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Doxorubicin Metabolism and Toxicity in Human Myocardium:  Role of Cytoplasmic Deglycosidation and Carbonyl Reduction

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Institutes of Pharmacology and Biochemistry, Catholic University School of Medicine, Rome, Italy, and Department of Drug Sciences, G. D'Annunzio University School of Pharmacy, Chieti, Italy
Cite this: Chem. Res. Toxicol. 2000, 13, 5, 414–420
Publication Date (Web):April 14, 2000
https://doi.org/10.1021/tx000013q
Copyright © 2000 American Chemical Society

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    Abstract

    The anthracycline doxorubicin (DOX) is an exceptionally good antineoplastic agent, but its use is limited by formation of metabolites which induce acute and chronic cardiac toxicities. Whereas the acute toxicity is mild, the chronic toxicity can produce a life-threatening cardiomyopathy. Studies in laboratory animals are of limited value in predicting the structure and reactivity of toxic metabolites in humans; therefore, we used an ethically acceptable system which is suitable for exploring DOX metabolism in human myocardium. The system involves cytosolic fractions from myocardial samples obtained during aorto-coronary bypass grafting. After reconstitution with NADPH and DOX, these fractions generate the alcohol metabolite doxorubicinol (DOXol) as well as DOX deoxyaglycone and DOXol hydroxyaglycone, reflecting reduction of the side chain carbonyl group, reductase-type deglycosidation of the anthracycline, and hydrolase-type deglycosidation followed by carbonyl reduction, respectively. The efficiency of each metabolic route has been evaluated at low and high DOX:protein ratios, reproducing acute, single-dose and chronic, multiple-dose regimens, respectively. Low DOX:protein ratios increase the efficiency of formation of DOX deoxyaglycone and DOXol hydroxyaglycone but decrease that of DOXol. Conversely, high DOX:protein ratios facilitate the formation of DOXol but impair reductase- or hydrolase-type deglycosidation and uncouple hydrolysis from carbonyl reduction, making DOXol accumulate at levels higher than those of DOX deoxyaglycone and DOXol hydroxyaglycone. Structure−activity considerations have suggested that aglycones and DOXol may inflict cardiac damage by inducing oxidative stress or by perturbing iron homeostasis, respectively. Having characterized the influence of DOX:protein ratios on deglycosidation or carbonyl reduction, we propose that the benign acute toxicity should be attributed to the oxidant activity of aglycones, whereas the life-threatening chronic toxicity should be attributed to alterations of iron homeostasis by DOXol. This picture rationalizes the limited protective efficacy of antioxidants against chronic cardiomyopathy vis-à-vis the better protection offered by iron chelators, and forms the basis for developing analogues which produce less DOXol.

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     Institute of Pharmacology, Catholic University School of Medicine.

     Institute of Biochemistry, Catholic University School of Medicine.

    *

     To whom correspondence should be addressed:  Department of Drug Sciences, G. D'Annunzio University School of Pharmacy, Via dei Vestini, 66013 Chieti, Italy. Phone: 011-39-0871-3555237. Fax: 011-39-0871-3555315. E-mail: [email protected].

    §

