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)

This study investigates the possible molecular basis leading to failure in a treatment that is composed of hypoxia and chemotherapy in a rat orthotopic hepatoma model. Hypoxia was induced by hepatic artery ligation, whereas chemotherapeutic effect was achieved by intraportal injection of cisplatin. High-dose sodium salicylate was administered to achieve transcriptional blockade. Significant prolongation of animal survival was observed in the groups receiving hepatic artery ligation with cisplatin or sodium salicylate. Massive tumor cell necrosis and apoptosis were found in the ligation and all of the combined treatment groups. Up-regulation of hypoxia inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) at both mRNA and protein levels were detected in the groups receiving ligation and ligation with cisplatin, whereas a decreased level of von Hippel-Lindau tumor suppressor protein was identified in the group receiving ligation with cisplatin. Sodium salicylate enhanced expression of von Hippel-Lindau tumor suppressor protein but down-regulated HIF-1alpha and VEGF levels after ligation with or without cisplatin. An increased number of activated hepatic stellate cells in the tumors were observed in the ligation and ligation with cisplatin groups, whereas they were greatly reduced by sodium salicylate. In vitro study revealed that under hypoxic condition, both cisplatin and sodium salicylate could remarkably augment P53 and caspase 3 levels. Cisplatin stimulated HIF-1alpha up-regulation, whereas sodium salicylate suppressed HIF-1alpha expression. In conclusion, tumor progression after hypoxia and chemotherapy might be related to up-regulation of HIF-1alpha and subsequent VEGF production, and transcriptional blockade by sodium salicylate could enhance the therapeutic efficacy of hypoxia and chemotherapy.
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PMID:The potential role of hypoxia inducible factor 1alpha in tumor progression after hypoxia and chemotherapy in hepatocellular carcinoma. 2990 84

Transcatheter arterial chemoinfusion (TACI) is the main treatment modality for advanced hepatocellular carcinoma (HCC). However, the therapeutic efficacy of TACI according to anti-cancer agents and prognostic factors for advanced HCC (TNM stage IVa) has not been previously clarified. A total of 127 patients with TNM stage IVa HCC were divided into intra-arterial Adriamycin (Group I) and intra-arterial Cisplatin (Group II) infused groups, according to the anticancer agents that were used. We compared the therapeutic efficacy of TACI applied anticancer agents, and we also analyzed the prognostic factors which influenced the survival rates. Chi-square test, t- test, Cox's proportional hazard regression model, and Kaplan- Meier method were performed. The overall survival was significantly different (10.0 vs 5.7 months, respectively) and the results favored Group I. On univariate analysis, the significant prognostic factors included age, portal vein thrombosis (PVT), tumor size (diameter > 5 cm), type of tumor, the reduction rate (tumor size and alpha- fetoprotein) after 3 months of chemotherapy, serum albumin level, serum alkaline phosphatase level and total serum bilirubin levels at the time of diagnosis. After repeated chemotherapy, Group I showed better survival (14.0 vs 7.9 months). However, there was no statistical difference in the survival rate of the two groups for cases involving large tumors, PVT and diffuse type of HCC. Group I showed better survival than Group II. However, when the other prognostic factors were taken into consideration, there was no significant difference in the survival rate of the two groups, except for the cases with small or nodular HCC.
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PMID:Treatment outcome of transcatheter arterial chemoinfusion according to anticancer agents and prognostic factors in patients with advanced hepatocellular carcinoma (TNM stage IVa). 1551 95

Proteins recognizing DNA damaged by the chemical carcinogen N-acetoxy-acetylaminofluorene (AAAF) were analyzed in nuclear extracts from rat tissues, using a 36 bp oligonucleotide as a substrate and electrophoretic mobility shift and Southwestern blot assays. One major damage-recognizing protein was detected, whose amount was estimated as at least 10(5) copies per cell. Levels of this protein were similar in extracts from brain, kidney and liver, but much lower in extracts from testis. The affinity of the detected protein for DNA damaged by AAAF was about 70-fold higher than for undamaged DNA. DNA damaged by cis-diamminedichloroplatinum (cis-DDP), benzo(a)pyrene diolepoxide (BPDE) or UV-radiation also bound this protein with an increased affinity, the former more strongly and the latter two more weakly as compared to AAAF-damaged DNA. The detected AAAF/DDP-damaged-DNA-binding (AAAF/DDP-DDB) protein had a molecular mass of about 25 kDa and was distinct from histone H1 or HMGB proteins, which are known to have a high affinity for cis-DDP-damaged DNA. The level of this damage-recognizing protein was not affected in rats treated with the carcinogen 2-acetylaminofluorene. The activity of an AAAF/DDP-DDB protein could also be detected in extracts from mouse liver cells but not from the Hep2G human hepatocellular carcinoma.
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PMID:Characterization of a novel protein that specifically binds to DNA modified by N-acetoxy-acetylaminofluorene and cis-diamminedichloroplatinum. 1594 Mar 47

