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)

p53 gene transfer has been proposed as a potential therapeutic option for treatment of hepatocellular carcinoma (HCC). Compared to other commonly used gene transfer vectors such as adenovirus and retrovirus, recombinant adeno-associated virus serotype 2 (rAAV2) has shown promising results in human clinical trials. Significant enhancement in the gene transfer efficiency is needed, however, for HCC applications. In the present study, we applied chemotherapy drug Doxorubicin (DOX) to induce rAAV2 transduction of hepatomas. Using reporter assays, we showed that the DOX-treated hepatomas became more susceptible to rAAV2 infection in comparison to untreated controls: the permissiveness increased >350-fold and >120-fold for HepG2 (p53 wild-type) and Hep3B (p53 null) hepatomas, respectively. Using the induced permissiveness, we applied rAAV2-p53 transduction to restore p53 expression in the p53-null Hep3B hepatomas. Compared to rAAV2-p53 transduction alone, rAAV2-p53 transduction with DOX resulted in a >16-fold induction of p53 expression. The transduced Hep3B expressed as much as 380% more immunoreactive p53 in comparison to the wild-type p53 expression in the HepG2 hepatomas. Significantly, when Hep3B cells were treated with 0.5 muM of DOX and rAAV2-p53 (MOI = 10) for twelve hours, the cell viability dropped to 66% four days after the administration. This decrease in cell viability was similar to that of treatment with 1 microM of DOX alone in the absence of rAAV2. The 50% reduction in DOX administration--from 1 microM to 0.5 microM--revealed the antitumor property of the rAAV2-p53 transduction as well as the joint cytotoxicity of DOX and rAAV2-p53 against the p53-null hepatomas. We conclude that DOX mediates the enhancement effect on rAAV2 transduction of human hepatomas. Combined DOX and rAAV2-p53 administration may facilitate more efficient treatment for the HCC caused by p53 mutations.
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PMID:Application of doxorubicin-induced rAAV2-p53 gene delivery in combined chemotherapy and gene therapy for hepatocellular carcinoma. 1805 87

The effect of cyclin-dependent kinase inhibitors Cip1/Waf1 (p21) on regulatory expression of survivin transcription in human hepatocellular carcinoma cell HepG2 was observed and the related mechanisms explored. Doxorubicin (DOX) was used to treat HepG2. Eukaryotic vector pEGFP-C2-p21 was transfected into HepG2 by lipofectamine and positive clones were screened out by G418. The mRNA expression of p21 and survivin was detected by real-time fluorescent quantitative polymerase chain reaction (RQ-PCR). Flow cytometry was used to examine the cell cycle, and reverse transcription polymerase chain reaction (RT-PCR) was used to measure the levels of E2F-1 and p300. The results showed that: (1) After treatment with DOX, the expression of p21 was increased, whereas that of survivin was reduced during 24 h of treatment; (2) After transfection of pEGFP-C2-p21 into HepG2, p21 level was significantly enhanced to 2100.11-folds or 980.89-folds in comparison to HepG2 or HepG2-C2 group, and survivin level was markedly down-regulated to 0.54% or 0.59% relative to the control groups; (3) Overexpressed p21 resulted in G1/G0 phase arrest (F=31.59, P<0.01), meanwhile E2F-1 mRNA and p300 mRNA were reduced as compared with those of controls (F(E2F-1)=125.28, P<0.05; F(p300)=46.01, P<0.01). It was suggested that p21 could be a potential mediator of survivin suppression at transcription level in HepG2 cell, which might be through the block at G1/G0 phase and down-regulation of transcription factors E2F-1 and p300.
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PMID:Effect of survivin regulation of transcription level by p21waf1 overexpression in HepG2 hepatocellular carcinoma cells. 1856 30

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. There is a substantial need for new chemotherapeutic drugs effective against this tumor. Doxorubicin (DOXO), used for chemoembolization of HCCs, is poorly efficacious when administered systemically at conventional doses; dose escalation is hindered by unacceptable toxicity. Here, we review preclinical experiments showing that the efficacy of DOXO against HCCs and its safety increased following conjugation to lactosaminated human albumin (L-HSA). L-HSA-DOXO was initially prepared to improve the anticancer activity of the drug on well-differentiated HCCs, which actively internalize L-HSA by means of the asialoglycoprotein receptor. Unexpectedly, it was found that the conjugate enhanced DOXO concentrations in all forms of HCCs, independently of their differentiation grade.
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PMID:Doxorubicin coupled to lactosaminated human albumin: a hepatocellular carcinoma targeted drug. 1875 87