     G. D'Annunzio University School of Pharmacy.

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    5. Olga Swiech, Anna Mieczkowska, Kazimierz Chmurski, and Renata Bilewicz . Intermolecular Interactions between Doxorubicin and β-Cyclodextrin 4-Methoxyphenol Conjugates. The Journal of Physical Chemistry B 2012, 116 (6) , 1765-1771. https://doi.org/10.1021/jp2091363
    6. Praveena Mohan and Natalya Rapoport. Doxorubicin as a Molecular Nanotheranostic Agent: Effect of Doxorubicin Encapsulation in Micelles or Nanoemulsions on the Ultrasound-Mediated Intracellular Delivery and Nuclear Trafficking. Molecular Pharmaceutics 2010, 7 (6) , 1959-1973. https://doi.org/10.1021/mp100269f
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    11. S. Malathi, Valappil Sisila, V. Singaravel, Nandakumar Venkatesan, Iqbal Pakrudheen, R. Dhanaraj, Niraikulam Ayyadurai, V. Bhuvarahamurthy, S. Narayana Kalkura. Epidermal growth factor receptor targeted doxorubicin and vitexin loaded niosomes for enhanced breast cancer therapy. Materials Advances 2023, 4 (21) , 5224-5237. https://doi.org/10.1039/D3MA00328K
    12. Nicoletta Bertorello, Roberto Luksch, Gianni Bisogno, Riccardo Haupt, Paolo Spallarossa, Rosita Cenna, Franca Fagioli. Cardiotoxicity in children with cancer treated with anthracyclines: A position statement on dexrazoxane. Pediatric Blood & Cancer 2023, 70 (9) https://doi.org/10.1002/pbc.30515
    13. Akshoo Rathi, Yogender Bahugana, Mohit Nagar. An Overview on Cardio-Protective Compound Dexrazoxane. International Journal Of Health Care And Nursing 2023, 2 (1) , 01-12. https://doi.org/10.55938/ijhcn.v1i2.44
    14. Janthima Methaneethorn, Kanokkan Tengcharoen, Nattawut Leelakanok, Rowan AlEjielat. Population pharmacokinetics of doxorubicin: A systematic review. Asia-Pacific Journal of Clinical Oncology 2023, 19 (1) , 9-26. https://doi.org/10.1111/ajco.13776
    15. Carmen Avendaño, J. Carlos Menéndez. Anticancer strategies involving radical species. 2023, 165-235. https://doi.org/10.1016/B978-0-12-818549-0.00015-7
    16. Kaiqiang Liu, Jian Zhang, Xinxin Li, Yingying Xie, Yong Li, Xu Wang, Xiaoyun Jiao, Xilei Xie, Bo Tang. Hypochlorous acid-activated two-photon fluorescent probe for evaluation of anticancer drug-induced cardiotoxicity and screening of antioxidant drugs. Organic Chemistry Frontiers 2022, 9 (24) , 6795-6801. https://doi.org/10.1039/D2QO01408D
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    18. Isobel C Jones, Crispin R Dass. Doxorubicin-induced cardiotoxicity: causative factors and possible interventions. Journal of Pharmacy and Pharmacology 2022, 74 (12) , 1677-1688. https://doi.org/10.1093/jpp/rgac063
    19. Margo Waters, Juliane Hopf, Emma Tam, Stephanie Wallace, Jordan Chang, Zach Bennett, Hadrian Aquino, Ryan Roeder, Paul Helquist, M. Stack, Prakash Nallathamby. Biocompatible, Multi-Mode, Fluorescent, T2 MRI Contrast Magnetoelectric-Silica Nanoparticles (MagSiNs), for On-Demand Doxorubicin Delivery to Metastatic Cancer Cells. Pharmaceuticals 2022, 15 (10) , 1216. https://doi.org/10.3390/ph15101216
