Interaction of Doxorubicin with Nuclei Isolated from Rat Liver and Kidney

Iga, Tatsuji; Sugiyama, Yuichi; Hanano, Manabu

doi:10.1002/jps.2600730423

Cited by 14 publications

(3 citation statements)

References 22 publications

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“…Secondly, AOT vesicle SEKC did not show enantioselectivity for racemic basic drugs such as verapamil, which does show enantioselective tissue distribution [41,43]. Thirdly, previous researchers have reported extensive interaction between some moderateto-strong basic drugs and tissue DNA [44,45], this could cause significantly under-predicting for drug candidates. Finally, some tissue proteins, such as a1-acid glycoprotein, also contribute to tissue affinities, although its impact on the regional distribution of the drug can be considered minimal [46].…”

Section: Correlation Of Sekc Retention To Tissue-to-plasma Water Partmentioning

confidence: 93%

A method for rapidly predicting drug tissue distribution using surfactant vesicle electrokinetic chromatography

2008

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Lung tissue distribution of an inhaled drug is important for its potency in the airways and with minimum systemic effects within its dose range. As the lung has the smallest diffusion distance of all the organs in the body and negligible diffusion delays, the characteristics of drug distribution in the lung will mainly depend on drug binding to both tissue and plasma protein. This research aims to develop and evaluate surfactant vesicle electrokinetic chromatography (SEKC) methods for high throughput profile prediction of tissue distribution for inhaled drugs. Several electrokinetic chromatography methods reported in the literature, as well as immobilised artificial membrane chromatography, were compared and evaluated in respect to chromatographic characteristics and statistical correlations. Among these methods, the docusate sodium salt (AOT) SEKC system showed good reproducibility, short run time, and the highest selectivity for alkylphenone test compounds. It also showed a significant statistical correlation between the retention of inhaled drugs and their in vivo volume of distribution at steady-state (V(ss)) in whole human body neglecting the plasma protein-binding differences. Stronger correlations were observed between the AOT SEKC retention of a series of basic drugs and their rat lung tissue-to-plasma water partitioning coefficient (K(pu)), which is affected only by drug binding to the tissue constituent. Further, on comparing correlations between AOT SEKC retention and K(pu) at various rat tissues, it was observed that the strongest correlation was with lung tissue distribution, while the weakest was with brain tissue distribution.

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Section: Correlation Of Sekc Retention To Tissue-to-plasma Water Partmentioning

confidence: 93%

A method for rapidly predicting drug tissue distribution using surfactant vesicle electrokinetic chromatography

2008

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“…1), (+)-(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione hydrochloride (SM-5887), amrubicinol hydrochloride and ICRF-193 were prepared by Sumitomo Pharmaceuticals Co., Ltd. (Osaka). 12,13) 14) Aliquots (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) µl) of DNA solution (0.2 mg/ml), up to 150 µl, were added to a cuvette filled with 3 ml of reaction buffer. The reaction mixture was stirred for 5 min, and the absorbance was measured on a spectrometer V-520-SR (Nihon Bunkoh, Tokyo) at 460 nm for amrubicin and amrubicinol, and 470 nm for DXR.…”

Section: Methodsmentioning

confidence: 99%

A New Antitumor Agent Amrubicin Induces Cell Growth Inhibition by Stabilizing Topoisomerase II‐DNA Complex

