The High Incidence of Atrial Thrombosis in Mice Given Doxorubicin

Fujihira, Shiro; Yamamoto, Takao; Matsumoto, Masahiro; Yoshizawa, Katsuhiko; Oishi, Yuji; Fujii, Toshiyuki; Noguchi, Hideyo; Mori, Hiroshi

doi:10.1177/019262339302100403

Cited by 27 publications

(23 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Atrial thrombosis has occurred at up to a 75% incidence in mice treated IV with 4 mg/kg of doxorubicin (Fujihira et al, 1993). The atrial thrombosis observed in the 3 rats treated with CEM, was comparable to that seen in mice treated with doxobucin (Fujihira et al, 1993).…”

Section: Discussionmentioning

confidence: 68%

Cardiac Damage in Rodents after Exposure to Bis(2-chloroethoxy)methane

et al. 2004

View full text Add to dashboard Cite

We report that an environmental agent, bis(2-chloroethoxy)methane (CEM), caused cardiac toxicity in male and female F344 rats and B6C3F1 mice exposed to the chemical by dermal administration at doses of 0, 50, 100, 200, 400 or 600 mg/kg 5 days a week for up to 14 weeks. Treatment-related deaths occurred in 10/10 male and 10/10 female rats at 600 mg/kg, in 2/10 female rats at 400 mg/kg, and in 3/10 female mice at 600 mg/kg. The heart lesions were more severe in rats than mice, and more severe in females than males. In rats, the no-observed-adverse-effect level (NOAEL) for the heart lesions was 200 mg/kg for males and 100 mg/kg for females; in mice, it was more than 600 mg/kg for males and 200 mg/kg for females. Multifocal, widespread vacuolization of the myocytes comprised the main morphological feature of the lesions, and only in rats was it accompanied by mononuclear cell infiltration, myocytic necrosis and atrial thrombosis. Hearts from male rats were immunohistochemically stained for troponin T (cTnT) protein. Loss of cytoplasmic cTnT correlated with histopathological damage only in the 600 mg/kg animals. CEM is metabolized to thiodiglycolic acid, a chemical that causes mitochondrial dysfunction. It is hypothesized that mitochondrial damage leads to the heart toxicity from bis(2-chloroethoxy)methane.

show abstract

Section: Discussionmentioning

confidence: 68%

Cardiac Damage in Rodents after Exposure to Bis(2-chloroethoxy)methane

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Mice fed with butter have been shown to have the highest frequency (92%) of atrial thrombosis (41). More recently, atrial thrombosis has been described in mice treated with doxorubicin (12,15).…”

Section: Discussionmentioning

confidence: 99%

Endocardial Myxomatous Change in Harlan Sprague-Dawley Rats (Hsd:S-D) and CD-1 Mice: Its Microscopic Resemblance to Drug-Induced Valvulopathy in Humans

Elangbam

Colman²,

Lightfoot

et al. 2002

Toxicologic Pathology

View full text Add to dashboard Cite

A full assessment of all heart valves in rats and mice is often impractical and is usually not performed in routine toxicity studies, largely due to an inevitable inconsistency of histological sampling. The majority of reported heart valve changes involve the examination of a single, semirandom section through the heart and the valvulopathy occurring with age or induced by xenobiotics may have been generally underestimated in mice and rats. Here we describe the incidence and microscopic features of endocardial myxomatous change (EMC) in Hsd:S-D rats and CD-1 mice. EMC was common and widespread in both CD-1 mice and Hsd:S-D rats (188 of 220 rats and 96 of 215 mice were affected by EMC). Microscopically, EMC consisted of focal or segmental thickening of valves, primarily due to the presence of fibromyxoid tissue in the subendocardium. Occasionally, fibrin or thrombi deposits and collection of neutrophils or mononuclear cells were observed. These microscopic features were similar to those seen in valvular disease in humans induced by fenfluramine-phentermine (fen-phen), ergot alkaloids (ergotamine, methysergide), and carcinoid syndrome. The mitral valve in rats and pulmonary valve in mice were most frequently affected. An association between murine progressive cardiomyopathy (MPC) and EMC was noted only in rats, suggesting that there may be a possible relationship between MPC and EMC. However, additional research is needed to confirm a relationship between EMC and MPC in rats and /or mice.

