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[]
["TTD - Therapeutic Targets Database"]
["Version 4.3.02 (2011.08.25)"]
["File Name: Pharmacodynamically antagonistic drug combinations."]
["Antagonism has been determined by established methods and its molecular mechanism has been revealed. The antagonism of the listed drug combinations is due to interfering actions of the partner drugs in each combination."]
[]
["Combination target relation","Drug A (mechanism of action related to antagonism)","Drug B (mechanism of action related to antagonism)","Reported antagonistic effect","Antagonism determination method","Possible mechanism of antagonism of interfering actions"]
["Different targets of related pathways that regulate the same target","17-AAG (heat-shock protein antagonist, induced cell cycle inhibition and apoptosis by inhibiting NF-kappaB, AP-1 and PI3K/Akt pathways (1), Hsp90/FLT3 inhibitor (2))","Cytarabine (DNA binder (3), inhibited synthesome associated DNA polymerase alpha activity (4))","17-AAG antagonized the cytotoxic activity of cytarabine (3)","Median dose effect analysis (Calcusym)","17-AAG altered the condition necessary for cytarabine to produce its activity. It induced G1 arrest, which subsequently prevented cytarabine incorporation into cellular DN (3)."]
[null,"Amphotericin B (formed ion channels in fungal membranes (5))","Ravuconazole (inhibited biosynthesis of ergosterol, a component of fungal cell membrane (6))","Antagonism in experimental invasive pulmonary aspergillosis (7, 8)","Loewe additivity-based drug-interaction model","Amphotericin B can form ion channels more easily in the presence of ergosterol (5), ravuconazole inhibition of ergosterol synthesis (6) can therefore reduce the activity of amphotericin B in forming ion channels (5)."]
["Same target","4-HPR (Reduced ERK activity to inhibit prostate cancer cells (9), activated JNK to induce apoptosis (10), suppressed IκBα phosphorylation which inhibited NF-κB activation and downregulated antiapoptotic genes (9))","Sodium butyrate (Reduced ERK activity to inhibit prostate cancer cells (9), activated JNK to induce apoptosis (10) suppressed IκBα phosphorylation which inhibited NF-κB activation and downregulated antiapoptotic genes (9))","Sodium butyrate and 4-HPR administered together antagonize effects of each other on prostate cancer (9)","Isobologram","Co-administration of 4-HPR and sodium butyrate possibly affected each other’s actions in suppressing IκBα phosphorylation, thereby reduced their inhibitory effects on NF-κB activation and antiapoptotic gene expression. NF-κB activation also downregulated JNK phosphorylation leading to inhibition of apoptosis in prostate cells (9)."]
[null,"Aminophylline (adenosine receptor antagonist, phosphodiesterase inhibitor, released intracellular calcium (11))","Theophylline (released intracellular calcium, adenosine receptor antagonist, phosphodiesterase inhibitor (11))","Antagonism of inhibitory adenosine autoreceptors and release of intracellular calcium (11)","Quantal release measurement","Adenosine receptor antagonist binding may be associated with non-unique binding site conformations (12). Aminophylline binding may lock the receptor into a unique conformation that hinder theophylline binding, thereby producing antagonistic effect."]
[]
["References:"]
[1,"Kawakami H, et al. (2007) Inhibition of heat shock protein-90 modulates multiple functions required for survival of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells. Int J Cancer 120(8):1811-1820."]
[2,"Yao Q, Weigel B, & Kersey J (2007) Synergism between etoposide and 17-AAG in leukemia cells: critical roles for Hsp90, FLT3, topoisomerase II, Chk1, and Rad51. Clin Cancer Res 13(5):1591-1600."]
[3,"Pelicano H, et al. (2006) Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C. Leukemia 20(4):610-619."]
[4,"Abdel-Aziz W, Jiang HY, Hickey RJ, & Malkas LH (2000) Ara-C affects formation of cancer cell DNA synthesome replication intermediates. Cancer Chemother Pharmacol 45(4):312-319."]
[5,"Huang W, et al. (2002) Ion channel behavior of amphotericin B in sterol-free and cholesterol- or ergosterol-containing supported phosphatidylcholine bilayer model membranes investigated by electrochemistry and spectroscopy. Biophys J 83(6):3245-3255."]
[6,"Walsh TJ, et al. (2000) New targets and delivery systems for antifungal therapy. Med Mycol 38 Suppl 1:335-347."]
[7,"Meletiadis J, et al. (2006) Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo correlation. J Infect Dis 194(7):1008-1018."]
[8,"Carrillo-Munoz AJ, Giusiano G, Ezkurra PA, & Quindos G (2006) Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter 19(2):130-139."]
[9,"Kuefer R, et al. (2007) Antagonistic effects of sodium butyrate and N-(4-hydroxyphenyl)-retinamide on prostate cancer. Neoplasia 9(3):246-253."]
[10,"Shimada K, et al. (2002) Contributions of mitogen-activated protein kinase and nuclear factor kappa B to N-(4-hydroxyphenyl)retinamide-induced apoptosis in prostate cancer cells. Mol Carcinog 35(3):127-137."]
[11,"Nickels TJ, et al. (2006) Effect of theophylline and aminophylline on transmitter release at the mammalian neuromuscular junction is not mediated by cAMP. Clin Exp Pharmacol Physiol 33(5-6):465-470."]
[12,"Barrington WW, Jacobson KA, & Stiles GL (1989) Demonstration of distinct agonist and antagonist conformations of the A1 adenosine receptor. J Biol Chem 264(22):13157-13164."]

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