    20. Dalia O. Saleh, Sawsan S. Mahmoud, Azza Hassan, Eman F. Sanad. Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2/HO-1 activation and PI3K/Akt/GSK-3β axis modulation. Saudi Journal of Biological Sciences 2022, 29 (7) , 103308. https://doi.org/10.1016/j.sjbs.2022.103308
    21. Rachel E. Nicoletto, Clyde M. Ofner. Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells. Cancer Chemotherapy and Pharmacology 2022, 89 (3) , 285-311. https://doi.org/10.1007/s00280-022-04400-y
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    26. Sabina Y. van der Zanden, Xiaohang Qiao, Jacques Neefjes. New insights into the activities and toxicities of the old anticancer drug doxorubicin. The FEBS Journal 2021, 288 (21) , 6095-6111. https://doi.org/10.1111/febs.15583
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    34. Christian Siebel, Claudia Lanvers-Kaminsky, Gudrun Würthwein, Georg Hempel, Joachim Boos. Bioanalysis of doxorubicin aglycone metabolites in human plasma samples–implications for doxorubicin drug monitoring. Scientific Reports 2020, 10 (1) https://doi.org/10.1038/s41598-020-75662-w
    35. Le Chen, Lin Li. Aminocaproylated nanodiamond prodrug for tumor intracellular enhanced delivery of doxorubicin. Journal of Drug Delivery Science and Technology 2020, 60 , 102017. https://doi.org/10.1016/j.jddst.2020.102017
    36. Dalia Saleh, Marawan Abdelbaset, Azza Hassan, Ola Sharaf, Sawsan Mahmoud, Rehab Hegazy, . Omega-3 fatty acids ameliorate doxorubicin-induced cardiorenal toxicity: In-vivo regulation of oxidative stress, apoptosis and renal Nox4, and in-vitro preservation of the cytotoxic efficacy. PLOS ONE 2020, 15 (11) , e0242175. https://doi.org/10.1371/journal.pone.0242175
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    41. Anchit Bhagat, Eugenie S. Kleinerman. Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention. 2020, 181-192. https://doi.org/10.1007/978-3-030-43032-0_15
    42. Xu Wang, Renjie Hui, Yun Chen, Wentao Wang, Yujiao Chen, Xiaohai Gong, Jian Jin. Discovery of Novel Doxorubicin Metabolites in MCF7 Doxorubicin-Resistant Cells. Frontiers in Pharmacology 2019, 10 https://doi.org/10.3389/fphar.2019.01434
    43. O. O. Shevchuk. ЕФЕКТИ ЕНТЕРОСОРБЦІЇ ТА ФІЛГРАСТИМУ ПРИ СУБХРОНІЧНІЙ ДОКСОРУБІЦИНОВІЙ ТОКСИЧНОСТІ. Здобутки клінічної і експериментальної медицини 2019, (3) , 146-156. https://doi.org/10.11603/1811-2471.2019.v.i3.10510
    44. Nadine Wenningmann, Merle Knapp, Anusha Ande, Tanaya R. Vaidya, Sihem Ait-Oudhia. Insights into Doxorubicin-induced Cardiotoxicity: Molecular Mechanisms, Preventive Strategies, and Early Monitoring. Molecular Pharmacology 2019, 96 (2) , 219-232. https://doi.org/10.1124/mol.119.115725
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    46. Shubhmita Bhatnagar, Neha Gajanan Bankar, Mrunal Vijay Kulkarni, Venkata Vamsi Krishna Venuganti. Dissolvable microneedle patch containing doxorubicin and docetaxel is effective in 4T1 xenografted breast cancer mouse model. International Journal of Pharmaceutics 2019, 556 , 263-275. https://doi.org/10.1016/j.ijpharm.2018.12.022
    47. Caroline Manto Chagas, Sara Moss, Laleh Alisaraie. Drug metabolites and their effects on the development of adverse reactions: Revisiting Lipinski’s Rule of Five. International Journal of Pharmaceutics 2018, 549 (1-2) , 133-149. https://doi.org/10.1016/j.ijpharm.2018.07.046
