Cardiac safety and antitumoral activity of a new nitric oxide derivative of pegylated epirubicin in mice.
The use of epirubicin is limited by the risk of a dilatory congestive heart failure that develops as a consequence of induction of a mitochondrial-dependent cardiomyocyte apoptosis. In a previous in-vitro study, we have provided evidence that a new formulation of pegylated epirubicin- bearing moieties that release nitric oxide, named BP-747, exerted a potent antitumoral activity against a colon cancer cell line, which was completely devoid of cytotoxic activity against cardiomyocytes. The aim of this study was to investigate the antitumoral and cardiotoxic profile of BP-747 in Caco-2 and SKOV-2 tumor-bearing mice. Epirubicin-induced cardiomyopathy was detected by clinical (survival, weight loss), anatomical (heart weight loss) and biochemical evaluations (measurement of serum troponin and creatine phosphokinase levels). The antitumoral activity was investigated by the measurement of tumor diameters and weight. In comparison with free epirubicin and pegylated epirubicin, BP-747 showed more potent antineoplastic effects, as demonstrated by the 95% reduction of tumor volume. Moreover, while administration of epirubicin and pegylated epirubicin resulted in the development of a severe anthracycline cardiomyopathy, BP-747-treated mice were virtually devoid of clinical and biochemical signs of cardiotoxicity. The present data provide evidence that addition of a nitric oxide-releasing moiety to pegylated epirubicin confers a new and unique cytotoxic profile to the drug.
Santucci
Luca
L
Struttura Complessa di Gastroenterologia, Azienda Ospedaliera di Perugia, Italy. lsant@unipg.it
Mencarelli
Andrea
A
Renga
Barbara
B
Ceccobelli
Daniela
D
Pasut
Gianfranco
G
Veronese
Francesco M
FM
Distrutti
Eleonora
E
Fiorucci
Stefano
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003402:Creatine Kinase / Q000097:blood; D015251:Epirubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014336:Troponin / Q000097:blood; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D014336:Troponin; C510090:nitric oxide-pegylated epirubicin; D011092:Polyethylene Glycols; D015251:Epirubicin; D003402:Creatine Kinase; D020169:Caspases