PHY906 is a standardized four-herb traditional Chinese formulation that has been used for over 1700 years in the treatment of gastrointestinal ailments and is currently in anticancer clinical trials in the US as an adjuvant to chemotherapy. Preliminary clinical results indicated PHY906 could decrease G.I. toxicity triggered by irinotecan for treating colon cancer. In a murine colon-38 allograft model, PHY906 (500 mg bid days 0-3) alone, does not significantly inhibit tumor growth. However, the combination of PHY906 and irinotecan (360mg/kg, day 1) had higher anti-tumor activity in comparison to irinotecan alone. Additionally, PHY906 decreased weight loss caused by irinotecan. The impact of PHY906 on the intestinal toxicity caused by irinotecan at day 2 and day 4 were studied. Adding PHY906 to irinotecan treatment, a) reduced irinotecan induced degenerative changes throughout different regions of the intestine on day 4 but not on day 2, b) reduced irinotecan induced DNA damage and apoptosis of intestinal cells on day 4, c) promoted the re-growth of crypt cells which could be partially attributed to the wnt3a-potentiation activity of the aglycone component(s) of PHY906 on day 4, d) inhibited TNF-\#945; induced NF-kB activity, e) decreased the infiltration of neutrophils in intestinal crypt areas and decreased pro-inflammatory cytokine levels. In summary, our studies suggest that PHY906 reduces intestinal damage caused by irinotecan through the inhibition of inflammation and enhancement of intestinal repair by promoting intestinal progenitor cell proliferation. This work is supported by a supplement grant: CA-63477 from NCI, USA Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4584.
YIV-906 (PHY906) is inspired by a traditional 1800-year Chinese herbal formulation, "Huang Qin Tang", which is commonly used for treating diarrhea. Following chemotherapy and radiation, preclinical and clinical results suggest that YIV-906 has the potential to improve the patient's quality of life and prolonging survival. Consistent preparations of PHY906 could be manufactured apart 15 years. The effects of YIV-906 were studied on the anti-tumor activity of anti-PD1 using BDF1 mice bearing Hepa 1-6 tumors. Results indicated that anti-PD1 alone had moderate effects on tumor growth however YIV-906 plus anti-PD1 eradicated all tumors in all tumor bearing mice. Further re-implantation of Hepa 1-6 cells did not grow in the "cured" mice, but implanted CMT167 (non-small lung carcinoma) cells or Pan02 (Pancreatic Ductal Adenocarcinoma) cells did grow; suggesting that YIV-906 plus anti-PD1 created a tumor-specific vaccine-like effect. The combination treatment exhibited a highly inflamed tumor microenvironment with more M1-like macrophage expression over M2. In culture YIV-906 could potentiate the action of IFNg (interferon gamma) to polarize bone marrow-derived macrophages (BMDM) into M1 macrophages while inhibiting IL4 action for M2 macrophage polarization. YIV-906 potentiated IFNg action through: 1) stimulating IFNg secretion, 2) phosphorylation of JAK1/2 and STAT1 and 3) increasing IRF1 protein expression. Scutellaria baicalensis Georgi (S) and its flavonoids of YIV-906 were responsible for potentiate the IFNg to polarize macrophage into M1. In conclusion, YIV-906 enhanced the anti-tumor activity of anti-PD1 by enhancing inflammation in the tumor microenvironment and enriching M1-like macrophages. This suggests the potential use of combination YIV-906 and anti-PD1 in cancer treatment. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA.Citation Format: Wing Lam, Xiaochen Yang, Zaoli Jiang, Xue han, Fulan Guan, Rong Hu, Chang-Hua Xu, Wei Cai, William Cheng, Shwu-Huey Liu, Yuping Cai, Nicholas Rattray, Caroline Johnson, Lieping Chen, Yung-chi Cheng. YIV-906 (PHY906) enhanced the anti-tumor activity of immune checkpoint blockade therapy (Anti-PD1) against liver cancer by changing the tumor micro-environment associated with M1 macrophages infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2252.