    48. Meetal Solanki, Amy Pointon, Barry Jones, Karl Herbert. Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity. Drug Metabolism and Disposition 2018, 46 (8) , 1053-1065. https://doi.org/10.1124/dmd.117.078964
    49. Evelyn C. da S. Santos, Amanda Watanabe, Maria D. Vargas, Marcelo N. Tanaka, Flavio Garcia, Célia M. Ronconi. AMF-responsive doxorubicin loaded β-cyclodextrin-decorated superparamagnetic nanoparticles. New Journal of Chemistry 2018, 42 (1) , 671-680. https://doi.org/10.1039/C7NJ02860A
    50. Rubén Ruiz-González, Paula Milán, Roger Bresolí-Obach, Juan Stockert, Angeles Villanueva, Magdalena Cañete, Santi Nonell. Photodynamic Synergistic Effect of Pheophorbide a and Doxorubicin in Combined Treatment against Tumoral Cells. Cancers 2017, 9 (12) , 18. https://doi.org/10.3390/cancers9020018
    51. Agata Krzak, Olga Swiech, Maciej Majdecki, Renata Bilewicz. Complexing daunorubicin with β-cyclodextrin derivative increases drug intercalation into DNA. Electrochimica Acta 2017, 247 , 139-148. https://doi.org/10.1016/j.electacta.2017.06.140
    52. Ivanna Hrynchak, Emília Sousa, Madalena Pinto, Vera Marisa Costa. The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs. Drug Metabolism Reviews 2017, 49 (2) , 158-196. https://doi.org/10.1080/03602532.2017.1316285
    53. Mariana Seke, Danijela Petrovic, Aleksandar Djordjevic, Danica Jovic, Milica Labudovic Borovic, Zdenko Kanacki, Milan Jankovic. Fullerenol/doxorubicin nanocomposite mitigates acute oxidative stress and modulates apoptosis in myocardial tissue. Nanotechnology 2016, 27 (48) , 485101. https://doi.org/10.1088/0957-4484/27/48/485101
    54. Tarek Magdy, Brian T. Burmeister, Paul W. Burridge. Validating the pharmacogenomics of chemotherapy-induced cardiotoxicity: What is missing?. Pharmacology & Therapeutics 2016, 168 , 113-125. https://doi.org/10.1016/j.pharmthera.2016.09.009
    55. Fahad Al-Abbasi, Eman Alghamdi, Mohammed Baghdadi, Abdulmohsin Alamoudi, Ali El-Halawany, Hany El-Bassossy, Ali Aseeri, Ahmed Al-Abd. Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity. Molecules 2016, 21 (7) , 886. https://doi.org/10.3390/molecules21070886
    56. Vikrant Vijay, Carrie L. Moland, Tao Han, James C. Fuscoe, Taewon Lee, Eugene H. Herman, G. Ronald Jenkins, Sherry M. Lewis, Connie A. Cummings, Yuan Gao, Zhijun Cao, Li-Rong Yu, Varsha G. Desai. Early transcriptional changes in cardiac mitochondria during chronic doxorubicin exposure and mitigation by dexrazoxane in mice. Toxicology and Applied Pharmacology 2016, 295 , 68-84. https://doi.org/10.1016/j.taap.2016.02.003
    57. Brenda Loaiza, Salomon Hernández-Gutierrez, Juan Jose Montesinos, Mahara Valverde, Emilio Rojas. Nuclear Transcription Factor Kappa B Downregulation Reduces Chemoresistance in Bone Marrow-derived Cells Through P-glycoprotein Modulation. Archives of Medical Research 2016, 47 (2) , 78-88. https://doi.org/10.1016/j.arcmed.2016.05.004