show abstract

“…The inflammatory effects of doxorubicin were not only found in the vasculature as phlebitis (Hecker, 1990) or as skin inflammation after local treatment in the eye lid of several laboratory animals (McLoon and Wirtschafter, 1997) but also in the vicinity of the heart tissue. An increase in neutrophil adhesion and thrombus formation has been found in the atrium of 75% of mice repeatedly injected with 4 mg kg À1 doxorubicin (Fujihira et al, 1993). It is remarkable that the authors found associated damage in the cardiomyocytes and the presence of interstitial inflammatory cell infiltration.…”

Section: Overexpression Of Cell Bound Adhesion Moleculesmentioning

confidence: 94%

“…Doxorubicin also causes inflammatory reactions in the vicinity of heart tissue where it was found to increase the incidence of thrombus formation in the atrium of mice (Fujihira et al, 1993).…”

mentioning

confidence: 99%

The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro

et al. 2003

View full text Add to dashboard Cite

Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo. It is not known yet whether monoHER can also protect against doxorubicin-induced inflammatory effects. The aim of the present study was (1) to illustrate the inflammatory effects of doxorubicin in vitro and (2) to evaluate a possibly protective effect of monoHER. In order to demonstrate the inflammatory effects of doxorubicin and the possible protection of monoHER, proliferating human umbilical cord vascular endothelial cells (HUVECs) were incubated with different concentrations of doxorubicin ranging from 12.5 to 600 nM with(out) 200 mM monoHER. Resting (confluent) HUVECs were incubated with (0.5 -25 mM) doxorubicin with(out) monoHER (0.2 -1.2 mM) and the viability of endothelial cells and their propensity to adhere to neutrophils were measured 24 h after treatment. The localisation of adhered neutrophils was determined with immunofluorescence microscopy. To further characterise the mechanism of doxorubicin-induced neutrophil adhesion, the expression of the HUVECs surface adhesion molecules was determined after doxorubicin treatment. Doxorubicin decreased the viability and proliferation capacity of HUVECs in a concentration-dependent manner. The proliferating HUVECs were much more sensitive to doxorubicin (IC 50 ¼ 60.0720.8 nM) than resting cells (LC 50 ¼ 4.070.3 mM). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of X0.4mM (P ¼ 0.0113). The induced neutrophil adhesion was accompanied by overexpression of VCAM and E-selectin but not ICAM. Although monoHER did not reverse the effect of doxorubicin on the proliferation of endothelial cells, it significantly protected resting HUVECs against the cytotoxic effect of doxorubicin (p25 mM, Po0.0015). In addition, monoHER completely protected against the stimulatory effect of doxorubicin on neutrophil adhesion, and inhibited the doxorubin-induced expression of VCAM and E-selectin on the surface of treated HUVECs. This study illustrates that monoHER, which protects against doxorubicin's cardiotoxic effect, can also protect against doxorubicin-induced inflammatory effects. These data prompt further investigation about the possible link between doxorubicin-induced inflammatory effects and its cardiotoxicity in vivo.

show abstract

The High Incidence of Atrial Thrombosis in Mice Given Doxorubicin

Cited by 27 publications

References 4 publications

Cardiac Damage in Rodents after Exposure to Bis(2-chloroethoxy)methane

Cardiac Damage in Rodents after Exposure to Bis(2-chloroethoxy)methane

Endocardial Myxomatous Change in Harlan Sprague-Dawley Rats (Hsd:S-D) and CD-1 Mice: Its Microscopic Resemblance to Drug-Induced Valvulopathy in Humans

The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro

Contact Info

Product

Resources

About