Hanada¹,

Mizuno²,

Fukushima³

et al. 1998

Japanese Journal of Cancer Research

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Amrubicin is a novel, completely synthetic 9-aminoanthracycline derivative. Amrubicin and its C-13 alcohol metabolite, amrubicinol, inhibited purified human DNA topoisomerase II (topo II). Compared with doxorubicin (DXR), amrubicin and amrubicinol induced extensive DNA-protein complex formation and double-strand DNA breaks in CCRF-CEM cells and KU-2 cells. In this study, we found that ICRF-193, a topo II catalytic inhibitor, antagonized both DNA-protein complex formation and double-strand DNA breaks induced by amrubicin and amrubicinol. Coordinately, cell growth inhibition induced by amrubicin and amrubicinol, but not that induced by DXR, was antagonized by ICRF-193. Taken together, these findings indicate that the cell growthinhibitory effects of amrubicin and amrubicinol are due to DNA-protein complex formation followed by double-strand DNA breaks, which are mediated by topo II.Key words: Amrubicin -Anthracycline -DNA-protein complex -Double-strand DNA break -DNA topoisomerase II DNA topoisomerase II (topo II) is a nuclear enzyme that regulates DNA topology through strand breakage, strand passage and religation. Thus, topo II is extensively involved in DNA metabolism, including replication, transcription, recombination and sister chromatid segregation.1) Mammalian topo II is the primary cellular target of a number of potent antitumor agents such as doxorubicin (DXR), daunorubicin (DNR), etoposide and amsacrine (m-AMSA).2) These agents interfere with the breakagereunion reaction of topo II by trapping a covalent enzyme-DNA complex, termed "cleavable complex," in which DNA strands are broken and their 5′ termini are covalently linked to the protein. In general, the cytotoxicity of these topo II poisons is dependent on stabilization of the cleavable complex followed by topo II-mediated DNA damage, rather than inactivation of topo II cellular functions. 3)Amrubicin is a novel, completely synthetic 9-aminoanthracycline derivative, and has antitumor activities in murine experimental tumor systems and human tumornude mouse systems. 4,5) Like other anthracycline derivatives, such as DXR and DNR, amrubicin is converted to its C-13 alcohol metabolite, amrubicinol.6) In contrast to doxorubicinol and daunorubicinol, amrubicinol has much higher antitumor activity than the parent drug in vitro. 6, 7)In addition, amrubicin showed much weaker cardiotoxicity than DXR in a rabbit chronic experimental model. 8)Phase II clinical trials of amrubicin for the treatment of malignant lymphoma, superficial bladder, small cell lung carcinoma, and non-small cell lung carcinoma are in progress. 9,10) Amrubicin showed substantial activity (response rate of 25%) against non-small cell lung cancer, and a response rate of 78.8% was obtained against small cell lung cancer.The mechanisms underlying the antitumor activities of amrubicin and amrubicinol are not well understood. Our present study has shown that amrubicin and amrubicinol target human topo II by stabilizing the cleavable complex. Furthermore, amrubicin and amrubicinol induced DNApro...

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“…These drugs were few of those whose association with chromatin and nucleosome was studied (Mizuno et al, 1975;Zunino et al, 1980;Chaires et al, 1982Chaires et al, , 1983Chaires et al, , 1990Ganguli et al, 1983;Terasaki et al, 1984;Fritzsche et al, 1987;Simpkins et al, 1984;Chaires, 1996;Chakrabarti et al, 1996) when the molecular nature of the chromatin was established. The first detailed structural study (Chaires et al, 1982) employed equilibrium, hydrodynamic, and electric dichroism studies of the complex of daunomycin with H1-depleted 175 bp nucleosomes, along with some comparative data for ethidium.…”

Section: Daunomycin Doxorubicinmentioning

confidence: 99%

Chromatin as a Target for the DNA-Binding Anticancer Drugs

Majumder

Pradhan

Devi

et al. 2007

Subcellular Biochemistry

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Chemotherapy has been a major approach to treat cancer. Both constituents of chromatin, chromosomal DNA and the associated chromosomal histone proteins are the molecular targets of the anticancer drugs. Small DNA binding ligands, which inhibit enzymatic processes with DNA substrate, are well known in cancer chemotherapy. These drugs inhibit the polymerase and topoisomerase activity. With the advent in the knowledge of chromatin chemistry and biology, attempts have shifted from studies of the structural basis of the association of these drugs or small ligands (with the potential of drugs) with DNA to their association with chromatin and nucleosome. These drugs often inhibit the expression of specific genes leading to a series of biochemical events. An overview will be given about the latest understanding of the molecular basis of their action. We shall restrict to those drugs, synthetic or natural, whose prime cellular targets are so far known to be chromosomal DNA

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Interaction of Doxorubicin with Nuclei Isolated from Rat Liver and Kidney

Cited by 14 publications

References 22 publications

A method for rapidly predicting drug tissue distribution using surfactant vesicle electrokinetic chromatography

A method for rapidly predicting drug tissue distribution using surfactant vesicle electrokinetic chromatography

A New Antitumor Agent Amrubicin Induces Cell Growth Inhibition by Stabilizing Topoisomerase II‐DNA Complex

Chromatin as a Target for the DNA-Binding Anticancer Drugs

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