In vivo and in vitro cardiotoxicity of a gold-containing antineoplastic drug candidate in the rabbit.
Bis[1,2-bis(diphenylphosphino)ethane] gold(I) chloride (Au(DPPE)+2), a cytotoxic antineoplastic drug candidate, was cardiotoxic in rabbits. Intravenous administration of Au(DPPE)+2 (15 mg/kg) as a single dose produced multiple, 2- to 5-mm subendocardial and myocardial lesions, macroscopically appearing as pale tan foci. Histologically, these lesions consisted of widely scattered zones of myocardial cell necrosis and mineralization. The myocardium also contained multifocal areas of contraction band necrosis in which aggregated clumps of disorganized myofilaments were contiguous with areas of sarcoplasm which were relatively devoid of myofilaments. In a series of in vitro studies, electron microscopic examination of isolated rabbit myocytes treated with 30 microM Au(DPPE)+2 for 15 min showed evidence of mitochondrial swelling and electron translucent mitochondrial matrices. After 60 min of incubation, myocytes had mitochondria that were condensed and disrupted but the cristae had retained their tubular profiles. Isolated rabbit myocytes exposed to 30 microM Au(DPPE)+2 had significant increases in the leakage of lactate dehydrogenase, an index of cell death. Cellular ATP content in myocytes exposed to 30 microM Au(DPPE)+2 was significantly reduced by 30 min. State 4 respiration in isolated rabbit mitochondria was significantly increased by Au(DPPE)+2 (30 microM) while state 3 respiration was unaffected. Au(DPPE)+2 also caused a rapid dissipation of the mitochondrial inner membrane electrochemical potential in a concentration-dependent manner and was accompanied by a ruthenium red-sensitive calcium efflux. These data suggest that disruption of mitochondrial function, leading to uncoupling of oxidative phosphorylation, decreased ATP synthesis, and altered mitochondrial calcium homeostasis, may be a contributing factor leading to cardiac myofibril necrosis produced by Au(DPPE)+2.
Smith Kline and French Laboratory, Department of Molecular Pharmacology, King of Prussia, Pennsylvania 19406-0939.
G D
GD
Hoke
R A
RA
Macia
P C
PC
Meunier
P J
PJ
Bugelski
C K
CK
Mirabelli
G F
GF
Rush
W D
WD
Matthews
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007275:Injections, Intravenous; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology; D009336:Necrosis / Q000473:pathology; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits
D000970:Antineoplastic Agents; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C050185:bis(1,2-bis(diphenylphosphino)ethane)gold(I); D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D002118:Calcium