PHY906, is a decoction of a mixture of the four herbs Scutellaria baicalensis Geori, Glycyrrhiza uralensis Fisch, Paeonia lactiflora Pall, and Ziziphus jujuba Mill. A combination of these four herbs has been in continuous use in traditional Chinese medicine for over 1800 years for treating a variety of gastrointestinal distress such as diarrhea, cramps, nausea, vomiting etc.Preclinical and clinical studies to find PHY906 enhances the therapeutic indices of a broad spectrum of anticancer agents.Using various mouse tumor xenograft and allograft models, PHY906 has been shown to enhance the chemotherapeutic efficacy of a variety of anticancer agents in various cancers. The PHY906 clinical program consists of five trials in three different types of cancers in both the United States and Taiwan. To date, approximately 150 subjects have received PHY906 in combination with chemotherapy in these five clinical studies.Preclinical studies have shown that PHY906 enhances the therapeutic indices of a broad spectrum of anticancer agents. These findings have been examined in clinical studies for colorectal, liver, and pancreatic cancers when PHY906 is used as an adjuvant to chemotherapy and the results were promising; i.e. PHY906 could reduce chemotherapy-induced toxicities and/or increase chemotherapeutic efficacy. Furthermore, PHY906 did not affect the pharmacokinetics of the chemotherapeutic agents used. Some information has been obtained regarding the mechanism of action of PHY906 in preclinical studies. A comprehensive platform, PhytomicsQC that integrates chemical and biological fingerprints together with a novel biostatistical methodology has been developed to assess the quality of different batches of PHY906.Over a ten-year period, the multiplex technology "PhytomicsQC" has been used to show batch-to-batch consistency of PHY906 production. Advanced clinical trials are ongoing to demonstrate the effectiveness of PHY906 as adjuvant therapy for cancer patients undergoing chemotherapy.
2',3'-Dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine [L(-)Fd4C] was found to be at least 10 times more potent than beta-L-2',3'-dideoxy-3'-thiacytidine [L(-)SddC; also called 3TC, or lamivudine]against hepatitis B virus (HBV) in culture. Its cytotoxicity against HepG2 growth in culture was also greater than that of L(-)SddC (3TC). There was no activity of this compound against mitochondrial DNA synthesis in cells at concentrations upto 10 microM. The dynamics of recovery of virus from the medium of cells pretreated with equal drug concentrations were slower with L(-)Fd4C than with L(-)SddC (3TC). L(-)Fd4C could be metabolized to mono-, di-, and triphosphate forms. The degree of L(-)Fd4C phosphorylation to the 5'-triphosphate metabolite was higher than the degree of L(-)SddC (3TC) phosphorylation when equal extracellular concentrations of the two drugs were used. The apparent K(m) of L(-)Fd4C phosphorylated metabolites formed intracellularly was higher than that for L(-)SddC (3TC). This may be due in part to a difference in the behavior of L(-)Fd4C and L(-)SddC (3TC) towards cytosolic deoxycytidine kinase. Furthermore, L(-)Fd4C 5'-triphosphate was retained longer within cells than L(-)SddC (3TC) 5-triphosphate. L(-)Fd4C 5'-triphosphate inhibited HBV DNA polymerase in competition with dCTP with a Ki of 0.069 +/- 0.015 microM. Given the antiviral potency and unique pharmacodynamic properties of L(-)Fd4C, this compound should be considered for development as an expanded-spectrum anti-HBV drug.
ABSTRACT The antiviral activity of 2′-fluoro-5-methyl-β- l -arabinofuranosyluracil ( l -FMAU), a novel l -nucleoside analog of thymidine known to be an inhibitor of hepatitis B virus (HBV) replication in hepatoma cells (2.2.1.5 cell line), was evaluated in the duck HBV (DHBV) model. Short-term oral administration (5 days) of l -FMAU (40 mg/kg of body weight/day) to experimentally infected ducklings induced a significant decrease in the level of viremia. This antiviral effect was sustained in animals when therapy was prolonged for 8 days. The histological study showed no evidence of liver toxicity in the l -FMAU-treated group. By contrast, microvesicular steatosis was found in the livers of dideoxycytidine-treated animals. l -FMAU administration in primary duck hepatocyte cultures infected with DHBV induced a dose-dependent inhibition of both virion release in culture supernatants and intracellular viral DNA synthesis, without clearance of viral covalently closed circular DNA. By using a cell-free system for the expression of an enzymatically active DHBV reverse transcriptase, it was shown that l -FMAU triphosphate exhibits an inhibitory effect on the incorporation of dAMP in the viral DNA primer. Thus, our data demonstrate that l -FMAU inhibits DHBV replication in vitro and in vivo. Long-term administration of l -FMAU for the eradication of viral infection in animal models of HBV infection should be evaluated.
