Average # hepatitis B core antigen (HBcAg) Nuclei, Average # HBcAg Cytoplasms, # HBcAg Nuclei per Quarter Field; serum Tryptophan, Kynurenine, Kyn/Trp, IL-1a, IL-1b, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12, MCP-1, TNF-a, MIP-1, GM-CSF, RANTES; and liver IL-6
The DCP Effects Model linear stepwise regression analysis identified a significant (p = .001) cluster of variables responding to the DCP treatment
Summary
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. Dipterinyl calcium pentahydrate (DCP), shown, has demonstrated significant antitumor activity associated with plasma IL-12 concentration increases in MDA-MB231 (human breast cancer) xenographs in nude mice [3,4]. This finding, along with previous work demonstrating IL-12 suppression of HBV replication in transgenic mice [5], prompted us to investigate the activities of DCP in the HBV transgenic mouse model. The investigators anticipated that DCP might work via cytokine/chemokine modulatory mechanisms similar to those described by others [5,6,7,8,9]
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