    58. Jan Hintzpeter, Jan Moritz Seliger, Jakub Hofman, Hans-Joerg Martin, Vladimir Wsol, Edmund Maser. Inhibition of human anthracycline reductases by emodin — A possible remedy for anthracycline resistance. Toxicology and Applied Pharmacology 2016, 293 , 21-29. https://doi.org/10.1016/j.taap.2016.01.003
    59. Masoumeh Taei, Foroozan Hasanpour, Hossein Salavati, Shekofeh Mohammadian. Fast and sensitive determination of doxorubicin using multi-walled carbon nanotubes as a sensor and CoFe2O4 magnetic nanoparticles as a mediator. Microchimica Acta 2016, 183 (1) , 49-56. https://doi.org/10.1007/s00604-015-1588-3
    60. Olga Swiech, Maciej Majdecki, Aleksander Debinski, Agata Krzak, Tomasz M. Stępkowski, Grzegorz Wójciuk, Marcin Kruszewski, Renata Bilewicz. Competition between self-inclusion and drug binding explains the pH dependence of the cyclodextrin drug carrier – molecular modelling and electrochemistry studies. Nanoscale 2016, 8 (37) , 16733-16742. https://doi.org/10.1039/C6NR05833G
    61. Lin Li, Lu Tian, Yongli Wang, Wenjing Zhao, Fangqin Cheng, Yingqi Li, Binsheng Yang. Smart pH-responsive and high doxorubicin loading nanodiamond for in vivo selective targeting, imaging, and enhancement of anticancer therapy. Journal of Materials Chemistry B 2016, 4 (29) , 5046-5058. https://doi.org/10.1039/C6TB00266H
    62. Masoumeh Taei, Foroozan Hasanpour, Elaheh Dehghani. Electrodepositing of copper nanowires on layered double hydroxide film modified glassy carbon electrode for the determination of doxorubicin. Journal of the Taiwan Institute of Chemical Engineers 2015, 54 , 183-190. https://doi.org/10.1016/j.jtice.2015.03.016
    63. Weiguo Xu, Jianxun Ding, Chunsheng Xiao, Lingyu Li, Xiuli Zhuang, Xuesi Chen. Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic. Biomaterials 2015, 54 , 72-86. https://doi.org/10.1016/j.biomaterials.2015.03.021
    64. Jan Hintzpeter, Jan Hornung, Bettina Ebert, Hans-Jörg Martin, Edmund Maser. Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase – Carbonyl reductase 1. Chemico-Biological Interactions 2015, 234 , 162-168. https://doi.org/10.1016/j.cbi.2014.12.019
    65. Gustav Holmgren, Jane Synnergren, Yalda Bogestål, Caroline Améen, Karolina Åkesson, Sandra Holmgren, Anders Lindahl, Peter Sartipy. Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology 2015, 328 , 102-111. https://doi.org/10.1016/j.tox.2014.12.018
    66. Carmen Avendaño, J. Carlos Menéndez. Anticancer Drugs Acting via Radical Species. 2015, 133-195. https://doi.org/10.1016/B978-0-444-62649-3.00004-1
    67. Mirta R. Alcaráz, Agustina V. Schenone, María J. Culzoni, Héctor C. Goicoechea. Modeling of second-order spectrophotometric data generated by a pH-gradient flow injection technique for the determination of doxorubicin in human plasma. Microchemical Journal 2014, 112 , 25-33. https://doi.org/10.1016/j.microc.2013.09.012
    68. Nengxuan Ma, Lin Zhang, Ruijin Li, Yehong Zhou, Zongwei Cai, Chuan Dong, Shaomin Shuang. Magnetic solid-phase extraction based on a trimethylstearylammonium bromide coated Fe 3 O 4 /SiO 2 composite for determination of adriamycin hydrochloride in human plasma and urine by HPLC-FLD. Anal. Methods 2014, 6 (17) , 6736-6744. https://doi.org/10.1039/C4AY00768A