l-(-)2′,3′-Dideoxythiacytidine (l(-)SddC, Lamivudine) resistant hepatitis B virus (HBV) develops in patients after prolonged treatment. Point mutations detected in the viral genome from these patients have been shown to be responsible for l(-)SddC resistance. Therefore, new drugs active against l(-)SddC resistant HBV are needed. Using a transient transfection system, we studied the sensitivity of l(-)SddC resistant HBV to other anti-HBV nucleoside analogues. It was found that the L526M mutation alone caused greater resistance to penciclovir (PCV) than did the V553I mutation alone. Both mutations also caused the virus to be less sensitive to l(-)SddC and 2′-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-FMAU), although the degree of resistance was much less than that to PCV. The A546V mutation had no impact on the sensitivity to l(-)SddC, l-FMAU, and PCV. When these single mutations were coupled with the M550V/I mutation, all the double mutants were resistant to those drugs. Although 2′,3′-dideoxy-2′,3′-didehydro-β-l(-)-5-fluorocytidine (l(-)Fd4C) was also less active, the ic50 of l(-)Fd4C against the l(-)SddC resistant mutant was at least fifty times lower than that against cell growth in culture. DNA polymerase associated with l(-)SddC resistant virions was also found to be less sensitive than that with wild-type HBV to those l-nucleoside triphosphates. All the l(-)SddC resistant mutants were still sensitive to 9-(2-phosphonylmethoxyethyl)-adenine (PMEA). These results suggest that different mutations in the HBV genome have a different impact on its sensitivity to those compounds, and l(-)SddC resistant HBV may also be resistant to PCV, l-FMAU, and l(-)Fd4C. A nucleoside analogue less toxic than PMEA could be developed against l(-)SddC resistant HBV.
The aqueous extract of Scutellariae baicalensis Georgi has inhibitory activity against P-gp 170, a multiple drug resistant gene product. Baicalein, one of the major flavones, was found to be responsible for this activity. The hydroxyl groups of the A ring of baicalein were systematically alkylated in order to assess the effect of such modifications on the activity against P-gp 170. The impact of the baicalein modifications on activity against the growth of a human nasopharyngeal cancer cell line KB and its P-gp 170 overexpressing cell line KB/MDR were also examined. The results indicate that alkylation of R5 of baicalein does not have a major impact on the interaction with P-gp 170, whereas alkylation of R6 or R7 alone or both, could enhance the interaction of baicalein with P-gp 170 as well as the amount of intracellular accumulation of vinblastine, a surrogate marker for the activity of P-gp 170 pump of KB/MDR cells. In this case, the optimal linear alkyl functionality is a propyl side chain. These modifications could also alter the activity of compounds inhibiting cell growth. Among the different compounds synthesized, the most potent molecule against P-gp 170 is 5-methoxy-6,7-dipropyloxyflavone (23). Its inhibitory activity against P-gp 170 is approximately 40 times better, based on EC50 (concentration of the compound enhancing 50% of the intracellular vinblastine accumulation in the KB/MDR cells) and 3 times higher, based on Amax (the intracellular vinblastine accumulation of the KB/MDR cells caused by the compound) as compared to baicalein. Compound 23 is also a more selective inhibitor than baicalein against P-gp 170, because its cytotoxicity is less than that observed for baicalein. The growth inhibitory IC50 of compound 23 against KB and KB/MDR cells are about the same, suggesting that compound 23 is unlikely to be a substrate of P-gp 170 pump. Acetylation of R6, R7 or both could also decrease EC50 and increase Amax. Acetylated compounds are more toxic than baicalein, and their potency against cell growth is compromised by the presence of P-gp 170, suggesting that these compounds are substrates of P-gp 170. Benzylation of R6 or R7 but not both also enhanced anti-P-gp170 activity and potency against cell growth; however, the presence of P-gp 170 in cells did not have an impact on their sensitivity to these molecules, suggesting that the benzylated compounds are inhibitors but not substrates of P-gp 170, and perhaps have a different mechanism of action. In conclusion, the substitutions of R6 and R7 hydroxyl groups by alkoxy groups, acetoxy groups, or benzyloxy groups could yield compounds with different modes of action against P-gp 170 with different mechanisms of action against cell growth.
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