Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to develop a polymeric delivery system for water-insoluble drug oridonin. Amphiphilic block copolymers, poly(epsilon-caprolactone)-poly(ethylene glycol)-poly (epsilon-caprolactone) (PCL-PEO-PCL), were synthesized by ring-opening polymerization of caprolactone initiated by the hydroxyl groups of poly(ethylene glycol)6000 (PEG-6000) with stannous octoate as catalyzer. Oridonin-loaded PCL-PEO-PCL copolymer nanoparticles (ORI-PCL-PEO-PCL-NPs) were prepared by the interfacial deposition method. The mean particle size of the drug-loaded nanoparticles was 97.5 nm and the zeta potential was - 25 mV. The entrapment efficiency and actual drug loading of the nanoparticles were 87.52% +/- 1.86% and 8.63% +/- 0.49%, respectively. The antitumor activity of ORI-PCL-PEO-PCL-NPs was evaluated by measuring changes in tumor volumes, tumor weights, and survival rates of mice with grafted hepatoma (H22). The results indicated that ORI-PCL-PEO-PCL-NPs prolonged the survival time of mice and exhibited higher therapeutic efficacy compared with free oridonin. Thus, ORI-PCL-PEO-PCL-NPs may be used as a promising delivery system for liver cancer treatment.
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PMID:Oridonin-loaded poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) copolymer nanoparticles: preparation, characterization, and antitumor activity on mice with transplanted hepatoma. 1860 60

Eukaryotic cells can synthesize the non-essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non-neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG-ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG-ADI on the in vivo growth of pancreatic xenografts was examined. Eighty-seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG-ADI specifically inhibited growth of those cell lines lacking ASS. PEG-ADI treatment induced caspase activation and induction of apoptosis. PEG-ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by approximately 50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG-ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.
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PMID:Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. 1866 17

Successful treatment of chronic hepatitis C virus (HCV) infection can prevent reinfection after orthotopic liver transplantation (OLT). Pegylated interferon (PEG-IFN) may ameliorate virological response (VR), making the risk-to-benefit ratio of therapy favorable in waiting list patients. From January 2001 to April 2006, we treated 15 HCV cirrhotics with PEG-IFN alpha-2b (1.5 microg/kg/week) and ribavirin (RIBA; >or=10.6 mg/kg/d). Their mean age was 51.5 years. There were 9 men. In 6 cases the genotype was 1b. With Child-Pugh scores >or=9 (range 9-12) and Model for End-Stage Liver Disease (MELD) scores >or=14 (range, 14-22). Adverse events occurred in all subjects: thrombocytopenia (<40,000/microL) in 8; neutropenia (<700/microL) in 10; anemia (Hb <8.5 g/dL) in 1; grade III hepatic encephalopathy in 2; pelvic infection in 1; variceal hemorrhage in 1; and hepatocellular carcinoma (HCC) recurrence in 1. Adverse events caused treatment withdrawal in 6 (40.0%) and RIBA and/or PEG-IFN dose reduction in 10 (66.6%). Early VR (EVR) was obtained in 9 subjects (60.0%), end-of-treatment (EOT) VR in 7 (46.6%), and sustained VR (SVR) in 3 (20.0%). Three subjects--2 nonresponder and 1 breakthrough--were transplanted at 25, 23, and 16 months after the EOT, respectively. Three subjects died at 6, 8, and 15 months after the EOT due to HCC, spontaneous bacterial peritonitis, and liver failure. Nine patients are awaiting OLT. The risk-to-benefit ratio is against PEG-INF and RIBA treatment of severely decompensated cirrhotics infected with genotype 1 awaiting OLT, but therapy is probably beneficial in genotype 2 subjects, due to an expected SVR rate of more than 40%. However, one must carefully consider the high risk for severe adverse events.
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PMID:Treatment of chronic hepatitis C virus infection with pegylated interferon and ribavirin in cirrhotic patients awaiting liver transplantation. 1867 89

Primary and secondary prevention of hepatocellular carcinoma (HCC) which has become endemic worldwide in recent years are the most important issues in reducing mortality of HCC patients. Among several compounds previously reported for secondary prevention, treatment with interferon (IFN) is widely applied and shows encouraging results. To date, there have been 8 published randomized control trials (RCTs) and 6 published non-RCTs on IFN therapy after curative treatment of HCCs. Positive results were shown in 6 of 8 RCTs and in all of 6 non-RCT cohort studies regarding either recurrence rate or patient survival. The impact of IFN therapy after curative treatment of HCC can be summarized as follows: (1) HCC incidence of recurrence is reduced through viral clearance or long-term IFN treatment, even though HCV is not cleared. (2) Low-dose, long-term IFN (maintenance) therapy may suppress HCC recurrence through direct action of IFN on tumor cells. (3) Patient survival is improved through growth inhibition of recurrent tumors, as well as preservation of liver function. (4) According to the above 3 points, there is more chance to receive curative treatment in the IFN than the non-IFN group. (5) Pegylated IFN (PEG-IFN) may be more beneficial than non-PEG-IFN products since IFN concentration is maintained in the body at a high level, which is favorable for its action as a direct anticancer agent. (6) It may be concluded that IFN treatment after curative treatment of HCC is beneficial at least in HCV-related HCC, since it lowers recurrence and improves survival.
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PMID:Impact of interferon therapy after curative treatment of hepatocellular carcinoma. 1909 70

