Complete protection by high-dose dexamethasone against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the rat.
Yondelis (ET-743) is a promising antitumor drug with hepatotoxic properties in animals and humans. Here the hypothesis was tested that dexamethasone can ameliorate manifestations of yondelis-induced hepatotoxicity in the female Wistar rat, which is the animal species with the highest sensitivity toward the adverse hepatic effect of yondelis. Hepatotoxicity was adjudged by measurement of plasma levels of alkaline phosphatase, aspartate aminotransferase, and bilirubin, and by liver histopathology. Yondelis (40 micro g/kg i.v.) alone caused a dramatic elevation of plasma alkaline phosphatase, aspartate aminotransferase, and bilirubin levels, and degeneration and patchy focal necrosis of bile duct epithelial cells. Pretreatment of rats with dexamethasone (5-20 mg/kg, p.o.) 24 h before yondelis ameliorated or abrogated the biochemical and histopathological manifestations of yondelis-induced liver changes. In contrast, when dexamethasone was administered simultaneously with yondelis, its toxicity was not reduced. Pretreatment with dexamethasone (10 mg/kg) also reversed the gene expression changes induced by yondelis in rat liver. However, dexamethasone pretreatment did not interfere with the antitumor efficacy of yondelis in rats bearing the 13762 mammary carcinoma or in four murine models. Dexamethasone (10 mg/kg) administered 24 h before yondelis decreased hepatic levels of yondelis dramatically compared with those obtained after administration of yondelis alone, whereas yondelis plasma levels after the drug combination were not markedly different from those in rats on yondelis alone. The results suggest that pretreatment with high-dose dexamethasone effectively protects rats against yondelis-mediated hepatic damage by decreasing hepatic exposure to yondelis, perhaps linked to induction of metabolism by cytochrome P450 enzymes. Pretreatment with high-dose dexamethasone should be investigated in patients who receive yondelis to ameliorate its unwanted effect on the liver.
Donald
Sarah
S
Department of Oncology, University of Leicester, United Kingdom.
Verschoyle
Richard D
RD
Greaves
Peter
P
Gant
Timothy W
TW
Colombo
Tina
T
Zaffaroni
Marco
M
Frapolli
Roberta
R
Zucchetti
Massimo
M
D'Incalci
Maurizio
M
Meco
Daniela
D
Riccardi
Riccardo
R
Lopez-Lazaro
Luis
L
Jimeno
Jose
J
Gescher
Andreas J
AJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000494:pharmacology*; D004149:Dioxoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007546:Isoquinolines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D008107:Liver Diseases / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D000972:Antineoplastic Agents, Phytogenic; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000077606:Trabectedin