    69. Onkar S. Bains, András Szeitz, Joanna M. Lubieniecka, Gina E. Cragg, Thomas A. Grigliatti, K. Wayne Riggs, Ronald E. Reid. A Correlation between Cytotoxicity and Reductase-Mediated Metabolism in Cell Lines Treated with Doxorubicin and Daunorubicin. Journal of Pharmacology and Experimental Therapeutics 2013, 347 (2) , 375-387. https://doi.org/10.1124/jpet.113.206805
    70. Ahmed M. Al-Abd, Fahad A. Al-Abbasi, Gihan F. Asaad, Ashraf B. Abdel-Naim. Didox potentiates the cytotoxic profile of doxorubicin and protects from its cardiotoxicity. European Journal of Pharmacology 2013, 718 (1-3) , 361-369. https://doi.org/10.1016/j.ejphar.2013.08.009
    71. Sigrid Baumgarten, Ron C. Gaba, Richard B. van Breemen. Confirmation of drug delivery after liver chemoembolization: direct tissue doxorubicin measurement by UHPLC‐MS‐MS. Biomedical Chromatography 2012, 26 (12) , 1529-1533. https://doi.org/10.1002/bmc.2727
    72. Erin L. Westman, Marc J. Canova, Inas J. Radhi, Kalinka Koteva, Inga Kireeva, Nicholas Waglechner, Gerard D. Wright. Bacterial Inactivation of the Anticancer Drug Doxorubicin. Chemistry & Biology 2012, 19 (10) , 1255-1264. https://doi.org/10.1016/j.chembiol.2012.08.011
    73. Ali Mokhtar Mahmoud, Ahmed M. Al-Abd, David A. Lightfoot, Hany A. El-Shemy. Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent. Journal of Enzyme Inhibition and Medicinal Chemistry 2012, 27 (5) , 673-679. https://doi.org/10.3109/14756366.2011.607446
    74. Jinhui Xu, Yuan Liu, Ying Yu, Qingjiang Ni, Yun Chen. Subcellular Quantification of Doxorubicin and Its Metabolite in Cultured Human Leukemia Cells Using Liquid Chromatography-Tandem Mass Spectrometry. Analytical Letters 2012, 45 (14) , 1980-1994. https://doi.org/10.1080/00032719.2012.680056
    75. Ja-an Annie Ho, Nien-chu Fan, Amily Fang-ju Jou, Li-chen Wu, Tai-ping Sun. Monitoring the subcellular localization of doxorubicin in CHO-K1 using MEKC−LIF: Liposomal carrier for enhanced drug delivery. Talanta 2012, 99 , 683-688. https://doi.org/10.1016/j.talanta.2012.06.077
    76. Megan M. Freeland, Jackeline Angulo, Alison L. Davis, Adam M. Flook, Brittany L. Garcia, Nathan A. King, Samuelle K. Mangibin, Kristin M. Paul, Megan E. Prosser, Nicole Sata, Jim L. Bentley, Lisa E. Olson. Sex differences in improved efficacy of doxorubicin chemotherapy in Cbr1+/− mice. Anti-Cancer Drugs 2012, 23 (6) , 584-589. https://doi.org/10.1097/CAD.0b013e3283512726
    77. V. Escudero-Ortiz, A. Ramón-López, M.a J. Duart, J.J. Pérez-Ruixo, B. Valenzuela. Farmacocinética poblacional de doxorubicina aplicada a la personalización de su dosificación en pacientes oncológicos. Farmacia Hospitalaria 2012, 36 (4) , 282-291. https://doi.org/10.1016/j.farma.2011.05.006
    78. Alvaro Mordente, Elisabetta Meucci, Andrea Silvestrini, Giuseppe Ettore Martorana, Bruno Giardina. Anthracyclines and Mitochondria. 2012, 385-419. https://doi.org/10.1007/978-94-007-2869-1_18
    79. A. M. Al-Abd, A. M. Mahmoud, G. A. El-Sherbiny, M. A. El-Moselhy, S. M. Nofal, H. A. El-Latif, W. I. El-Eraky, H. A. El-Shemy. Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro. Cell Proliferation 2011, 44 (6) , 591-601. https://doi.org/10.1111/j.1365-2184.2011.00783.x
