Intracellular localization of 6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquino line-1,3-diones (azonafides) is not the limiting factor for their cytotoxicity: an in vitro confocal microscopy study.
The intracellular localization of 14 structurally unique azonafide analogs was studied to determine if intracellular drug distribution is the limiting factor in azonafide cytotoxicity. Using scanning laser confocal microscopy, cytotoxicity of the azonafide analogs studies was observed in Chinese hamster ovary cells immediately after a 1 h exposure. The intracellular drug distribution patterns varied significantly for different analogs. Eight analogs showed primarily nuclear localization, five analogs showed primarily cytoplasmic localization and two analogs displayed perinuclear localization. In general, the type of chemical substitution on the anthracene nucleus determined the distribution pattern. For example, for each analog seven of eight nuclear-localizing analogs were amine-substituted agents, while four of five cytoplasmic-localized agents were ethoxy-substituted analogs. The individual exception within these groups was the 6-[(dimethylamino)ethoxy] agent that was nuclear localized. The two perinuclear-localized agents included the unsubstituted parent, azonafide, and its 6-methyl azonafide analog. Comparison of the cytotoxicity of the azonafides, based on intracellular localization, revealed that none of the localization patterns were associated with increased cytotoxicity. These results show that minor structural changes in the azonafide class of antitumor agents involving substitution along an anthracene chromophore result in substantially different intracellular drug distribution patterns. However, these distribution differences do not determine relative cytotoxic potency in vitro.
Mayr
C A
CA
Department of Pharmacology and Toxicology, The Arizona Cancer Center, Tucson 85724, USA.
Sami
S M
SM
Remers
W A
WA
Dorr
R T
RT
D000704:Analysis of Variance; D000818:Animals; D000873:Anthracenes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D018613:Microscopy, Confocal; D053644:Naphthalimides; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D000873:Anthracenes; D000970:Antineoplastic Agents; D007546:Isoquinolines; D053644:Naphthalimides; C092761:azonafide; C034020:anthracene