Amelioration of doxorubicin-induced cardiac and renal toxicity by pirfenidone in rats.
OBJECTIVE
Doxorubicin (DXR) is an anthracycline glycoside with a broad spectrum of therapeutic activity against various tumors. However, the clinical use of DXR has been limited by its undesirable systemic toxicity, especially in the heart and kidney. This study was designed to test the effectiveness of dietary intake of pirfenidone (PD) against DXR-induced cardiac and renal toxicity.


METHODS
Male Sprague Dawley rats were placed into four treatment groups: saline injected intraperitoneally (i.p.) plus regular diet (SA+RD); DXR i.p. plus regular diet (DXR+RD); saline i.p. plus the same diet mixed with 0.6% PD (SA+PD); and DXR i.p. plus the same diet mixed with 0.6% PD (DXR+PD). The animals were fed regular or regular plus PD diets 3 days prior to i.p. injections of either saline or DXR and continuing throughout the study. A total dose of DXR (16.25 mg/kg) or an equivalent volume of saline was administered in seven injections (2.32 mg/kg per injection) three times per week with an additional dose on the 12th day. At 25 days following the last DXR or saline injection, some animals were anesthetized for the measurement of cardiac and pulmonary function, and others were killed by an overdose of pentobarbital. At the time the animals were killed, abdominal fluid was collected. Kidney and heart were removed, weighed, fixed with 10% formalin or frozen in liquid nitrogen. The fixed tissues were used for histological examination and the frozen tissues were used for biochemical studies.


RESULTS
The average volumes of abdominal fluid in the DXR+RD and DXR+PD groups were 9.42 ml and 3.42 ml and the protein contents of abdominal fluid in the DXR+RD and DXR+PD groups were 218 mg and 70 mg, respectively. A 12.5% mortality occurred in the DXR+RD group as compared to 0% in DXR+PD group. There were no changes in any of the cardiac or pulmonary physiological parameters in any of the four groups. The changes in the heart and kidney of the DXR+RD group included reduction in organ weight, increase in hydroxyproline content of heart, increase in hydroxyproline, and lipid peroxidation in the kidney and plasma, and increase in protein concentration in urine as compared to rats in the control, SA+RD and SA+PD groups. Treatment with PD abrogated the DXR-induced increases in hydroxyproline content in the heart and kidney, lipid peroxidation of the kidney and plasma, and protein content of the urine in the DXR+PD group. DXR treatment alone caused disorganization of cardiac myofibrils, vacuolization of the myofibers, and renal tubular dilation with protein casts in both the cortical and medullary regions. Treatment with PD minimized the DXR-induced histopathological changes of heart and kidney in the DXR+PD group.


CONCLUSIONS
Treatment with PD reduced the severity of DXR-induced toxicity as assessed by reduced mortality, diminished volume of recovered fluid in the abdominal cavity, and severity of cardiac and renal lesions at both the biochemical and morphological levels. These results indicate that PD has the potential to prevent DXR-induced cardiac and renal damage in humans on DXR therapy.
Giri
Shri N
SN
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. solananinc@aol.com
Al-Bayati
Mohammed Ali
MA
Du
Xiaogu
X
Schelegle
Edward
E
Mohr
F Charles
FC
Margolin
Solomon B
SB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004317:Doxorubicin / Q000009:adverse effects* / Q000627:therapeutic use; D004435:Eating / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009206:Myocardium / Q000473:pathology; D011728:Pyridones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic; D011728:Pyridones; D004317:Doxorubicin; C093844:pirfenidone