A high concentration of cisplatin induces apoptosis in many tumor cell lines. Whether cisplatin induces apoptosis even in a controlled release formulation has not been determined. We therefore studied the relationship between the dosing regimen of cisplatin and the induction of apoptosis in rat hepatoma AH-109A cells. A colorimetric assay was used to quantify cell proliferation and viability, and caspase activity was determined using an exogenous fluorogenic peptide substrate. When delivered as a single dose, cisplatin caused a dose-dependent inhibition of AH-109A growth and enhancement of caspase-3 activity. Also, DNA laddering was detected in cells that had elevated caspase-3 activity. However, caspase-3 activity was low and DNA laddering and a sub-G1 population were not detected when cells were treated with a combination of cisplatin and the caspase inhibitor Z-VAD-FMK. These results suggest that cisplatin is cytotoxic in AH-109A cells because it induces apoptosis. We next examined intermittent exposure to cisplatin to estimate the effects of continuous exposure by a controlled release formulation. Cisplatin was divided into equal parts and was added intermittently into the medium resulting in the same final concentration as the single dose. The individual additions alone were not cytotoxic, but all of the doses together had a similar cytotoxic effect as a single exposure of cisplatin. The intermittent exposure resulted caspase-3 activity even higher than a single dose. These findings indicate that cisplatin induces apoptosis in AH-109A cells when delivered continuously even at the concentration that alone have no activity.
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PMID:Continuous exposure to low-dose cisplatin and apoptosis. 1620 53

Metallothionein (MT) is a high-affinity metal binding protein thought to mitigate the toxicity of various metals. Cisplatin is a widely used cancer chemotherapeutic that is a rodent carcinogen and may have carcinogenic potential in humans. MT seems to reduce cisplatin toxicity by binding the metal compound but how MT deficiency might impact the carcinogenic effects of cisplatin is unknown. Thus, groups (n = 25) of male MT-I/II double knockout (MT-null) or MT wild-type (WT) mice were exposed to a single treatment of cisplatin (5 or 10 mg/kg, i.p.), or left untreated (control) and observed over the next 104 weeks. The doses of cisplatin used equate to only a fraction of the total dose used typically in clinical settings. In cisplatin-treated MT-null mice, a dose-related increase in hepatocellular carcinoma (HCC) occurred (control, 0%; 5 mg/kg, 17%; 10 mg/kg, 36%) that was not seen in WT mice. Similarly, liver carcinoma multiplicity (HCC/liver) was increased markedly by cisplatin but only in MT-null mice, indicating the formation of multiple primaries in MT deficient mice. Harderian gland carcinoma incidence was also increased by cisplatin treatment in MT-null mice but not WT mice. Our results indicate that MT-null mice are hypersusceptible to the hepatocarcinogenic effects of cisplatin, and poor MT expression may be a predisposing factor for cisplatin-induced secondary tumors after chemotherapy.
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PMID:Hypersusceptibility to cisplatin carcinogenicity in metallothionein-I/II double knockout mice: production of hepatocellular carcinoma at clinically relevant doses. 1643 36

Soluble Flk-1, a soluble vascular endothelial growth factor (VEGF) receptor, is a potent inhibitor of angiogenesis, which could restrain growth and metastasis of some experimental tumors. However, antiangiogenic agents alone cannot eradicate tumor completely, and should be combined with other therapy to enhance their effects. In this study, we evaluated the antitumor activity of the combination therapy in the immunocompetent BALB/c mice bearing H22 hepatoma and Meth A fibrosarcoma, respectively. Mice were treated with either msFlk-1 i.m. at 100 microg/mouse once every 3 days for four times from day 3 after the tumor cell injection, cisplatin cycled twice (2 mg/kg i.p. on days 4 and 11 after the tumor cell inoculation), or both agents together. Tumor growth and survival time were continually observed. Antiangiogenesis in vivo was determined by CD31 immunohistochemistry. Assessment of apoptotic cells and histological analysis was also conducted in tumor tissues. Our results showed that the combination therapy could evidently improve antitumor efficacy, including tumor growth suppression, mice survival prolongation, tumor cell apoptosis augmentation as well as neovascularization inhibition as compared with controls, without serious adverse effects. Our data suggest that the combination of DDP with msFlk-1 is more effective to suppress tumor growth in mice than either agent alone, and this combination regimen showed its potential for future clinical application.
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PMID:Systemic inhibition of tumor growth by soluble Flk-1 gene therapy combined with cisplatin. 1679 69

