[Analysis of cardiac toxicity caused by cyclophosphamide in the H9c2 cell line and isolated and perfused rat hearts].
Cyclophosphamide is used for liver cancer, breast cancer and multiple myeloma, and the pretreatment of hematopoietic stem cell transplantation. A medium to high dose of cyclophosphamide is known to cause irreversible heart failure in some cases, and recently cardiac tamponade and pericarditis have been reported to occur when cyclophosphamide is administered for the pretreatment of hematopoietic stem cell transplantation. To test whether cyclophosphamide itself induces cellular toxicity, we investigated a toxic effect of cyclophosphamide, acrolein, a metabolite of cyclophosphamide, and doxorubicin, which is known to have cardiac toxicity, in the H9c2 cell line and the isolated Langendorff-perfused rat hearts. Cyclophosphamide itself did not have a toxic effect, whereas the toxicity of acrolein is 1, 000 times higher than that of doxorubicin in the H9c2 cell line. Acrolein, but not cyclophosphamide, reduced the left ventricular developed pressure and heart rate, and increased the left ventricular end diastolic pressure. These results suggest that the cardiac toxicity of cyclophosphamide may be caused by acrolein, one of its metabolites. Cyclophosphamide is known to cause hemorrhagic cystitis, and uromitexan was shown not to protect against the cardiac toxicity of cyclophosphamide. Development of new cardioprotective compounds is needed to administer CPA more safely.
Nakamura
Seiji
S
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.
Aoki
Manahito
M
Mori
Asami
A
Nakahara
Tsutomu
T
Sakamoto
Kenji
K
Ishii
Kunio
K
D000171:Acrolein / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000378:metabolism / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D000171:Acrolein; D004317:Doxorubicin; D003520:Cyclophosphamide