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)

There is no well-defined curative treatment for advanced and unresectable hepatocellular carcinoma. The widely used transarterial chemoembolization (TACE) with a doxorubicin-Lipiodol emulsion has not been shown to improve survival in randomized studies. Further, obstruction of the hepatic artery used in the procedure is badly tolerated in patients with cirrhosis. Drugs with a more rapid penetration into the cancer cells are likely to eliminate the need for obstruction of the hepatic artery. We therefore compared the cytotoxicity of another anthracycline pirarubicin with that of the commonly used doxorubicin. In this report, we show that pirarubicin has a greater in vitro cytotoxic effect than doxorubicin on the HepG2 and Hu-H7 human hepatoma cell lines. Pirarubicin emulsion with Lipiodol is more stable at 37 degrees C than doxorubicin-Lipiodol. Moreover, pirarubicin accumulates at a greater extent in the oil phase, permitting Lipiodol to act as a slow-releasing vector for the anthracycline. Further, amiodarone, a multidrug resistance inhibitor, was shown to decrease the intrinsic resistance of HepG2 and Hu-H7 cells to both anthracyclines, and the presence of polysorbate 80 in the amiodarone preparation increased the stability of the anthracycline-Lipiodol emulsions. We therefore conclude that pirarubicin is a better candidate for TACE than doxorubicin. The rapid and increased cytotoxicity of pirarubicin on hepatoma cancer cells and the stability of the pirarubicin-Lipiodol amiodarone emulsion could avoid the complete obstruction of the hepatic artery by Gelfoam sponges, and provide a better tolerated method of TACE in patients with latent liver insufficiency.
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PMID:Increased cytotoxicity and stability of Lipiodol-pirarubicin emulsion compared to classical doxorubicin-Lipiodol: potential advantage for chemoembolization of unresectable hepatocellular carcinoma. 1170 47

Although chemoembolization is known to be an effective palliative treatment in hepatocellular carcinoma, it has a limited effect in large tumors. We report the case of a patient with a large hepatocellular carcinoma of the left liver who had a significant and sustained clinical response after six sessions of chemoembolization with a pirarubicin/amiodarone/lipiodol emulsion. Pirarubicin is an anthracycline which penetrates faster than doxorubicin into cancer cells. Amiodarone is a multidrug resistance inhibitor. Polysorbate 80, an excipient of injectable amiodarone stabilizes the anthracycline/lipiodol emulsion. The clinical efficacy of this new formulation could be evaluated in a phase II clinical trial.
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PMID:[Sustained clinical response of large hepatocellular carcinoma after chemoembolization with pirarubicin, amiodarone and Lipiodol]. 1567 39

Hepatocellular carcinoma arises from hepatocytes, it is the most common primary malignant tumor of the liver and accounts for the majority of liver cancers. Pirarubicin is a compound analog to the antineoplastic anthracycline antibiotic doxorubicin. Thereby as an intercalator of DNA, pirarubicin has shown efficacy in reducing tumor activity of hepatocellular carcinoma. Utilizing in silico optimized similarity of structure search of data base and replacement by isosteres, a total of nine analogs to pirarubicin were generated. The molecular size of ring substituents (approximately a base pair) were preserved and isosteres chosen to preserve the weak electrostatic properties permitting DNA intercalation. Only a small range in molecular weight and volume was permitted in order to preserve intercalation activity. Standard deviations for polar surface area, number of heavy atoms, molecular weight, molecular volume, and number of oxygens and nitrogens, were only 3.98%, 1.76%, 16.5%, 2.51%, and 0%, respectively, of the overall average for these properties. Variation of the target substituent resulted in insignificant changes in many properties; there was a striking variation in the lipophilic property Log P. Values of Log P ranged from 0.142 to 2.078 inclusive of pirarubicin and plays an important role in bioavailability. Hierarchical cluster analysis indicated that all analogs, except analog 6, were substantially similar to pirarubicin. A similar outcome was obtained from non-metric multidimensional scaling of descriptors. However detrended correspondence analysis distinguished both analogs 6 and 5 from the remaining analogs and pirarubicin. Nonhierarchical K-means clustering analysis determined greater differentiation among the analogs and pirarubicin. Analysis of similarity (ANOSIM) affirmed all compounds to be highly similar which shows structural optimization was achieved.
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PMID:Variation of substituents on pirarubicin for enhancing response to hepatocellular carcinoma and pattern recognition analysis to determine analogy to parent drug. 2007 39

Pirarubicin (THP) is a new generation cell cycle nonspecific anthracycline anticancer drug. Pirarubicin and pirarubicin-based combination therapies have been demonstrated to be effective against HCC in TACE. However, the drug resistance limits its therapeutic efficacy. Receptor-interacting protein kinase 1 (RIPK1) displays a critical role in cell death. Here we found that RIPK1 and p21 may participate in the resistance to pirarubicin. In this study, we first found that inhibition of RIPK1 significantly decreased pAKT and increased p21, accompanied by G0/G1 phase cell cycle arrest and cell anti-proliferation in pirarubicin-treated hepatocellular carcinoma cells. Moreover, phosphorylation of AKT reversed the anti-proliferative effect of RIPK1 inhibitor in HCC, which proved that RIPK1-AKT-P21-dependent pathway played a key role in pirarubicin resistance. Using a mouse xenograft model, we further found that RIPK1 inhibitor combined with pirarubicin exerted synergistic anti-tumor effect in vivo. Upon exposure to pirarubicin treatment, xenografts under RIPK1 inhibition maintained higher levels of p21 than control xenografts. In conclusion, the results in our study demonstrated that RIPK1 inhibition enhances the anti-tumor effect of pirarubicin by overcoming drug resistance. RIPK1 inhibitor might be used as an adjuvant to potentiate the inhibitory effect of pirarubicin against primary hepatocellular carcinoma.
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PMID:RIPK1 Inhibition Enhances Pirarubicin Cytotoxic Efficacy through AKT-P21-dependent Pathway in Hepatocellular Carcinoma. 3058 88