title: Cytostatic versus cytocidal profiling of quinoline drug combinations via modified fixed-ratio isobologram analysis.
abstract: BACKGROUND
  Drug combination therapy is the frontline of malaria treatment. There is an ever-accelerating need for new, efficacious combination therapies active against drug resistant malaria. Proven drugs already in the treatment pipeline, such as the quinolines, are important components of current combination therapy and also present an attractive test bank for rapid development of new concepts.
  
  
  METHODS
  The efficacy of several drug combinations versus chloroquine-sensitive and chloroquine-resistant strains was measured using both cytostatic and cytocidal potency assays.
  
  
  CONCLUSIONS
  These screens identify quinoline and non-quinoline pairs that exhibit synergy, additivity, or antagonism using the fixed-ratio isobologram method and find tafenoquine - methylene blue combination to be the most synergistic. Also, interestingly, for selected pairs, additivity, synergy, or antagonism defined by quantifying IC50 (cytostatic potency) does not necessarily predict similar behaviour when potency is defined by LD50 (cytocidal potency). These data further support an evolving new model for quinoline anti-malarials, wherein haem and haemozoin are the principle target for cytostatic activity, but may not be the only target relevant for cytocidal activity.
authors.affiliation: Department of Chemistry, Department of Biochemistry, Cellular, & Molecular Biology, and Center for Infectious Disease, Georgetown University, 37th and 'O' Sts, NW, Washington, DC, 20057, USA. roepep@georgetown.edu.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Gorka
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Jacobs
authors.forename: Paul D
authors.initials: PD
authors.lastname: Roepe
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D011804:Quinolines; C037219:quinoline
references.citation: J Pharmacol Exp Ther. 2006 Oct;319(1):1-7
references.pmid: 16670349
references.citation: Antimicrob Agents Chemother. 2005 Nov;49(11):4592-7
references.pmid: 16251300
references.citation: J Infect Dis. 1995 Jun;171(6):1678-82
references.pmid: 7769318
references.citation: J Med Chem. 2001 Nov 22;44(24):4268-76
references.pmid: 11708927
references.citation: Antimicrob Agents Chemother. 2013 Jan;57(1):356-64
references.pmid: 23114783
references.citation: Malar J. 2012 Dec 14;11:418
references.pmid: 23237606
references.citation: Antimicrob Agents Chemother. 2004 May;48(5):1807-10
references.pmid: 15105139
references.citation: Am J Trop Med Hyg. 2002 Jun;66(6):659-60
references.pmid: 12224570
references.citation: PLoS One. 2009;4(5):e5318
references.pmid: 19415120
references.citation: Clin Infect Dis. 2001 Dec 15;33(12):1968-74
references.pmid: 11700577
references.citation: Antimicrob Agents Chemother. 2013 Jan;57(1):365-74
references.pmid: 23114754
references.citation: Trends Parasitol. 2010 Mar;26(3):145-51
references.pmid: 20133198
references.citation: Am J Trop Med Hyg. 2011 Dec;85(6):1010-4
references.pmid: 22144436
references.citation: Nat Rev Drug Discov. 2009 Nov;8(11):879-91
references.pmid: 19834482
references.citation: Antimicrob Agents Chemother. 2004 Nov;48(11):4097-102
references.pmid: 15504827
references.citation: Science. 2012 Apr 6;336(6077):79-82
references.pmid: 22491853
references.citation: J Infect Dis. 2009 Mar 1;199(5):750-7
references.pmid: 19210165
references.citation: J Med Chem. 2013 Jul 11;56(13):5231-46
references.pmid: 23586757
references.citation: Biochem Pharmacol. 1996 Mar 8;51(5):693-700
references.pmid: 8615907
references.citation: Clin Infect Dis. 2003 Dec 15;37(12):1654-8
references.pmid: 14689348