Hepatitis B virus (HBV) infection is a worldwide public health problem. There are an estimated 350 million persons with chronic HBV infection that could progress to cirrhosis and hepatocarcinoma with nearly one million deaths per year. In the last few years the therapeutic options in chronic hepatitis B have increased and currently six treatments are authorized: standard interferon (IFN)-alpha, pegylated interferon-alpha (PEG-IFNalpha), lamivudine, adefovir, entecavir, and telbivudine. For the last 25 years, conventional IFNalpha has been used as the treatment of chronic hepatitis B (CHB) and currently PEG-IFNalpha is indicated due to its greater effectiveness. Both drugs are first line options for HBeAg(+) and HBeAg(-) CHB. The advantages of IFNalpha and PEG-IFNalpha are that these drugs are administered for a limited time period, they achieve a higher sustained response rate and do not induce HBV mutants with antiviral resistance. These drugs achieve greater HBeAG and HBsAG clearance due to their antiviral and immunomodulatory activity. PEG-IFNalpha induces sustained biochemical and virological response in approximately one third of patients with HBeAg(+) CHB. The best response to IFNalpha and PEG-IFNalpha is obtained in patients with elevated transaminase levels, moderate viral load and HBV genotypes A and B. The disadvantages of IFNalpha and PEG-IFNalpha are their adverse effects and contraindications. These drugs cannot be administered in patients with decompensated cirrhosis. The combination of nucleos(t)ide analogs with PEG-IFNalpha could achieve much higher sustained response rates; however, which treatment constitutes the most suitable therapeutic strategy requires investigation.
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PMID:[Interferon in hepatitis B]. 1910 Feb 28

Human hepatocellular carcinoma (HCC) has an elevated requirement for arginine in vitro, and pegylated recombinant human arginase I (rhArg-PEG), an arginine-depleting enzyme, can inhibit the growth of arginine-dependent tumors. While supplementation of the culture medium with ornithine failed to rescue Hep3B cells from growth inhibition induced by rhArg-PEG, citrulline successfully restored cell growth. The data support the roles previously proposed for ornithine transcarbamylase (OTC) in the arginine auxotrophy and rhArg-PEG sensitivity of HCC cells. Expression profiling of argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and OTC in 40 HCC tumor biopsy specimens predicted that 16 of the patients would be rhArg-sensitive, compared with 5 who would be sensitive to arginine deiminase (ADI), another arginine-depleting enzyme with anti-tumor activity. Furthermore, rhArg-PEG-mediated deprivation of arginine from the culture medium of different HCC cell lines produced cell cycle arrests at the G(2)/M or S phase, possibly mediated by transcriptional modulation of cyclins and/or cyclin dependent kinases (CDKs). Based on these results, together with further validation of the in vivo efficacy of rhArg-PEG against HCC, we propose that the application of rhArg-PEG alone or in combination with existing chemotherapeutic drugs may represent a specific and effective therapeutic strategy against HCC.
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PMID:Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest. 1913 17

All but about 10% of patients with chronic hepatitis C (CHC) (predominantly those infected with genotype 1) can respond to some degree to 'combination' therapy with interferon (IFN) and ribavirin. The slower the virological response to treatment, the less likely sustained viral clearance will take place. Many factors influence response to antiviral therapy; most cannot be reversed (e.g. sex, age, cirrhosis, genotype and viral load). A sustained viral clearance is considerably facilitated by compliance with full-dose therapy for the prescribed time. The potential cause(s) for non-response need(s) to be ascertained before attempting retreatment. The 10% of patients who are true 'null' responders may respond to the new specifically targeted antiviral therapies but whether the response can be sustained off-therapy is unclear. Adjunctive therapies may facilitate response to retreatment if intolerance to treatment leading to diminished or absent doses was problematic in the past. Retreatment with a long-acting IFN and an adequate ribavirin dose (15 mg/kg), but given for 72 weeks in prior relapsers following 48 weeks of treatment, will enhance sustained virological response (SVR) rates. No benefit is gained from changing one pegylated IFNalpha (PEG IFNalpha) to another unless the treatment duration is extended. Only alpha-interferons are effective. For those individuals who still fail to achieve SVR, recruitment to trials of new treatments should be encouraged particularly for those with advanced liver disease. Lifestyle modification may be appropriate in attempt to reduce the chance of complications of liver disease, namely hepatocellular carcinoma, by smoking cessation, eliminating obesity and increasing coffee consumption.
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PMID:Retreatment of chronic hepatitis C: who and how? 1920 66