(NH3)2Pt(triacid) and (PPh3)2Pt(dehydrocholate)2 are novel bile acid-conjugated platinum complexes administered by oral route. The aims of the present study were to evaluate their in vitro cytotoxic activities on rat hepatoma cell line N1-S1, the in vivo antitumour effects in a syngeneic and orthotopic rat hepatoma model and the drug-related toxicities. Cisplatin, carboplatin and mitoxantrone were used as control drugs. In vitro experiments showed a concentration- and time-dependent antiproliferative activity of bile-conjugated platinum complexes. (NH3)2Pt(triacid) had similar effects on cell growth of cisplatin and carboplatin (e.g. at 48 h, IC50 0.7+/-0.05 microM vs. 0.63+/-0.28 microM and 1.1+/-0.3 microM, respectively; mean+/-S.D.). (NH3)2Pt(triacid) was able to inhibit tumour growth in a dose-dependent extent, reaching the maximum inhibitory effect at the 80 mg/kg dose (1.95+/-0.5 g vs. 13.85+/-3.9 g of control tumour weight). By contrast, despite the promising in vitro antiproliferative activity, (PPh3)2Pt(dehydrocholate)2 showed no significant in vivo antitumour effect. The toxicity profile of (NH3)2Pt(triacid) resulted favourable with minimal loss of weight and no gastrointestinal or neurological symptoms. Instead, (PPh3)2Pt(dehydrocholate)2 showed dose-dependent signs of severe weight loss and neurological alterations. In conclusion (NH3)2Pt(triacid) is a tolerable and active platinum derivative endowed by a preclinical antitumour activity by oral route.
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PMID:In vitro and in vivo antitumour effects of novel, orally active bile acid-conjugated platinum complexes on rat hepatoma. 1697 99

Two different hepatoma cell lines were incubated for 48h with chemotherapeutic drugs cisplatin, paclitaxel and 5-FU to determine their ability to induce cytotoxicity and DNA fragmentation as well as to modify the expression of some cell death-related genes that could be involved in the resistance to therapy. We observed that cisplatin and paclitaxel induced cytotoxicity, but significant differences between both cell lines, were found only in the case of paclitaxel. At 48h, apoptosis was clearly present in Hep3B cells treated with cisplatin and HepG2 cells treated with paclitaxel. 5-FU induced cytotoxicity in both cell lines but only at higher concentrations than the other two drugs, triggering apoptosis and necrosis in HepG2 cells and only necrosis in Hep3B. When a time course was performed for the first 8h of treatment to elucidate the initial mechanism of cell death responsible for DNA fragmentation, we observed that 5-FU in Hep3B, and cisplatin in both cell lines, induces primary necrosis, whereas at the concentration tested here, paclitaxel clearly triggers apoptosis in both cell lines. HepG2 cells were weakly sensitive to 5-FU in the first 8h of treatment, so the primary mechanism of cell death was not clear, but results seem to indicate that it could be apoptosis. At 48h, Bax was not up-regulated with any of the treatments, whereas cisplatin was able to induce Bcl-xL down-regulation in both cell lines. Treatment with 5-FU also down-regulated Bcl-xL in HepG2 cells. We also measured variations in the expression of survivin, an inhibitor of apoptosis that has also been involved in mitototic catastrophe. Hep3B cells seem to show an increase in protein levels with all treatments. Exposure to paclitaxel resulted in the highest effect. In the case of HepG2 cells, there was a decrease in survivin expression when cells were treated with 5FU and paclitaxel, both treatments showing complete loss of the protein. Using an antibody that recognizes unprocessed caspase-3, we observed that the enzyme was assumingly activated in HepG2 cells treated with 5FU and paclitaxel, but only weakly after treatment with cisplatin. Hep3B cells did not show activation since the levels of the pro-enzyme remained the same as that in the control. In conclusion, the three drugs tested in this study could induce cell death, with paclitaxel being more effective inducing apoptosis. 5FU was only effective at high doses and its mechanism seems to be primarily related to necrosis in Hep3B and probably apoptosis in HepG2. Cisplatin mechanism of cell death is probably mediated by the decrease in anti-apoptotic protein Bcl-xL whereas paclitaxel and 5FU are decreasing the apoptosis inhibitor survivin. According to pro-enzyme levels, caspase-3 was only activated in HepG2 cells, whereas in the case of Hep3B cells the mechanisms of toxicity appear to be caspase-3-independent at the time and concentrations tested in this study. The resistance of Hep3B cells to death induced by chemotherapy could be related to an increase in the expression of IAP survivin, which can decrease cell response to the treatment or even switch the type of death from apoptosis to another kind, making therapy less efficient.
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PMID:Characterization of cell death events induced by anti-neoplastic drugs cisplatin, paclitaxel and 5-fluorouracil on human hepatoma cell lines: Possible mechanisms of cell resistance. 1739 42