Genomic gain represents an important mechanism in the activation of proto-oncogenes. In many instances, induced oncogenes hold clinical implications both as prognostic markers and targets for therapeutic design. In hepatocellular carcinoma (HCC), although chromosomal gains are common, information on underlying oncogenes induced remains minimal. Here, we examined 7 causal sites of HCC for overexpressed genes by array-based transcriptional mapping. In 22 HCC cell lines and early passages of cultures studied, clusters of up-regulated genes were indicated, where TOP2A expression ranked the highest. Distinct TOP2A transcriptions were confirmed in an independent series of HCC tumors relative to adjacent non-tumoral liver (p=0.0018). By tissue microarray analysis of 172 HCC, we found TOP2A expressions correlated with advance histological grading (p<0.001), microvascular invasion (p=0.004) and an early age onset of the malignancy (<or=40 years; p=0.007). In conjunction with P-gp and MRP1, TOP2A were further assessed for its association with chemotherapy responsiveness and survival in 148 patients who entered our recently reported Phase III prospective randomized study. In 73 chemoresistant and 75 nonresistant patients, only TOP2A positivity correlated with chemoresistance (p=0.029) and shorter patients survival (p<0.0001). The potential therapeutic value in targeting TOP2A by Etoposide, as a single agent, and in combination with Doxorubicin was also explored. In vitro cytotoxic studies suggested Etoposide at IC20 readily reduced IC50 values of Doxorubicin by a magnitude of approximately 3.5 to 10-fold compared to Doxorubicin alone (p<0.028). Our study highlighted for the first time the prognostic value of TOP2A in HCC and the potential use of TOP2A reactive agents in therapy.
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PMID:TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance. 1900 83

Sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell and hepatocellular carcinoma (HCC) and is well tolerated when combined with doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin 60 mg/m(2) IV for up to six 3-week cycles. Sorafenib 400mg bid was administered continuously starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The most frequent grade 3-4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%) and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC (21%) and C(max) (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%. Sorafenib plus doxorubicin appears to be well tolerated and more effective in the treatment of HCC than doxorubicin alone. Follow-up with single-agent sorafenib in these patients also appears to be well tolerated.
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PMID:Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial. 1910 Nov 37

Amphiphilic macromolecules (AMs) have unique branched hydrophobic domains attached to linear PEG chains. AMs self-assemble in aqueous solution to form micelles that are hydrolytically stable in physiological conditions (37 degrees C, pH 7.4) over 4 weeks. Evidence of AM biodegradability was demonstrated by complete AM degradation after 6 d in the presence of lipase. Doxorubicin (DOX) was chemically conjugated to AMs via a hydrazone linker to form DOX-AM conjugates that self-assembled into micelles in aqueous solution. The conjugates were compared with DOX-loaded AM micelles (i.e., physically loaded DOX) on DOX content, micellar sizes and in vitro cytotoxicity. Physically encapsulated DOX loading was higher (12 wt.-%) than chemically bound DOX (6 wt.-%), and micellar sizes of DOX-loaded AMs (approximately 16 nm) were smaller than DOX-AMs (approximately 30 nm). In vitro DOX release from DOX-AM conjugates was faster at pH 5.0 (100%) compared to pH 7.4 (78%) after 48 h, 37 degrees C. Compared to free DOX and physically encapsulated DOX, chemically bound DOX had significantly higher cytotoxicity at 10(-7) M DOX dose against human hepatocellular carcinoma cells after 72 h. Overall, DOX-AM micelles showed promising characteristics as stable, biodegradable DOX nanocarriers.
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PMID:Micellar nanocarriers assembled from doxorubicin-conjugated amphiphilic macromolecules (DOX-AM). 2012 69