    80. Yaohua Wang, Joseph B. Katzenmeyer, Edgar A. Arriaga. Combination of Micellar Electrokinetic and High-Performance Liquid Chromatographies to Assess Age-Related Changes in the In Vitro Metabolism of Fischer 344 Rat Liver. The Journals of Gerontology: Series A 2011, 66A (9) , 935-943. https://doi.org/10.1093/gerona/glr074
    81. Adam Skarka, Lucie Škarydová, Hana Štambergová, Vladimír Wsól. Anthracyclines and their metabolism in human liver microsomes and the participation of the new microsomal carbonyl reductase. Chemico-Biological Interactions 2011, 191 (1-3) , 66-74. https://doi.org/10.1016/j.cbi.2010.12.016
    82. Pei-Lin Lu, Yi-Chun Chen, Ta-Wei Ou, Hung-Hao Chen, Hsieh-Chih Tsai, Chih-Jen Wen, Chun-Liang Lo, Shiaw-Pyng Wey, Kun-Ju Lin, Tzu-Chen Yen, Ging-Ho Hsiue. Multifunctional hollow nanoparticles based on graft-diblock copolymers for doxorubicin delivery. Biomaterials 2011, 32 (8) , 2213-2221. https://doi.org/10.1016/j.biomaterials.2010.11.051
    83. Eryun Yan, Yilong Fu, Xue Wang, Yin Ding, Hanqing Qian, Chi-Hwa Wang, Yong Hu, Xiqun Jiang. Hollow chitosan–silica nanospheres for doxorubicin delivery to cancer cells with enhanced antitumor effect in vivo. Journal of Materials Chemistry 2011, 21 (9) , 3147. https://doi.org/10.1039/c0jm03234d
    84. Xing-Chen Peng, Feng-Ming Gong, Meng Wei, Xi Chen, Ye Chen, Ke Cheng, Feng Gao, Feng Xu, Feng Bi, Ji-Yan Liu. Proteomic analysis of cell lines to identify the irinotecan resistance proteins. Journal of Biosciences 2010, 35 (4) , 557-564. https://doi.org/10.1007/s12038-010-0064-9
    85. Ze Fu, Jiabin Guo, Li Jing, Ruisheng Li, Tingfen Zhang, Shuangqing Peng. Enhanced toxicity and ROS generation by doxorubicin in primary cultures of cardiomyocytes from neonatal metallothionein-I/II null mice. Toxicology in Vitro 2010, 24 (6) , 1584-1591. https://doi.org/10.1016/j.tiv.2010.06.009
    86. Vijay Kumar Sripuram, Harish K. Kaushik, Satish K. Bedada, Narasimha Y. Reddy, Kiran Kumar Vangara, S. Praneeth Kumar, G. IndiraPriyadarshini, Krishna R. Devarakonda. Development and validation of rapid and sensitive HPLC method for the quantitative determination of doxorubicin in human plasma. Clinical Research and Regulatory Affairs 2010, 27 (3) , 75-81. https://doi.org/10.3109/10601333.2010.486404
    87. Weixue Huang, Liya Ding, Qiang Huang, Hairong Hu, Shan Liu, Xianmei Yang, Xiaohui Hu, Yongjun Dang, Suqin Shen, Jie Li, Xiaona Ji, Songmin Jiang, Jun O. Liu, Long Yu. Carbonyl reductase 1 as a novel target of (−)-epigallocatechin gallate against hepatocellular carcinoma. Hepatology 2010, 52 (2) , 703-714. https://doi.org/10.1002/hep.23723
    88. Kumiko Sakai-Kato, Eiko Saito, Keiko Ishikura, Toru Kawanishi. Analysis of intracellular doxorubicin and its metabolites by ultra-high-performance liquid chromatography. Journal of Chromatography B 2010, 878 (19) , 1466-1470. https://doi.org/10.1016/j.jchromb.2010.03.040
    89. Onkar S. Bains, Morgan J. Karkling, Joanna M. Lubieniecka, Thomas A. Grigliatti, Ronald E. Reid, K. Wayne Riggs. Naturally Occurring Variants of Human CBR3 Alter Anthracycline In Vitro Metabolism. Journal of Pharmacology and Experimental Therapeutics 2010, 332 (3) , 755-763. https://doi.org/10.1124/jpet.109.160614
