Comparison of the chronic toxicity of piroxantrone, losoxantrone and doxorubicin in spontaneously hypertensive rats.
Comparisons were made of the toxic effects produced in the heart, kidney and small intestine of spontaneously hypertensive rats (SHR) by the administration of 12 consecutive weekly doses of doxorubicin (1 mg/kg), and high, intermediate and low doses of piroxantrone (3, 1.5 and 0.75 mg/kg) and losoxantrone (1, 0.5 and 0.25 mg/kg). Animals receiving saline were used as controls. The toxicities of the three drugs were evaluated by clinical chemistry and hematological determinations, light microscopy and transmission electron microscopy. The severity of the histologic alterations in heart, kidney and small intestine was assessed semiquantitatively. Biochemical and molecular modeling studies were made to evaluate the formation of complexes of Fe(III) with piroxantrone and losoxantrone. The cardiac (myofibrillar loss and dilatation of the sarcoplasmic reticulum) and renal (glomerular vacuolization, tubular damage and laboratory evidence of a nephrotic syndrome) lesions induced by all three agents had similar features. However, the cardiac lesions induced by losoxantrone and doxorubicin were significantly more severe (Billingham scores) than those produced by piroxantrone. The renal lesions induced by piroxantrone and losoxantrone were less severe than those produced by doxorubicin. Similarly losoxantrone and piroxantrone-induced intestinal alterations (denudation of epithelial layer and inflammatory cellular infiltration) were less severe than those occurring after treatment with doxorubicin. Both losoxantrone and piroxantrone were shown to form Fe(III): drug complexes that may cause oxidative damage to various tissues.
Division of Applied Pharmacology Research, Food and Drug Administration, Laurel, MD 20708, USA.
E H
EH
Herman
J
J
Zhang
B B
BB
Hasinoff
K T
KT
Tran
D P
DP
Chadwick
J R
JR
Clark
V J
VJ
Ferrans
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity*; D005290:Ferric Compounds / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D011720:Pyrazoles / Q000378:metabolism / Q000633:toxicity*; D047069:Pyrazolones; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D005290:Ferric Compounds; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone; D004317:Doxorubicin; C046659:piroxantrone