New derivatives of thiophenes 2, 12, iminoaminothieno[2,3-d]pyrimidines 3, 5, and 6, triazolothieno[2,3-d]pyrimidines 8-11, pyrazolo- and triazinothieno[2,3-d]pyrimidines 4, 7, respectively, have been prepared by different synthetic procedures. Structure elucidation of the newly synthesized compounds was carried out via elemental analyses and spectral data. The antitumor activity of compounds 2, 3, and 9-12 was evaluated against in-vitro cell lines (HEPG-2 and MCF-7). Compounds 2, 3, 10, 11, and 12 showed significant in-vitro cytotoxic activity against hepatocellular carcinoma (HEPG-2) compared to the reference drug Doxorubicin. Compound 2 showed significant in-vitro cytotoxic activity against breast cancer (MCF-7) cells compared to the reference drug Doxorubicin. The augmenting effect of gamma-radiation was assessed; here, compounds 2, 3, 10, and 11 showed the most potent in-vitro anticancer activity.
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PMID:Novel thiophenes, thienopyrimidines, and triazolothienopyrimidines for the evaluation of anticancer and augmentation effects of gamma-radiation. 2037 69

Biocompatible bovine serum albumin (BSA)-dextran-chitosan nanoparticles were fabricated by heating the mixture of chitosan and BSA-dextran conjugates by virtue of the electrostatic attraction between BSA and chitosan as well as the gelation of BSA. The BSA-dextran conjugates were prepared by Maillard reaction. The nanoparticles were characterized by light scattering, zeta-potential, atomic force microscopy and pyrene fluorescence. The nanoparticles having a spherical shape and hydrodynamic diameters of 130-230 nm are stable in physiological condition. Doxorubicin can be effectively loaded into the nanoparticles after changing the pH of their mixture to 7.4 by virtue of the electrostatic and hydrophobic interactions between the nanoparticles and doxorubicin. The antitumor effects of doxorubicin loaded nanoparticles were investigated by the tumor inhibition and survivability of murine ascites hepatoma H22 tumor-bearing mice. The loaded nanoparticles can largely decrease the toxicity of doxorubicin and significantly increase the survivability of the tumor-bearing mice.
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PMID:Nanoparticles with dextran/chitosan shell and BSA/chitosan core--doxorubicin loading and delivery. 2038 98

Hypoxia may activate survival signals in cancer cells. Moreover, hypoxic cells are less sensitive than normoxic cells to doxorubicin cytotoxicity, a potent activator of the p53 tumor suppressor gene. N-myc downstream-regulated gene-1 (NDRG1) is a hypoxia- and retinoic acid-inducible protein, and has been previously implicated in carcinogenesis. As this protein is also a downstream target of p53 and hepatocellular carcinoma (HCC) cells frequently evidence resistance to retinoic acid (RA) cytotoxicity, we attempted to determine whether the suppression of NDRG1 expression may sensitize HCC cells to doxorubicin and/or RA cytotoxicity. HCC cells expressed NDRG1 protein, and the expression of this protein was hypoxia- and RA-inducible. Doxorubicin treatment induced HCC cell cytotoxicity via the activation of mitochondrial apoptotic signals, including caspase-9 activation. Hypoxic HCC cells are less sensitive to doxorubicin-induced apoptosis. The suppression of NDRG1 expression either by siRNA or flavopiridol sensitized hypoxic HCC cells to doxorubicin cytotoxicity, and this was attributed to more profound augmentation of JNK and caspase-9 activation. The suppression of NDRG1 expression also sensitized RA-resistant HCC cells to RA-induced apoptosis, and this sensitization was more apparent in hypoxic HCC cells than in normoxic cells. Glutaredoxin2 expression was down-regulated in NDRG1-suppressed HCC cells. These results show that hypoxia- and RA-inducible NDRG1 expression is responsible for doxorubicin and RA resistance in HCC cells. Thus, the selective interruption of NDRG1 signaling may prove to be therapeutically useful in HCCs, particularly in the advanced infiltrative type of tumors exposed to hypoxic environments.
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PMID:Hypoxia and retinoic acid-inducible NDRG1 expression is responsible for doxorubicin and retinoic acid resistance in hepatocellular carcinoma cells. 2057 44

Doxorubicin-eluting-bead embolization (DEB) is considered a safe and efficient treatment of hepatocellular carcinoma (HCC) with a low complication rate and an increased tumor response compared with conventional transarterial chemoembolization. We describe a case of a 69-year-old patient who underwent DEB for HCC and who developed a liver abscess requiring urgent left liver lobectomy. Despite this severe complication, efficacy of DEB embolization was histologically proved as a large ischemic zone with complete tumor necrosis.
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PMID:Severe complication after a doxorubicin-eluting-bead embolization: surgical management and pathological findings. 2071 71


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