references.citation: Redox Rep. 2003;8(5):272-5
references.pmid: 14962363
references.citation: Am J Trop Med Hyg. 1998 May;58(5):645-9
references.pmid: 9598455
references.citation: Nature. 2009 May 14;459(7244):270-3
references.pmid: 19357645
references.citation: Bull World Health Organ. 1968;38(4):625-32
references.pmid: 4876731
references.citation: Ann Trop Med Parasitol. 1999 Mar;93(2):179-82
references.pmid: 10474643
references.citation: Mol Biochem Parasitol. 2011 Jul-Aug;178(1-2):1-6
references.pmid: 21470564
references.citation: J Biol Chem. 2010 Aug 27;285(35):27045-27056
references.pmid: 20573956
references.citation: Am J Trop Med Hyg. 1986 Mar;35(2):263-74
references.pmid: 3513645
references.citation: Mol Cell. 2000 Oct;6(4):861-71
references.pmid: 11090624
references.citation: Parasitol Int. 2011 Dec;60(4):341-6
references.pmid: 21645634
references.citation: Lancet Infect Dis. 2013 Feb;13(2):175-81
references.pmid: 23182932
references.citation: Biochemistry. 2009 Dec 1;48(47):11152-4
references.pmid: 19883122
references.citation: Redox Rep. 2003;8(5):276-9
references.pmid: 14962364
references.citation: PLoS One. 2008 Feb 20;3(2):e1630
references.pmid: 18286187
references.citation: Antimicrob Agents Chemother. 2006 Sep;50(9):3225-6
references.pmid: 16940138
references.citation: Antimicrob Agents Chemother. 1995 Dec;39(12):2671-7
references.pmid: 8593000
references.citation: Biochem Pharmacol. 1998 Mar 15;55(6):727-36
references.pmid: 9586944
references.citation: Future Microbiol. 2009 May;4(4):441-55
references.pmid: 19416013
references.citation: Parasite. 2007 Jun;14(2):135-40
references.pmid: 17645185
references.citation: Biochem J. 2002 Dec 15;368(Pt 3):761-8
references.pmid: 12225291
references.citation: Trans R Soc Trop Med Hyg. 1996 Mar-Apr;90(2):147-51
references.pmid: 8761575
references.citation: Biochem Pharmacol. 1998 Feb 15;55(4):433-40
references.pmid: 9514077
references.citation: J Infect Dis. 2009 Nov 15;200(10):1518-21
references.pmid: 19848586
references.citation: J Lab Clin Med. 1955 Sep;46(3):391-7
references.pmid: 13252317
references.citation: Lancet. 2008 Jan 5;371(9606):64-74
references.pmid: 18177777
references.citation: Malar J. 2006 Oct 08;5:84
references.pmid: 17026773
references.citation: FEBS Lett. 1998 Feb 6;422(3):311-4
references.pmid: 9498806
references.citation: Bioorg Med Chem. 2011 Jan 1;19(1):197-210
references.pmid: 21172735
references.citation: Mol Biochem Parasitol. 2011 Dec;180(2):127-31
references.pmid: 21939693
references.citation: Malar J. 2012 Oct 30;11:360
references.pmid: 23130957
references.citation: FEBS Lett. 1994 Sep 19;352(1):54-7
references.pmid: 7925942
references.citation: J Infect Dis. 1978 Feb;137(2):122-30
references.pmid: 627734
references.citation: Antimicrob Agents Chemother. 2008 Jan;52(1):183-91
references.pmid: 17967916
references.citation: Exp Parasitol. 2000 Dec;96(4):249-56
references.pmid: 11162378
references.citation: Nature. 1990 May 17;345(6272):255-8
references.pmid: 2185424
references.citation: Br J Clin Pharmacol. 1985 Jun;19(6):745-50
references.pmid: 4027117
references.citation: Antimicrob Agents Chemother. 2006 Jun;50(6):1927-30
references.pmid: 16723547
references.citation: J Med Chem. 2012 Dec 13;55(23):10328-44
references.pmid: 23075290
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):E1214-23
references.pmid: 22042867
references.citation: Science. 1976 Aug 20;193(4254):673-5
references.pmid: 781840
references.citation: J Infect Dis. 1994 Apr;169(4):932-5
references.pmid: 8133114
references.citation: Biochem Pharmacol. 2005 Oct 15;70(8):1158-66
references.pmid: 16139253
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):4133-40
references.pmid: 17846138