    90. Ahmed M. Al-Abd, Ki-Yun Hong, Soo-Chang Song, Hyo-Jeong Kuh. Pharmacokinetics of doxorubicin after intratumoral injection using a thermosensitive hydrogel in tumor-bearing mice. Journal of Controlled Release 2010, 142 (1) , 101-107. https://doi.org/10.1016/j.jconrel.2009.10.003
    91. Yunfang Zhang, Haitham El-Sikhry, Ketul R. Chaudhary, Sri Nagarjun Batchu, Anooshirvan Shayeganpour, Taibeh Orujy Jukar, J. Alyce Bradbury, Joan P. Graves, Laura M. DeGraff, Page Myers, Douglas C. Rouse, Julie Foley, Abraham Nyska, Darryl C. Zeldin, John M. Seubert. Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity. American Journal of Physiology-Heart and Circulatory Physiology 2009, 297 (1) , H37-H46. https://doi.org/10.1152/ajpheart.00983.2008
    92. Onkar S. Bains, Morgan J. Karkling, Thomas A. Grigliatti, Ronald E. Reid, K. Wayne Riggs. Two Nonsynonymous Single Nucleotide Polymorphisms of Human Carbonyl Reductase 1 Demonstrate Reduced in Vitro Metabolism of Daunorubicin and Doxorubicin. Drug Metabolism and Disposition 2009, 37 (5) , 1107-1114. https://doi.org/10.1124/dmd.108.024711
    93. Ahmed M. Al-Abd, Nam Ho Kim, Soo-Chang Song, Seung Jin Lee, Hyo-Jeong Kuh. A simple HPLC method for doxorubicin in plasma and tissues of nude mice. Archives of Pharmacal Research 2009, 32 (4) , 605-611. https://doi.org/10.1007/s12272-009-1417-5
    94. Ryan H. Takahashi, Onkar S. Bains, Tom A. Pfeifer, Thomas A. Grigliatti, Ronald E. Reid, K. Wayne Riggs. Aldo-Keto Reductase 1C2 Fails to Metabolize Doxorubicin and Daunorubicin in Vitro. Drug Metabolism and Disposition 2008, 36 (6) , 991-994. https://doi.org/10.1124/dmd.108.020388
    95. Onkar S. Bains, Ryan H. Takahashi, Tom A. Pfeifer, Thomas A. Grigliatti, Ronald E. Reid, K. Wayne Riggs. Two Allelic Variants of Aldo-Keto Reductase 1A1 Exhibit Reduced in Vitro Metabolism of Daunorubicin. Drug Metabolism and Disposition 2008, 36 (5) , 904-910. https://doi.org/10.1124/dmd.107.018895
    96. Carmen Avendaño, J. Carlos Menéndez. Anticancer Drugs Acting via Radical Species, Photosensitizers and Photodynamic Therapy of Cancer. 2008, 93-138. https://doi.org/10.1016/B978-0-444-52824-7.00004-4
    97. María Castro‐Puyana, Antonio L. Crego, María L. Marina. Recent advances in the analysis of antibiotics by CE and CEC. ELECTROPHORESIS 2008, 29 (1) , 274-293. https://doi.org/10.1002/elps.200700485
    98. Mariann Plebuch, Michael Soldan, Christoph Hungerer, Lutz Koch, Edmund Maser. Increased resistance of tumor cells to daunorubicin after transfection of cDNAs coding for anthracycline inactivating enzymes. Cancer Letters 2007, 255 (1) , 49-56. https://doi.org/10.1016/j.canlet.2007.03.018
    99. W.H. Gotlieb, I. Bruchim, G. Ben-Baruch, B. Davidson, A. Zeltser, A. Andersen, H. Olsen. Doxorubicin levels in the serum and ascites of patients with ovarian cancer. European Journal of Surgical Oncology (EJSO) 2007, 33 (2) , 213-215. https://doi.org/10.1016/j.ejso.2006.11.006
    100. Pierantonio Menna, Emanuela Salvatorelli, Luca Gianni, Giorgio Minotti. Anthracycline Cardiotoxicity. 2007, 21-44. https://doi.org/10.1007/128_2007_11
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