Worldwide, chronic hepatitis B virus infection is a major cause of end-stage liver disease and hepatocellular carcinoma. While the past two decades have brought major advances in the availability of treatments to help delay or prevent these outcomes, treatment of chronic hepatitis B remains a serious challenge. With the recent availability of potent new nucleot(s)ide such as entecavir, tenofovir and telbuvidine, I still use pegylated interferon (PEG-IFN)-alpha for the treatment of chronic HBeAg-positive patients. This is based on its relatively higher effectiveness in restoring the host immune control on viral replication, resulting in sustained diseases remission in a proportion of patients, a finite course of therapy and the absence of viral resistance. The two major hindrances to its wide application are its lack of effectiveness in a large proportion of patients and its side-effect profile. The former shortcoming can be circumvented to a certain extent with the use of response predictor models. Recently, based on long-term follow-up study, the better durability of sustained response further enhances the confidence in the use of PEG-IFN-alpha in chronic HBeAg-positive patients.
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PMID:HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated interferon. 1920 75

Patients with renal disease are at increased risk of acquiring hepatitis C virus (HCV) infection because of their frequent exposure to blood from transfusions or exposure to HCV-contaminated medical equipment during hemodialysis. The prevalence of anti-HCV antibodies among hemodialysis patients varies between 5-10% in the developed world, and 10-70% in developing countries. Acute hepatitis C is often mild and associated with few, if any symptoms. The major complication of acute HCV infection is chronic hepatitis, which occurs in up to 80% of the cases, the long-term outcome being cirrhosis, portal hypertension, hepatic failure, and hepatocellular carcinoma. Interferon alpha (IFN-alpha) has shown activity against HCV. Twenty four to 48 week course of therapy with interferon could lead to a sustained loss of HCV RNA, normalization of alanine aminotrasferase (ALT) levels, and resolution of the liver disease. Sustained viral response was achieved in approximately half of the treated patients. Therapy with interferon was associated with a number of adverse events such as: "flu-like" symptoms, neurological, gastrointestinal symptoms, anemia, fatigue, thrombocytopenia, leucopenia. A major advance in therapy came with the addition of ribavirin to interferon therapy. Peginterferon-alpha-2a (40KD) is a new 'pegylated' subcutaneous formulation of interferon-alpha-2a, that was developed to improve the pharmacokinetic profile and therapeutic efficacy of interferon-alpha-2a. In our study, fourteen hemodialysis patients with chronic hepatitis C received 135 microg PEG-IFN alpha-2a subcutaneously, once a week, after dialysis session for a period of 48 weeks. In the intention-to-treat analysis, sustained viral response was present in 36% of the patients (five out of fourteen patients) at the end of the follow up period. The biochemical response with normalization of serum ALT levels during the treatment was observed in all treated patients (83 +/- 20.1 U/L at base line vs. 23.4 +/- 4.6 U/L after the 48 weeks; p < 0.01). At present, therapy for hepatitis C should be considered in hemodialysis patients with significant liver disease, minimal other co morbidities, and a reasonable likelihood of prolonged survival or if renal transplantation is planned.
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PMID:New approaches in the therapy of hepatitis C in dialysis patients. 1925 44

Globally, hepatic diseases are an important cause of mortality and morbidity. Harnessing RNA interference (RNAi) to silence pathology-causing genes specifically offers exciting possibilities for improvement of treatment. Nevertheless achieving efficient and safe delivery of RNAi activators remains an important objective before this gene silencing approach realizes its full therapeutic potential. Several viral and non viral vectors (NVVs) are being developed for hepatotropic delivery of synthetic and expressed RNAi activators. Each has advantages and disadvantages that are suited to particular disease conditions. Amongst the viral vectors, recombinant adeno-associated viruses and PEG-modified helper dependent adenoviruses show promise for situations that require intermediate to long term expression of RNAi activators. Recombinant lentiviruses have not been used extensively as hepatotropic RNAi vectors, but are likely to find application where lasting therapeutic silencing is required. NVVs are a particularly important class of vector and are effective for delivery of synthetic RNAi activators to the liver. Preclinical investigations using RNAi-mediated gene silencing to counter persistent hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, hypercholesterolemia and cirrhosis are discussed in this review. Although obstacles remain, vigorous research has given impetus to the field and RNAi-based treatment of liver diseases is likely to become a reality in the near future.
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PMID:Hepatic delivery of RNA interference activators for therapeutic application. 1935 67


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