We experienced 20 cases of advanced hepatocellular carcinoma with portal vein tumor thrombosis treated with low-dose cisplatin and 5-fluorouracil (5-FU) chemotherapy via implanted fusion port between August 1999 and September 2003. A fusion port was implanted by inserting an intraarterial catheter into the hepatic artery. Cisplatin (10 mg/day, 5 times/week, 4 weeks) and 5-FU (250 mg/day, 5 times/week, 4 weeks) were administered for one cycle. The treatment was performed repeatedly until the patient showed progressive disease (PD) with an off period of 4 to 12 weeks. The average number of cycles was 1.7+/-0.73. Responses were complete response (CR) 0/20, partial response (PR) 6/20, no change (NC) 8/20, and PD 6/20, and the overall response rate was 30%. The 1-year survival rate was 48.5%, and the average observation period was 357 days. The toxicities of grade 3 and above were leukocytopenia (2 cases; 10%), thrombocytopenia (2 cases; 10%), nausea (1 case; 5%), and epigastralgia (1 case; 5%). Complications with reservoir implantation included 2 cases of catheter dislocation, 1 case of wound separation,1 case of bleeding from the port implantation site, 1 case of development of collateral circulation,and 1 case of catheter occlusion. The outcomes were survival in 5 cases (25%) and death in 15 cases (75%). The causes of death included cancer (12 cases; 60%), varices rupture (2 cases; 10%),and hemoptysis (1 case; 5%). The group with a CLIP score of 3 or less showed a significantly higher survival rate than the group with a CLIP score of 4 or more (survival rates were 80% and 12.5%, respectively; p=0.0032, logrank test). Among CLIP score factors, tumor morphology (TM) was particularly related to life convalescence,and TM 1 group with the tumor occupying less than half of the liver showed a significantly higher survival rate than the TM 2 group with the tumor occupying more than half of the liver (p=0.0003, logrank test) with one-year survival rates of 88.9% and 10.9%, respectively. CLIP score and TM were also significantly reflected in life convalescence on multivariate analysis. While low-dose cisplatin and 5-FU chemotherapy via an implanted fusion port were regarded as a useful therapeutic regimen to improve life convalescence for cases of progressive hepatocellular carcinoma with portal vein tumor thrombosis (Vp 3/4), life convalescence in those with a CLIP score of 3 and above,particularly in the TM 2 group, was poor. We consider that treatment in such cases should be decided carefully, taking into consideration their quality of life.
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PMID:[Clinical study of low-dose cisplatin and 5-fluorouracil chemotherapy via implanted fusion port in 20 patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis]. 1749 46

Cisplatin is commonly used as a chemotherapeutic agent for hepatocellular carcinoma (HCC). However, it cannot satisfactorily improve the survival rate for patients with advanced HCC due to intrinsic or acquired drug resistance caused by multidrug resistance-associated proteins (MRPs). To clarify whether or not glycyrrhizin and lamivudine have modulator effects on HCC treated with cisplatin, we established a cisplatin-resistant Huh7 HCC cell line and analyzed the mRNA expression of MRPs in the resistant cells. The resistant cells showed 14.1-fold higher resistance to cisplatin, and they expressed higher levels of MRP2 (6.29-fold), MRP3 (3.2-fold), MRP4 (11.3-fold) and MRP5 (3.39-fold) mRNAs than the wild-type cells by using real-time PCR. However, MRP1, MDR1 and GST-pi mRNA were not induced. Compared with the treatment of the resistant cells with cisplatin only, co-treatment with cisplatin and glycyrrhizin or lamivudine significantly decreased the cell viability to 76.8% and 79.5%, respectively. Co-treatment with cisplatin and both glycyrrhizin and lamivudine further decreased the cell viability to 65.1%. Intracellular concentration of cisplatin in the resistant cells decreased to 36.4% of that of the wild-type cells while it increased to 47.7% or 48.4% when glycyrrhizin or lamivudine were added separately, or 60% when they were added together. Our findings indicate the following: i) high expression of MRP2, MRP3, MRP4 and MRP5 decreases cisplatin accumulation in cisplatin-resistant HCC cells and contributes to cisplatin resistance; ii) glycyrrhizin and/or lamivudine accumulate cisplatin in resistant cells by inhibiting the cisplatin efflux from the cells; and iii) glycyrrhizin and lamivudine both act as modulators and have the effect of reversing cisplatin resistance, and co-treatment with glycyrrhizin and lamivudine enhances modulator activity in reversing the cisplatin resistance.
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PMID:The combination of glycyrrhizin and lamivudine can reverse the cisplatin resistance in hepatocellular carcinoma cells through inhibition of multidrug resistance-associated proteins. 1798 73


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